Datasets:

Haxirus

/

SLM_Pre-training_Dataset

like 0

Does Abatacept and Fruquintinib interact?

•Drug A: Abatacept •Drug B: Fruquintinib •Severity: MODERATE •Description: The metabolism of Fruquintinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fruquintinib is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In vitro studies showed fruquintinib inhibited VEGF-mediated endothelial cell proliferation and tubular formation, while in vivo studies demonstrated fruquintinib-mediated tumor growth inhibition in a tumor xenograft mouse model of colon cancer. Inhibition of VEGF-induced VEGFR-2 phosphorylation was illustrated in both in vitro and in vivo studies. Fruquintinib exposure-response relationships and the time course of pharmacodynamic response are unknown. A mean increase in QTc interval >20 milliseconds (ms) was not observed at the approved recommended dosage. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fruquintinib is a small-molecule kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 with IC 50 values of 33, 35, and 0.5 nM, respectively •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The fruquintinib steady-state geometric mean (% coefficient of variation [CV]) maximum concentration (C max ) is 300 ng/mL (28%) and the area under the concentration-time curve for the dosing interval (AUC 0-24h ) is 5880 ng∙h/mL (29%) at the recommended dosage. The fruquintinib C max and AUC 0-24h are dose-proportional across the dosage range of 1 to 6 mg (0.2 to 1.2 times the recommended dosage). Fruquintinib steady state is achieved after 14 days with a mean AUC 0-24h accumulation of 4-fold. The fruquintinib median (min, max) time to C max is approximately 2 hours (0, 26 hours). No clinically significant differences in fruquintinib pharmacokinetics were observed following administration of a high-fat meal (800 to 1000 calories, 50% fat). •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean (SD) apparent volume of distribution of fruquintinib is approximately 46 (13) L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of fruquintinib is approximately 95%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fruquintinib is primarily eliminated by CYP450 and non-CYP450 (i.e., sulfation and glucuronidation) metabolism. CYP3A and to a lesser extent CYP2C8, CYP2C9, and CYP2C19 are the CYP450 enzymes involved in fruquintinib's metabolism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration of a 5 mg radiolabeled fruquintinib dose, approximately 60% of the dose was recovered in urine (0.5% unchanged) and 30% of the dose was recovered in feces (5% unchanged). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The fruquintinib's mean (SD) elimination half-life is approximately 42 (11) hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent clearance (SD) of fruquintinib is 14.8 (4.4) mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on findings in animal studies and its mechanism of action, fruquintinib can cause fetal harm when administered to a pregnant woman. In an embryo-fetal developmental study in pregnant rats, oral administration of fruquintinib during the period of organogenesis resulted in teratogenicity and embryo lethality at exposures below the clinical exposure. There are no data on the use of fruquintinib in pregnant women. Advise pregnant women of the potential risk to a fetus. Carcinogenicity studies have not been conducted with fruquintinib. Fruquintinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenicin the in vitro Chinese hamster ovary chromosome aberration assay. Fruquintinib was not genotoxic in the in vivo rat micronucleus or alkaline comet assays. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Fruzaqla •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fruquintinib is a VEGF receptor inhibitor used to treat metastatic colorectal cancer.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fruquintinib interact? Information: •Drug A: Abatacept •Drug B: Fruquintinib •Severity: MODERATE •Description: The metabolism of Fruquintinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Fruquintinib is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In vitro studies showed fruquintinib inhibited VEGF-mediated endothelial cell proliferation and tubular formation, while in vivo studies demonstrated fruquintinib-mediated tumor growth inhibition in a tumor xenograft mouse model of colon cancer. Inhibition of VEGF-induced VEGFR-2 phosphorylation was illustrated in both in vitro and in vivo studies. Fruquintinib exposure-response relationships and the time course of pharmacodynamic response are unknown. A mean increase in QTc interval >20 milliseconds (ms) was not observed at the approved recommended dosage. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fruquintinib is a small-molecule kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 with IC 50 values of 33, 35, and 0.5 nM, respectively •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The fruquintinib steady-state geometric mean (% coefficient of variation [CV]) maximum concentration (C max ) is 300 ng/mL (28%) and the area under the concentration-time curve for the dosing interval (AUC 0-24h ) is 5880 ng∙h/mL (29%) at the recommended dosage. The fruquintinib C max and AUC 0-24h are dose-proportional across the dosage range of 1 to 6 mg (0.2 to 1.2 times the recommended dosage). Fruquintinib steady state is achieved after 14 days with a mean AUC 0-24h accumulation of 4-fold. The fruquintinib median (min, max) time to C max is approximately 2 hours (0, 26 hours). No clinically significant differences in fruquintinib pharmacokinetics were observed following administration of a high-fat meal (800 to 1000 calories, 50% fat). •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean (SD) apparent volume of distribution of fruquintinib is approximately 46 (13) L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of fruquintinib is approximately 95%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Fruquintinib is primarily eliminated by CYP450 and non-CYP450 (i.e., sulfation and glucuronidation) metabolism. CYP3A and to a lesser extent CYP2C8, CYP2C9, and CYP2C19 are the CYP450 enzymes involved in fruquintinib's metabolism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration of a 5 mg radiolabeled fruquintinib dose, approximately 60% of the dose was recovered in urine (0.5% unchanged) and 30% of the dose was recovered in feces (5% unchanged). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The fruquintinib's mean (SD) elimination half-life is approximately 42 (11) hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent clearance (SD) of fruquintinib is 14.8 (4.4) mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on findings in animal studies and its mechanism of action, fruquintinib can cause fetal harm when administered to a pregnant woman. In an embryo-fetal developmental study in pregnant rats, oral administration of fruquintinib during the period of organogenesis resulted in teratogenicity and embryo lethality at exposures below the clinical exposure. There are no data on the use of fruquintinib in pregnant women. Advise pregnant women of the potential risk to a fetus. Carcinogenicity studies have not been conducted with fruquintinib. Fruquintinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenicin the in vitro Chinese hamster ovary chromosome aberration assay. Fruquintinib was not genotoxic in the in vivo rat micronucleus or alkaline comet assays. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Fruzaqla •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fruquintinib is a VEGF receptor inhibitor used to treat metastatic colorectal cancer. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Fusidic acid interact?

•Drug A: Abatacept •Drug B: Fusidic acid •Severity: MODERATE •Description: The metabolism of Fusidic acid can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of bacterial infections. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fusidic acid is a bacteriostatic antibiotic and helps prevent bacterial growth while the immune system clears the infection. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fusidic acid works by interfering with bacterial protein synthesis, specifically by preventing the translocation of the elongation factor G (EF-G) from the ribosome. It also can inhibit chloramphenicol acetyltransferase enzymes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Sodium fusidic acid tablets have a 91% oral bioavailability. Absorption of the film-coated tablets is complete when compared to a solution, however oral absorption is variable. Oral fusidic acid hemihydrate (suspension) achieved a 22.5% bioavailability in pediatric patients following a 20 milligram/kilogram dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 97 to 99% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolites include dicarboxylic ester/acid, 3-keto fusidic acid, hydroxy fusidic acid, glucuronide fusidic acid and a glycol metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Approximately 5 to 6 hours in adults. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Fucibet, Fucidin, Fucithalmic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fusidic acid is a topical antibacterial agent used to prevent and treat mild to moderate skin infections caused by susceptible bacteria.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Fusidic acid interact? Information: •Drug A: Abatacept •Drug B: Fusidic acid •Severity: MODERATE •Description: The metabolism of Fusidic acid can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of bacterial infections. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Fusidic acid is a bacteriostatic antibiotic and helps prevent bacterial growth while the immune system clears the infection. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fusidic acid works by interfering with bacterial protein synthesis, specifically by preventing the translocation of the elongation factor G (EF-G) from the ribosome. It also can inhibit chloramphenicol acetyltransferase enzymes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Sodium fusidic acid tablets have a 91% oral bioavailability. Absorption of the film-coated tablets is complete when compared to a solution, however oral absorption is variable. Oral fusidic acid hemihydrate (suspension) achieved a 22.5% bioavailability in pediatric patients following a 20 milligram/kilogram dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 97 to 99% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolites include dicarboxylic ester/acid, 3-keto fusidic acid, hydroxy fusidic acid, glucuronide fusidic acid and a glycol metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Approximately 5 to 6 hours in adults. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Fucibet, Fucidin, Fucithalmic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Fusidic acid is a topical antibacterial agent used to prevent and treat mild to moderate skin infections caused by susceptible bacteria. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Galantamine interact?

•Drug A: Abatacept •Drug B: Galantamine •Severity: MODERATE •Description: The metabolism of Galantamine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Galantamine is indicated for the treatment of mild to moderate dementia of the Alzheimer’s type. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Galantamine is a competitive and reversible inhibitor of acetylcholinesterase that works to increase acetylcholine levels. Galantamine acts both centrally and peripherally to inhibit both muscle and brain acetylcholinesterase, thereby increasing cholinergic tone. Galantamine is also a positive allosteric modulator of neuronal nicotinic acetylcholine receptors. As dementia is a progressive neurodegenerative disease, galatamine has a negligible effect in altering the course of the underlying process of dementia and may exert its therapeutic effectiveness for a short period of time. However, galantamine promoted improvements in cognition, global function, activities of daily living, and behavioural symptoms in clinical studies of Alzheimer’s disease. Galantamine exhibited therapeutic efficacy in studies of vascular dementia and Alzheimer’s disease with cerebrovascular disease. In one study, galantamine reversed scopolamine-induced acute anticholinergic syndrome that was characterized by drowsiness, disorientation, and delirium. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Alzheimer’s disease is characterized by progressive, irreversible degeneration of acetylcholine-producing neurons, cognitive impairment, and the accumulation of neurofibrillary tangles and amyloid plaques. The cholinergic system plays a critical role in memory, alongside other important neural functions such as attention, learning, stress response, wakefulness and sleep, and sensory information. Studies show that acetylcholine (ACh) is involved in the modulation of acquisition, encoding, consolidation, reconsolidation, extinction, and retrieval of memory. The gradual loss of cholinergic neurons in Alzheimer’s disease (AD) may, therefore, contribute to the memory loss exhibited by AD patients. Acetylcholinesterase is secreted by cholinergic neurons to rapidly hydrolyze ACh at the synaptic cleft to release acetate and choline. Choline is later recycled back into the presynaptic cholinergic neuron via reuptake by the high-affinity choline transporter. There is some evidence demonstrating the potential involvement of the acetylcholinesterase enzyme in the formation of amyloid fibrils. Galantamine competitively and reversibly inhibits the anticholinesterase enzyme in the CNS (namely in the frontal cortex and hippocampal regions) by binding to the choline-binding site and acyl-binding pocket of the enzyme active site. By blocking the breakdown of ACh, galantamine enhances ACh levels in the synaptic cleft. Nicotinic acetylcholine receptors (nAChR) in the CNS are mostly expressed at the presynaptic neuronal membrane to control the release of multiple neurotransmitters, such as ACh, glutamate, GABA, dopamine, serotonin, norepinephrine. Agonists of nAChRs improve performance in cognitive tasks, while antagonists of nAChR impair cognitive processes. Some studies show a decrease in the expression and activity of nAChRs in patients with AD, which may explain the reduction in central cholinergic neurotransmission in these patients. Galantamine binds to nAChRs at the allosteric site, leading to a conformational change of the receptor, increased ACh release, and increased activity of neighbouring glutaminergic and serotoninergic neurons. The modulation of nAChRs facilitates both excitatory and inhibitory cholinergic transmissions in brain tissues and increases receptor sensitivity. The modulated release of other neurotransmitters by galantamine may also contribute to the upregulation of nAChRs and amelioration of behavioural symptoms in AD. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Over a dose range of 8-32 mg/day, galantamine exhibits a dose-linear pharmacokinetic profile. The oral bioavailability of galantamine ranges from 90-100%. Following oral administration, the Tmax is about 1 hour. Following 10 hours of administration, the mean galantamine plasma concentrations were 82–97 µg/L for the 24 mg/day dose and 114–126 µg/L for the 32 mg/day dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean volume of distribution is 175 L. About 52.7% of galantamine is distributed to blood cells, the blood to plasma concentration ratio of galantamine is 1.2. Galantamine penetrates the blood–brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of galantamine is 18% at therapeutically relevant concentrations. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro study findings suggest that about 75% of the drug is metabolized by CYP2D6 and CYP3A4. CYP2D6 promotes O-demethylation of the drug to form O-desmethyl-galantamine and the CYP3A4-mediated pathway forms the galantamine-N-oxide. Important metabolic pathways also include N-demethylation, epimerization, and sulfate conjugation. Other metabolites include norgalantamine, O-desmethyl-galantamine, O-desmethyl-norgalantamine, epigalantamine and galantaminone, which do not retain clinically significant pharmacology activities. Galantamine can also undergo glucuronidation: in one oral radiolabeled drug study in poor and extensive CYP2D6 metabolizers, about 14-24% of the total radioactivity was identified as galantamine glucuronide 8 hours post-dose. O-demethylation by CYP2D6 becomes prominent in patients with who are extensive metabolizers of CYP2D6, but unchanged galatamine (39-77%) and its glucuronide metabolite (14-24%) predominated in the plasma of both poor and extensive metabolizers of CYP2D6 in a radiolabelled drug study. The total plasma clearance, or nonrenal clearnace, accounts for 20–25% of drug elimination. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Renal clearance accounts for about 20–25% of total plasma clearance of the drug in healthy individuals: the elimination of galantamine has been shown to be decreased in subjects with renal impairment. Following oral or intravenous administration, approximately 20% of the dose is excreted as unchanged in the urine within 24 h. In a radiolabelled drug study, about 95% and 5% of the total radioactivity was recovered in the urine and feces, respectively. Of the dose recovered in the urine, about 32% was in the unchanged parent compound, and 12% was in the glucuronide form. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Galantamine has a terminal half-life of about 7 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The renal clearance is 65 mL/min and the total plasma clearance is about 300 mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 of the active ingredient, galantamine hydrobromide, in rats is 75 mg/kg. Symptoms of overdose are expected to be similar to those of cholinomimetics, which involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. Effects of a cholinergic crisis include severe nausea, vomiting, gastrointestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions. Muscle weakness or fasciculations may also occur, with respiratory muscle weakness having the potential to bring fatal results. In one patient who consumed an oral daily dose of 32 mg developed bradycardia, QT prolongation, ventricular tachycardia and torsades de pointes accompanied by a brief loss of consciousness. In one patient with a history of hallucinations who consumed a daily dose of 24 mg galantamine, hallucinations requiring hospitalization occurred. A patient who ingested 160 mg of galantamine from an oral solution developed sweating, vomiting, bradycardia, and near-syncope one hour following consumption. As in any case of overdose, general supportive measures should be initiated. Tertiary anticholinergics such as intravenous atropine may be used to reverse the cholinergic effects of galantamine. The recommended initial dose of atropine intravenously administered for galantamine overdose ranges from 0.5 to 1.0 mg. It is not known whether galantamine can be removed by dialysis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Razadyne •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Galantamina Galantamine Galanthamine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Galantamine is a cholinesterase inhibitor used to manage mild to moderate dementia associated with Alzheimer's Disease.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Galantamine interact? Information: •Drug A: Abatacept •Drug B: Galantamine •Severity: MODERATE •Description: The metabolism of Galantamine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Galantamine is indicated for the treatment of mild to moderate dementia of the Alzheimer’s type. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Galantamine is a competitive and reversible inhibitor of acetylcholinesterase that works to increase acetylcholine levels. Galantamine acts both centrally and peripherally to inhibit both muscle and brain acetylcholinesterase, thereby increasing cholinergic tone. Galantamine is also a positive allosteric modulator of neuronal nicotinic acetylcholine receptors. As dementia is a progressive neurodegenerative disease, galatamine has a negligible effect in altering the course of the underlying process of dementia and may exert its therapeutic effectiveness for a short period of time. However, galantamine promoted improvements in cognition, global function, activities of daily living, and behavioural symptoms in clinical studies of Alzheimer’s disease. Galantamine exhibited therapeutic efficacy in studies of vascular dementia and Alzheimer’s disease with cerebrovascular disease. In one study, galantamine reversed scopolamine-induced acute anticholinergic syndrome that was characterized by drowsiness, disorientation, and delirium. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Alzheimer’s disease is characterized by progressive, irreversible degeneration of acetylcholine-producing neurons, cognitive impairment, and the accumulation of neurofibrillary tangles and amyloid plaques. The cholinergic system plays a critical role in memory, alongside other important neural functions such as attention, learning, stress response, wakefulness and sleep, and sensory information. Studies show that acetylcholine (ACh) is involved in the modulation of acquisition, encoding, consolidation, reconsolidation, extinction, and retrieval of memory. The gradual loss of cholinergic neurons in Alzheimer’s disease (AD) may, therefore, contribute to the memory loss exhibited by AD patients. Acetylcholinesterase is secreted by cholinergic neurons to rapidly hydrolyze ACh at the synaptic cleft to release acetate and choline. Choline is later recycled back into the presynaptic cholinergic neuron via reuptake by the high-affinity choline transporter. There is some evidence demonstrating the potential involvement of the acetylcholinesterase enzyme in the formation of amyloid fibrils. Galantamine competitively and reversibly inhibits the anticholinesterase enzyme in the CNS (namely in the frontal cortex and hippocampal regions) by binding to the choline-binding site and acyl-binding pocket of the enzyme active site. By blocking the breakdown of ACh, galantamine enhances ACh levels in the synaptic cleft. Nicotinic acetylcholine receptors (nAChR) in the CNS are mostly expressed at the presynaptic neuronal membrane to control the release of multiple neurotransmitters, such as ACh, glutamate, GABA, dopamine, serotonin, norepinephrine. Agonists of nAChRs improve performance in cognitive tasks, while antagonists of nAChR impair cognitive processes. Some studies show a decrease in the expression and activity of nAChRs in patients with AD, which may explain the reduction in central cholinergic neurotransmission in these patients. Galantamine binds to nAChRs at the allosteric site, leading to a conformational change of the receptor, increased ACh release, and increased activity of neighbouring glutaminergic and serotoninergic neurons. The modulation of nAChRs facilitates both excitatory and inhibitory cholinergic transmissions in brain tissues and increases receptor sensitivity. The modulated release of other neurotransmitters by galantamine may also contribute to the upregulation of nAChRs and amelioration of behavioural symptoms in AD. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Over a dose range of 8-32 mg/day, galantamine exhibits a dose-linear pharmacokinetic profile. The oral bioavailability of galantamine ranges from 90-100%. Following oral administration, the Tmax is about 1 hour. Following 10 hours of administration, the mean galantamine plasma concentrations were 82–97 µg/L for the 24 mg/day dose and 114–126 µg/L for the 32 mg/day dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean volume of distribution is 175 L. About 52.7% of galantamine is distributed to blood cells, the blood to plasma concentration ratio of galantamine is 1.2. Galantamine penetrates the blood–brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of galantamine is 18% at therapeutically relevant concentrations. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro study findings suggest that about 75% of the drug is metabolized by CYP2D6 and CYP3A4. CYP2D6 promotes O-demethylation of the drug to form O-desmethyl-galantamine and the CYP3A4-mediated pathway forms the galantamine-N-oxide. Important metabolic pathways also include N-demethylation, epimerization, and sulfate conjugation. Other metabolites include norgalantamine, O-desmethyl-galantamine, O-desmethyl-norgalantamine, epigalantamine and galantaminone, which do not retain clinically significant pharmacology activities. Galantamine can also undergo glucuronidation: in one oral radiolabeled drug study in poor and extensive CYP2D6 metabolizers, about 14-24% of the total radioactivity was identified as galantamine glucuronide 8 hours post-dose. O-demethylation by CYP2D6 becomes prominent in patients with who are extensive metabolizers of CYP2D6, but unchanged galatamine (39-77%) and its glucuronide metabolite (14-24%) predominated in the plasma of both poor and extensive metabolizers of CYP2D6 in a radiolabelled drug study. The total plasma clearance, or nonrenal clearnace, accounts for 20–25% of drug elimination. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Renal clearance accounts for about 20–25% of total plasma clearance of the drug in healthy individuals: the elimination of galantamine has been shown to be decreased in subjects with renal impairment. Following oral or intravenous administration, approximately 20% of the dose is excreted as unchanged in the urine within 24 h. In a radiolabelled drug study, about 95% and 5% of the total radioactivity was recovered in the urine and feces, respectively. Of the dose recovered in the urine, about 32% was in the unchanged parent compound, and 12% was in the glucuronide form. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Galantamine has a terminal half-life of about 7 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The renal clearance is 65 mL/min and the total plasma clearance is about 300 mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 of the active ingredient, galantamine hydrobromide, in rats is 75 mg/kg. Symptoms of overdose are expected to be similar to those of cholinomimetics, which involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. Effects of a cholinergic crisis include severe nausea, vomiting, gastrointestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions. Muscle weakness or fasciculations may also occur, with respiratory muscle weakness having the potential to bring fatal results. In one patient who consumed an oral daily dose of 32 mg developed bradycardia, QT prolongation, ventricular tachycardia and torsades de pointes accompanied by a brief loss of consciousness. In one patient with a history of hallucinations who consumed a daily dose of 24 mg galantamine, hallucinations requiring hospitalization occurred. A patient who ingested 160 mg of galantamine from an oral solution developed sweating, vomiting, bradycardia, and near-syncope one hour following consumption. As in any case of overdose, general supportive measures should be initiated. Tertiary anticholinergics such as intravenous atropine may be used to reverse the cholinergic effects of galantamine. The recommended initial dose of atropine intravenously administered for galantamine overdose ranges from 0.5 to 1.0 mg. It is not known whether galantamine can be removed by dialysis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Razadyne •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Galantamina Galantamine Galanthamine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Galantamine is a cholinesterase inhibitor used to manage mild to moderate dementia associated with Alzheimer's Disease. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Gefitinib interact?

•Drug A: Abatacept •Drug B: Gefitinib •Severity: MODERATE •Description: The metabolism of Gefitinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of either platinum-based or docetaxel chemotherapies. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase that binds to the adenosine triphosphate (ATP)-binding site of the enzyme. EGFR is often shown to be overexpressed in certain human carcinoma cells, such as lung and breast cancer cells. Overexpression leads to enhanced activation of the anti-apoptotic Ras signal transduction cascades, subsequently resulting in increased survival of cancer cells and uncontrolled cell proliferation. Gefitinib is the first selective inhibitor of the EGFR tyrosine kinase which is also referred to as Her1 or ErbB-1. By inhibiting EGFR tyrosine kinase, the downstream signaling cascades are also inhibited, resulting in inhibited malignant cell proliferation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorbed slowly after oral administration with a mean bioavailability of 60%. Peak plasma levels occurs 3-7 hours post-administration. Food does not affect the bioavailability of gefitinib. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 1400 L [IV administration] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 90% primarily to serum albumin and alpha 1-acid glycoproteins (independent of drug concentrations). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic via CYP3A4. Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino-group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Elimination is by metabolism (primarily CYP3A4) and excretion in feces. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 48 hours [IV administration] •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 595 mL/min [IV administration] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The acute toxicity of gefitinib up to 500 mg in clinical studies has been low. In non-clinical studies, a single dose of 12,000 mg/m (about 80 times the recommended clinical dose on a mg/m basis) was lethal to rats. Half this dose caused no mortality in mice. Symptoms of overdose include diarrhea and skin rash. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Iressa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Gefitinib •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Gefitinib is a tyrosine kinase inhibitor used as first-line therapy to treat non-small cell lung carcinoma (NSCLC) that meets certain genetic mutation criteria.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Gefitinib interact? Information: •Drug A: Abatacept •Drug B: Gefitinib •Severity: MODERATE •Description: The metabolism of Gefitinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of either platinum-based or docetaxel chemotherapies. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase that binds to the adenosine triphosphate (ATP)-binding site of the enzyme. EGFR is often shown to be overexpressed in certain human carcinoma cells, such as lung and breast cancer cells. Overexpression leads to enhanced activation of the anti-apoptotic Ras signal transduction cascades, subsequently resulting in increased survival of cancer cells and uncontrolled cell proliferation. Gefitinib is the first selective inhibitor of the EGFR tyrosine kinase which is also referred to as Her1 or ErbB-1. By inhibiting EGFR tyrosine kinase, the downstream signaling cascades are also inhibited, resulting in inhibited malignant cell proliferation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorbed slowly after oral administration with a mean bioavailability of 60%. Peak plasma levels occurs 3-7 hours post-administration. Food does not affect the bioavailability of gefitinib. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 1400 L [IV administration] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 90% primarily to serum albumin and alpha 1-acid glycoproteins (independent of drug concentrations). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic via CYP3A4. Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino-group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Elimination is by metabolism (primarily CYP3A4) and excretion in feces. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 48 hours [IV administration] •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 595 mL/min [IV administration] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The acute toxicity of gefitinib up to 500 mg in clinical studies has been low. In non-clinical studies, a single dose of 12,000 mg/m (about 80 times the recommended clinical dose on a mg/m basis) was lethal to rats. Half this dose caused no mortality in mice. Symptoms of overdose include diarrhea and skin rash. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Iressa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Gefitinib •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Gefitinib is a tyrosine kinase inhibitor used as first-line therapy to treat non-small cell lung carcinoma (NSCLC) that meets certain genetic mutation criteria. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Gemcitabine interact?

•Drug A: Abatacept •Drug B: Gemcitabine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Gemcitabine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Gemcitabine is a chemotherapeutic agent used as monotherapy or in combination with other anticancer agents. In combination with carboplatin, it is indicated for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. Gemcitabine in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. In combination with cisplatin, gemcitabine is indicated for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) non-small cell lung cancer (NSCLC). Dual therapy with cisplatin is also used to treat patients with Stage IV (locally advanced or metastatic) transitional cell carcinoma (TCC) of the bladder. Gemcitabine is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine is indicated for patients previously treated with fluorouracil. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Gemcitabine is a nucleoside analog that mediates its antitumour effects by promoting apoptosis of malignant cells undergoing DNA synthesis. More specifically, it blocks the progression of cells through the G1/S-phase boundary. Gemcitabine demonstrated cytotoxic effects against a broad range of cancer cell lines in vitro. It displayed schedule-dependent antitumour activity in various animal models and xenografts from human non-small cell lung cancer (NSCLC) and pancreatic cancer. Therefore, the antineoplastic effects of gemcitabine are enhanced through prolonged infusion time rather than higher dosage. Gemcitabine inhibited the growth of human xenografts from carcinoma of the lung, pancreas, ovaries, head and neck, and breast. In mice, gemcitabine inhibited the growth of human tumour xenografts from the breast, colon, lung or pancreas by 69 to 99%. In clinical trials of advanced NSCLC, gemcitabine monotherapy produced objective response rates ranging from 18 to 26%, with a median duration of response ranging from 3.3 to 12.7 months. Overall median survival time was 6.2 to 12.3 months. The combined use of cisplatin and gemcitabine produced better objective response rates compared to monotherapy. In patients with advanced pancreatic cancer, objective response rates in patients ranged from 5.to 12%, with a median survival duration of 3.9 to 6.3 months. In Phase II trials involving patients with metastatic breast cancer, treatment with gemcitabine alone or with adjuvant chemotherapies resulted in response rate ranging from 13 to 42% and median survival duration ranging from 11.5 to 17.8 months. In metastatic bladder cancer, gemcitabine has a response rate 20 to 28%. In Phase II trials of advanced ovarian cancer, patients treated with gemcitabine had response rate of 57.1%, with progression free survival of 13.4 months and median survival of 24 months. Gemcitabine causes dose-limiting myelosuppression, such as anemia, leukopenia, neutropenia, and thrombocytopenia; however, events leading to discontinuation tend to occur less than 1% of the patients. Gemcitabine can elevate ALT, AST and alkaline phosphatase levels. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Gemcitabine is a potent and specific deoxycytidine analog. After uptake into malignant cells, gemcitabine is phosphorylated by deoxycytidine kinase to form gemcitabine monophosphate, which is then converted to the active compounds, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). These active metabolites are nucleosides that mediate antitumour effects. dFdCTP competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA, thereby competitively inhibiting DNA chain elongation. The non-terminal position of dFdCTP in the DNA chain prevents detection of dFdCTP in the chain and repair by proof-reading 3′5′-exonuclease: this process is referred to as "masked DNA chain termination." Incorporation of dFdCTP into the DNA chain ultimately leads to chain termination, DNA fragmentation, and apoptotic cell death of malignant cells. Gemcitabine has self-potentiating pharmacological actions that can increase the probability of successful incorporation of gemcitabine triphosphate into the DNA chain: dFdCDP inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate dCTP for DNA synthesis. Since dFdCDP reduces the levels of dCTP, there is less competition for gemcitabine triphosphate for incorporation into DNA. Gemcitabine can also reduce metabolism and elimination of active metabolites from the target ce1l, prolonging high intracellular concentrations of the active metabolites. Such self-potentiating effects are not present with cytarabine. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Peak plasma concentrations of gemcitabine range from 10 to 40 mg/L following a 30-minute intravenous infusion, and are reached at 15 to 30 minutes. One study showed that steady-state concentrations of gemcitabine showed a linear relationship to dose over the dose range 53 to 1000 mg/m. Gemcitabine triphosphate, the active metabolite of gemcitabine, can accumulate in circulating peripheral blood mononuclear cells. In one study, the C max of gemcitabine triphosphate in peripheral blood mononuclear cells occurred within 30 minutes of the end of the infusion period and increased increased proportionally with gemcitabine doses of up to 350 mg/m. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): In patients with various solid tumours, the volume of distribution increased with infusion length. The volume of distribution of gemcitabine was 50 L/m following infusions lasting less than 70 minutes. For long infusions, the volume of distribution rose to 370 L/m. Gemcitabine triphosphate, the active metabolite of gemcitabine, accumulates and retains in solid tumour cells in vitro and in vivo. It is not extensively distributed to tissues after short infusions that last less than 70 minutes. It is not known whether gemcitabine crosses the blood-brain barrier, but gemcitabine is widely distributed into tissues, including ascitic fluid. In rats, placental and lacteal transfer occurred rapidly at five to 15 minutes following drug administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Gemcitabine plasma protein binding is less than 10%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Following administration and uptake into cancer cells, gemcitabine is initially phosphorylated by deoxycytidine kinase (dCK), and to a lower extent, the extra-mitochondrial thymidine kinase 2 to form gemcitabine monophosphate (dFdCMP). dFdCMP is subsequently phosphorylated by nucleoside kinases to form active metabolites, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). Gemcitabine is also deaminated intracellularly and extracellularly by cytidine deaminase to its inactive metabolite 2′,2′-difluorodeoxyuridine or 2´-deoxy-2´,2´-difluorouridine (dFdU). Deamination occurs in the blood, liver, kidneys, and other tissues, and this metabolic pathway accounts for most of drug clearance. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Gemcitabine mainly undergoes renal excretion. Within a week following administration of a single dose of 1000 mg/m infused over 30 minutes, about 92-98% of the dose was recovered in urine where 89% of the recovered dose was excreted as difluorodeoxyuridine (dFdU) and less than 10% as gemcitabine. Monophosphate, diphosphate, or triphosphate metabolites of gemcitabine are not detectable in urine. In a single-dose study, about 1% of the administered dose was recovered in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Following intravenous infusions lasting less than 70 minutes, the terminal half-life ranged from 0.7 to 1.6 hours. Following infusions ranging from 70 to 285 minutes, the terminal half-life ranged from 4.1 to 10.6 hours. Females tend to have longer half-lives than male patients. Gemcitabine triphosphate, the active metabolite of gemcitabine, can accumulate in circulating peripheral blood mononuclear cells. The terminal half-life of gemcitabine triphosphate, the active metabolite, from mononuclear cells ranges from 1.7 to 19.4 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Following intravenous infusions lasting less than 70 minutes, clearance ranged from 41 to 92 L/h/m in males and ranged from 31 to 69 L/h/m in females. Clearance decreases with age. Females have about 30% lower clearance than male patients. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 is 333 mg/kg in mice and >500 mg/kg in rats. The dermal LD 50 in rabbits is >1000 mg/kg. There is no known antidote for gemcitabine overdose. In a dose-escalation study, patients were administered a single dose of gemcitabine as high as 5700 mg/m administered by intravenous infusion over 30 minutes every two weeks: main observed toxicities were myelosuppression, paresthesia, and severe rash. In the event of a suspected drug overdose, blood counts should be monitored, and patients should be provided with supportive therapy, as necessary. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Gemzar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Gemcitabin Gemcitabina Gemcitabine Gemcitabinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Gemcitabine is a nucleoside metabolic inhibitor used as adjunct therapy in the treatment of certain types of ovarian cancer, non-small cell lung carcinoma, metastatic breast cancer, and as a single agent for pancreatic cancer.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Gemcitabine interact? Information: •Drug A: Abatacept •Drug B: Gemcitabine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Gemcitabine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Gemcitabine is a chemotherapeutic agent used as monotherapy or in combination with other anticancer agents. In combination with carboplatin, it is indicated for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. Gemcitabine in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. In combination with cisplatin, gemcitabine is indicated for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) non-small cell lung cancer (NSCLC). Dual therapy with cisplatin is also used to treat patients with Stage IV (locally advanced or metastatic) transitional cell carcinoma (TCC) of the bladder. Gemcitabine is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine is indicated for patients previously treated with fluorouracil. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Gemcitabine is a nucleoside analog that mediates its antitumour effects by promoting apoptosis of malignant cells undergoing DNA synthesis. More specifically, it blocks the progression of cells through the G1/S-phase boundary. Gemcitabine demonstrated cytotoxic effects against a broad range of cancer cell lines in vitro. It displayed schedule-dependent antitumour activity in various animal models and xenografts from human non-small cell lung cancer (NSCLC) and pancreatic cancer. Therefore, the antineoplastic effects of gemcitabine are enhanced through prolonged infusion time rather than higher dosage. Gemcitabine inhibited the growth of human xenografts from carcinoma of the lung, pancreas, ovaries, head and neck, and breast. In mice, gemcitabine inhibited the growth of human tumour xenografts from the breast, colon, lung or pancreas by 69 to 99%. In clinical trials of advanced NSCLC, gemcitabine monotherapy produced objective response rates ranging from 18 to 26%, with a median duration of response ranging from 3.3 to 12.7 months. Overall median survival time was 6.2 to 12.3 months. The combined use of cisplatin and gemcitabine produced better objective response rates compared to monotherapy. In patients with advanced pancreatic cancer, objective response rates in patients ranged from 5.to 12%, with a median survival duration of 3.9 to 6.3 months. In Phase II trials involving patients with metastatic breast cancer, treatment with gemcitabine alone or with adjuvant chemotherapies resulted in response rate ranging from 13 to 42% and median survival duration ranging from 11.5 to 17.8 months. In metastatic bladder cancer, gemcitabine has a response rate 20 to 28%. In Phase II trials of advanced ovarian cancer, patients treated with gemcitabine had response rate of 57.1%, with progression free survival of 13.4 months and median survival of 24 months. Gemcitabine causes dose-limiting myelosuppression, such as anemia, leukopenia, neutropenia, and thrombocytopenia; however, events leading to discontinuation tend to occur less than 1% of the patients. Gemcitabine can elevate ALT, AST and alkaline phosphatase levels. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Gemcitabine is a potent and specific deoxycytidine analog. After uptake into malignant cells, gemcitabine is phosphorylated by deoxycytidine kinase to form gemcitabine monophosphate, which is then converted to the active compounds, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). These active metabolites are nucleosides that mediate antitumour effects. dFdCTP competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA, thereby competitively inhibiting DNA chain elongation. The non-terminal position of dFdCTP in the DNA chain prevents detection of dFdCTP in the chain and repair by proof-reading 3′5′-exonuclease: this process is referred to as "masked DNA chain termination." Incorporation of dFdCTP into the DNA chain ultimately leads to chain termination, DNA fragmentation, and apoptotic cell death of malignant cells. Gemcitabine has self-potentiating pharmacological actions that can increase the probability of successful incorporation of gemcitabine triphosphate into the DNA chain: dFdCDP inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate dCTP for DNA synthesis. Since dFdCDP reduces the levels of dCTP, there is less competition for gemcitabine triphosphate for incorporation into DNA. Gemcitabine can also reduce metabolism and elimination of active metabolites from the target ce1l, prolonging high intracellular concentrations of the active metabolites. Such self-potentiating effects are not present with cytarabine. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Peak plasma concentrations of gemcitabine range from 10 to 40 mg/L following a 30-minute intravenous infusion, and are reached at 15 to 30 minutes. One study showed that steady-state concentrations of gemcitabine showed a linear relationship to dose over the dose range 53 to 1000 mg/m. Gemcitabine triphosphate, the active metabolite of gemcitabine, can accumulate in circulating peripheral blood mononuclear cells. In one study, the C max of gemcitabine triphosphate in peripheral blood mononuclear cells occurred within 30 minutes of the end of the infusion period and increased increased proportionally with gemcitabine doses of up to 350 mg/m. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): In patients with various solid tumours, the volume of distribution increased with infusion length. The volume of distribution of gemcitabine was 50 L/m following infusions lasting less than 70 minutes. For long infusions, the volume of distribution rose to 370 L/m. Gemcitabine triphosphate, the active metabolite of gemcitabine, accumulates and retains in solid tumour cells in vitro and in vivo. It is not extensively distributed to tissues after short infusions that last less than 70 minutes. It is not known whether gemcitabine crosses the blood-brain barrier, but gemcitabine is widely distributed into tissues, including ascitic fluid. In rats, placental and lacteal transfer occurred rapidly at five to 15 minutes following drug administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Gemcitabine plasma protein binding is less than 10%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Following administration and uptake into cancer cells, gemcitabine is initially phosphorylated by deoxycytidine kinase (dCK), and to a lower extent, the extra-mitochondrial thymidine kinase 2 to form gemcitabine monophosphate (dFdCMP). dFdCMP is subsequently phosphorylated by nucleoside kinases to form active metabolites, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). Gemcitabine is also deaminated intracellularly and extracellularly by cytidine deaminase to its inactive metabolite 2′,2′-difluorodeoxyuridine or 2´-deoxy-2´,2´-difluorouridine (dFdU). Deamination occurs in the blood, liver, kidneys, and other tissues, and this metabolic pathway accounts for most of drug clearance. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Gemcitabine mainly undergoes renal excretion. Within a week following administration of a single dose of 1000 mg/m infused over 30 minutes, about 92-98% of the dose was recovered in urine where 89% of the recovered dose was excreted as difluorodeoxyuridine (dFdU) and less than 10% as gemcitabine. Monophosphate, diphosphate, or triphosphate metabolites of gemcitabine are not detectable in urine. In a single-dose study, about 1% of the administered dose was recovered in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Following intravenous infusions lasting less than 70 minutes, the terminal half-life ranged from 0.7 to 1.6 hours. Following infusions ranging from 70 to 285 minutes, the terminal half-life ranged from 4.1 to 10.6 hours. Females tend to have longer half-lives than male patients. Gemcitabine triphosphate, the active metabolite of gemcitabine, can accumulate in circulating peripheral blood mononuclear cells. The terminal half-life of gemcitabine triphosphate, the active metabolite, from mononuclear cells ranges from 1.7 to 19.4 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Following intravenous infusions lasting less than 70 minutes, clearance ranged from 41 to 92 L/h/m in males and ranged from 31 to 69 L/h/m in females. Clearance decreases with age. Females have about 30% lower clearance than male patients. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 is 333 mg/kg in mice and >500 mg/kg in rats. The dermal LD 50 in rabbits is >1000 mg/kg. There is no known antidote for gemcitabine overdose. In a dose-escalation study, patients were administered a single dose of gemcitabine as high as 5700 mg/m administered by intravenous infusion over 30 minutes every two weeks: main observed toxicities were myelosuppression, paresthesia, and severe rash. In the event of a suspected drug overdose, blood counts should be monitored, and patients should be provided with supportive therapy, as necessary. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Gemzar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Gemcitabin Gemcitabina Gemcitabine Gemcitabinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Gemcitabine is a nucleoside metabolic inhibitor used as adjunct therapy in the treatment of certain types of ovarian cancer, non-small cell lung carcinoma, metastatic breast cancer, and as a single agent for pancreatic cancer. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Gemtuzumab ozogamicin interact?

•Drug A: Abatacept •Drug B: Gemtuzumab ozogamicin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Gemtuzumab ozogamicin is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for the treatment of patients with CD33 positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy. Indicated for the treatment of patients aged 2 years and older with CD33-positive AML who have experienced a relapse or who have not responded to initial treatment (refractory). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Used for the treatment of acute myeloid leukemia (AML), mylotarg binds to the CD33 antigen, which is expressed on the surface of leukemic cells in more than 80% of patients with AML. The CD33 antigen is not expressed on pluripotent hematopoietic stem cells or nonhematopoietic cells. This gives mylotarg the selectivity needed to target leukemic cells. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Mylotarg is directed against the CD33 antigen expressed by hematopoietic cells. Binding of the anti-CD33 antibody portion of Mylotarg with the CD33 antigen results in the formation of a complex that is internalized. Upon internalization, the calicheamicin derivative is released inside the lysosomes of the myeloid cell. The released calicheamicin derivative binds to DNA in the minor groove resulting in site-specific DNA double strand breaks via formation of a p-benzene diradical. Eventually, cell death is induced. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In pediatric patients receiving a dose level of 9mg/m^2, the peak plasma concentration (Cmax) was approximately 3.47±1.04 mg/L with the AUC of 136 ±107 mg * h/L. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution at steady state (Vss) was approximately 6.5 ± 5.5 L in pediatric patients receiving a dose level of 9mg/m^2. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolic studies indicate hydrolytic release of the calicheamicin derivative from gemtuzumab ozogamicin. The drug is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In pediatric patients receiving a dose level of 9mg/m^2, the half life was approximately 64±44 h after the first dose. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean clearance rate was approximately 0.12±0.15 L/h/m^2 in pediatric patients receiving a dose level of 9mg/m^2. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The most frequently reported toxicities are myelosuppression and hepatic veno-occlusive disorder. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Mylotarg •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Gemtuzumab ozogamicin is a monoclonal anti-CD33 antibody used to treat CD33-positive acute myeloid leukemia.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Gemtuzumab ozogamicin interact? Information: •Drug A: Abatacept •Drug B: Gemtuzumab ozogamicin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Gemtuzumab ozogamicin is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for the treatment of patients with CD33 positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy. Indicated for the treatment of patients aged 2 years and older with CD33-positive AML who have experienced a relapse or who have not responded to initial treatment (refractory). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Used for the treatment of acute myeloid leukemia (AML), mylotarg binds to the CD33 antigen, which is expressed on the surface of leukemic cells in more than 80% of patients with AML. The CD33 antigen is not expressed on pluripotent hematopoietic stem cells or nonhematopoietic cells. This gives mylotarg the selectivity needed to target leukemic cells. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Mylotarg is directed against the CD33 antigen expressed by hematopoietic cells. Binding of the anti-CD33 antibody portion of Mylotarg with the CD33 antigen results in the formation of a complex that is internalized. Upon internalization, the calicheamicin derivative is released inside the lysosomes of the myeloid cell. The released calicheamicin derivative binds to DNA in the minor groove resulting in site-specific DNA double strand breaks via formation of a p-benzene diradical. Eventually, cell death is induced. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In pediatric patients receiving a dose level of 9mg/m^2, the peak plasma concentration (Cmax) was approximately 3.47±1.04 mg/L with the AUC of 136 ±107 mg * h/L. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution at steady state (Vss) was approximately 6.5 ± 5.5 L in pediatric patients receiving a dose level of 9mg/m^2. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolic studies indicate hydrolytic release of the calicheamicin derivative from gemtuzumab ozogamicin. The drug is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In pediatric patients receiving a dose level of 9mg/m^2, the half life was approximately 64±44 h after the first dose. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean clearance rate was approximately 0.12±0.15 L/h/m^2 in pediatric patients receiving a dose level of 9mg/m^2. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The most frequently reported toxicities are myelosuppression and hepatic veno-occlusive disorder. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Mylotarg •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Gemtuzumab ozogamicin is a monoclonal anti-CD33 antibody used to treat CD33-positive acute myeloid leukemia. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Gilteritinib interact?

•Drug A: Abatacept •Drug B: Gilteritinib •Severity: MODERATE •Description: The metabolism of Gilteritinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Gilteritinib is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia with an FLT3 mutation detected by an FDA-approved test. This indication was expanded for a companion diagnostic to include use with gilteritinib such as the LeukoStrat CDx FLT3 Mutation Assay. Acute myeloid leukemia is cancer that impacts the blood and bone marrow with a rapid progression. This condition produces low numbers of normal blood cells and the requirement of continuous need for transfusions. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In preclinical trials, gilteritinib demonstrate an IC50 for the wild-type receptor of 5 nM, 0.7-1.8 nM for ITD-mutated and comparable inhibition to other therapies in the TKD-mutated. As well, data showed a gilteritinib-driven inhibition of the receptor tyrosine kinase AXL which is known to modulate the activity of FLT3 in acute myeloid leukemia. Another important result in vivo was the localization in high levels in xenografted tumors which indicated high selectivity. In phase 1/2 clinical trials, gilteritinib was shown to present a composite complete response of 41%, an overall response rate of 52%, a median duration of response of 20 weeks with a median overall survival of 31 weeks. In phase III clinical trials, gilteritinib reported a complete remission or complete remission with partial hematologic recovery in 21% of the patients. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Gilteritinib is a potent selective inhibitor of both of the mutations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD), of the FLT3 receptor. In the same note, gilteritinib also inhibits AXL and ALK tyrosine kinases. FLT3 and AXL are molecules involved in the growth of cancer cells. The activity of gilteritinib permits an inhibition of the phosphorylation of FLT3 and its downstream targets such as STAT5, ERK and AKT. The interest in FLT3 transmembrane tyrosine kinases was raised when studies reported that approximately 30% of the patients with acute myeloid leukemia presented a mutationally activated isoform. As well, the mutation ITD is associated with poor patient outcomes while the mutation TKD produces a resistance mechanism to FLT3 tyrosine kinase inhibitors and the AXL tyrosine kinase tends to produce a resistance mechanism to chemotherapies. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In preclinical trials, the maximal plasma concentration of gilteritinib was observed 2 hours after oral administration and followed by a maximal intratumor concentration after 4-8 hours. The maximum concentration, as well as the AUC, were modified correspondingly with the dose and were reported to be 374 ng/ml and 6943 ng.h/ml, respectively. The steady-state plasma level is reached within 15 days of dosing with an approximate 10-fold bioaccumulation. In a fasted state in humans, the tmax is reported to be of 4-6 hours. The Cmax and AUC were decreased by 26% and 10% respectively by the co-ingestion of a high-fat meal with a tmax delay of 2 hours. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The estimated apparent central and peripheral volume of distribution is 1092 L and 1100 L respectively. This value indicated an extensive tissue distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Gilteritinib is reported to be highly bound to plasma proteins, representing 94% of the dose. From this ratio, the main protein-bound is serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Gilteritinib is primarily metabolized in the liver by the activity of CYP3A4. Its metabolism is driven by reactions of N-dealkylation and oxidation which forms the metabolite M17, M16 and M10. From the plasma concentration, the major form is the unchanged drug. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): From the administered dose, gilteritinib is mainly excreted in feces which represents 64.5% of the administered dose while 16.4% is recovered in urine either as the unchanged drug or as its metabolites. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The reported median half-life of gilteritinib was of approximate 45-159 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The estimated clearance of gilteritinib is 14.85 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Gilteritinib is not reported to be mutagenic in bacterial mutagenesis assays nor clastogenic in aberration test assays in Chinese hamster lung cells. However, it resulted positive for the induction of micronuclei in mouse bone marrow and for the degeneration and necrosis of germ cells and spermatid giant cell formation in testis as well as single cell necrosis of the epididymal duct epithelia. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Xospata •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Gilteritinib is an AXL receptor tyrosine kinase inhibitor used to treat relapsed or refractory acute myeloid leukemia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Gilteritinib interact? Information: •Drug A: Abatacept •Drug B: Gilteritinib •Severity: MODERATE •Description: The metabolism of Gilteritinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Gilteritinib is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia with an FLT3 mutation detected by an FDA-approved test. This indication was expanded for a companion diagnostic to include use with gilteritinib such as the LeukoStrat CDx FLT3 Mutation Assay. Acute myeloid leukemia is cancer that impacts the blood and bone marrow with a rapid progression. This condition produces low numbers of normal blood cells and the requirement of continuous need for transfusions. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In preclinical trials, gilteritinib demonstrate an IC50 for the wild-type receptor of 5 nM, 0.7-1.8 nM for ITD-mutated and comparable inhibition to other therapies in the TKD-mutated. As well, data showed a gilteritinib-driven inhibition of the receptor tyrosine kinase AXL which is known to modulate the activity of FLT3 in acute myeloid leukemia. Another important result in vivo was the localization in high levels in xenografted tumors which indicated high selectivity. In phase 1/2 clinical trials, gilteritinib was shown to present a composite complete response of 41%, an overall response rate of 52%, a median duration of response of 20 weeks with a median overall survival of 31 weeks. In phase III clinical trials, gilteritinib reported a complete remission or complete remission with partial hematologic recovery in 21% of the patients. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Gilteritinib is a potent selective inhibitor of both of the mutations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD), of the FLT3 receptor. In the same note, gilteritinib also inhibits AXL and ALK tyrosine kinases. FLT3 and AXL are molecules involved in the growth of cancer cells. The activity of gilteritinib permits an inhibition of the phosphorylation of FLT3 and its downstream targets such as STAT5, ERK and AKT. The interest in FLT3 transmembrane tyrosine kinases was raised when studies reported that approximately 30% of the patients with acute myeloid leukemia presented a mutationally activated isoform. As well, the mutation ITD is associated with poor patient outcomes while the mutation TKD produces a resistance mechanism to FLT3 tyrosine kinase inhibitors and the AXL tyrosine kinase tends to produce a resistance mechanism to chemotherapies. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In preclinical trials, the maximal plasma concentration of gilteritinib was observed 2 hours after oral administration and followed by a maximal intratumor concentration after 4-8 hours. The maximum concentration, as well as the AUC, were modified correspondingly with the dose and were reported to be 374 ng/ml and 6943 ng.h/ml, respectively. The steady-state plasma level is reached within 15 days of dosing with an approximate 10-fold bioaccumulation. In a fasted state in humans, the tmax is reported to be of 4-6 hours. The Cmax and AUC were decreased by 26% and 10% respectively by the co-ingestion of a high-fat meal with a tmax delay of 2 hours. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The estimated apparent central and peripheral volume of distribution is 1092 L and 1100 L respectively. This value indicated an extensive tissue distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Gilteritinib is reported to be highly bound to plasma proteins, representing 94% of the dose. From this ratio, the main protein-bound is serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Gilteritinib is primarily metabolized in the liver by the activity of CYP3A4. Its metabolism is driven by reactions of N-dealkylation and oxidation which forms the metabolite M17, M16 and M10. From the plasma concentration, the major form is the unchanged drug. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): From the administered dose, gilteritinib is mainly excreted in feces which represents 64.5% of the administered dose while 16.4% is recovered in urine either as the unchanged drug or as its metabolites. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The reported median half-life of gilteritinib was of approximate 45-159 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The estimated clearance of gilteritinib is 14.85 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Gilteritinib is not reported to be mutagenic in bacterial mutagenesis assays nor clastogenic in aberration test assays in Chinese hamster lung cells. However, it resulted positive for the induction of micronuclei in mouse bone marrow and for the degeneration and necrosis of germ cells and spermatid giant cell formation in testis as well as single cell necrosis of the epididymal duct epithelia. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Xospata •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Gilteritinib is an AXL receptor tyrosine kinase inhibitor used to treat relapsed or refractory acute myeloid leukemia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Does Abatacept and Glasdegib interact?

•Drug A: Abatacept •Drug B: Glasdegib •Severity: MODERATE •Description: The metabolism of Glasdegib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Glasdegib, in combination with cytarabine, is indicated for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are over 75 years old or that have co-morbidities that preclude intensive induction chemotherapy. Acute myeloid leukemia is characterized by abnormal production of myeloblasts, red cells, or platelets. It is considered a cancer of blood and bone marrow and it is the most common type of acute leukemia in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In preclinical studies, glasdegib achieved a significant reduction in leukemic stem cell burden in xenograft models and a reduction in cell population expressing leukemic stem cell markers. In clinical trials, glasdegib demonstrated a marked downregulation of more than 80% of the expression of glioma-associated transcriptional regulator GL11 in skin. In this same study 8% of the studied individuals with acute myeloid leukemia achieved morphological complete remission while 31% achieved stable disease state. The latest clinical trial proved glasdegib to generate an overall survival of 8.3 months which was almost double to what has been observed in patients under low-dose cytarabine treatment. As well, there have been reports of dose-dependent QTc prolongation in patients administered with glasdegib. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Glasdegib is a potent and selective inhibitor of the hedgehog signaling pathway that acts by binding to the smoothened (SMO) receptor. The hedgehog signaling pathway is involved in maintenance of neural and skin stem cells. In this pathway, the binding of specific ligands to the transmembrane receptor patched (PTCH1) allows the activation of the transcriptional regulators GL11, GL12 and modulation of the gene expression through SMO-mediated signaling. The aberrant activation of the hedgehog pathway is thought to be implicated in the pathogenesis of chronic myeloid leukemia, medulloblastoma and basal cell carcinoma due to the hyperproliferative state that a modification on this pathway will produce. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Glasdegib presents a dose-proportional pharmacokinetic profile which is observed by the presence of a broad dose-proportional maximum plasma concentration. In this study and on a dose of 50 mg, the median time to reach a maximum concentration of 321 ng/ml was of 4 hours with an AUC of 9587 ng.h/ml. The oral bioavailability of glasdegib is reported to be of 55%. In a multiple dose study of 50 mg, the Cmax, tmax and AUC was reported to be 542 ng/ml, 4 h and 9310 ng.h/ml respectively. In this same study, the average concentration at a steady state was of 388 ng/ml. The absorption rates of glasdegib can be modified by the concomitant consumption of a high-fat, high-calorie meal. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Glasdegib reported volume of distribution in a dose of 50 mg is 225 L. The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Glasdegib is reported to be 91% protein bounded which is explained due to its high lipophilic profile. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): After oral administration, glasdegib was primarily metabolized by CYP3A4 with minor contributions of CYP2C8 and UGT1A9. The amount of unchanged glasdegib in plasma accounts only for 69% of the administered dose. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): From a single oral dose of 100 mg radiolabeled glasdegib, 49% is eliminated in the urine from which 17% is excreted as the unchanged form while 42% is eliminated in feces where 20% represents the unchanged form. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The reported half-life of glasdegib is of 17.4 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance rate of 50 mg of glasdegib is reported to be of 5.22 L/h. The geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following 100 mg once daily dosing in patients with hematologic malignancies. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, glasdegib can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of glasdegib in pregnant women to inform of a drug-associated risk of major birth defects and miscarriage. Glasdegib is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating treatment with glasdegib. Report pregnancy exposures to Pfizer at 1-800-438-1985. In animal embryo-fetal developmental toxicity studies, repeat-dose oral administration of glasdegib during organogenesis at maternal exposures that were less than the human exposure at the recommended dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Carcinogenicity studies have not been performed with glasdegib. Glasdegib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay in human lymphocytes. Glasdegib was not clastogenic or aneugenic in the rat micronucleus assay. Based on nonclinical safety findings, glasdegib has the potential to impair reproductive function in males. Men should seek advice on effective fertility preservation before treatment. In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses ≥50 mg/kg/day and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6 times (based on AUC) those associated with the observed human exposure at the 100 mg once daily dose. There is no specific antidote for DAURISMO. Management of DAURISMO overdose should include symptomatic treatment and ECG monitoring. Glasdegib has been administered in clinical studies up to a dose of 640 mg/day. At the highest dosage, the adverse reactions that were dose-limiting were nausea, vomiting, dehydration, hypotension, fatigue, and dizziness. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Daurismo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Glasdegib is a sonic hedgehog receptor inhibitor used to treat newly diagnosed acute myeloid leukemia in patients over 75 years who cannot receive intense chemotherapy.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Glasdegib interact? Information: •Drug A: Abatacept •Drug B: Glasdegib •Severity: MODERATE •Description: The metabolism of Glasdegib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Glasdegib, in combination with cytarabine, is indicated for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are over 75 years old or that have co-morbidities that preclude intensive induction chemotherapy. Acute myeloid leukemia is characterized by abnormal production of myeloblasts, red cells, or platelets. It is considered a cancer of blood and bone marrow and it is the most common type of acute leukemia in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In preclinical studies, glasdegib achieved a significant reduction in leukemic stem cell burden in xenograft models and a reduction in cell population expressing leukemic stem cell markers. In clinical trials, glasdegib demonstrated a marked downregulation of more than 80% of the expression of glioma-associated transcriptional regulator GL11 in skin. In this same study 8% of the studied individuals with acute myeloid leukemia achieved morphological complete remission while 31% achieved stable disease state. The latest clinical trial proved glasdegib to generate an overall survival of 8.3 months which was almost double to what has been observed in patients under low-dose cytarabine treatment. As well, there have been reports of dose-dependent QTc prolongation in patients administered with glasdegib. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Glasdegib is a potent and selective inhibitor of the hedgehog signaling pathway that acts by binding to the smoothened (SMO) receptor. The hedgehog signaling pathway is involved in maintenance of neural and skin stem cells. In this pathway, the binding of specific ligands to the transmembrane receptor patched (PTCH1) allows the activation of the transcriptional regulators GL11, GL12 and modulation of the gene expression through SMO-mediated signaling. The aberrant activation of the hedgehog pathway is thought to be implicated in the pathogenesis of chronic myeloid leukemia, medulloblastoma and basal cell carcinoma due to the hyperproliferative state that a modification on this pathway will produce. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Glasdegib presents a dose-proportional pharmacokinetic profile which is observed by the presence of a broad dose-proportional maximum plasma concentration. In this study and on a dose of 50 mg, the median time to reach a maximum concentration of 321 ng/ml was of 4 hours with an AUC of 9587 ng.h/ml. The oral bioavailability of glasdegib is reported to be of 55%. In a multiple dose study of 50 mg, the Cmax, tmax and AUC was reported to be 542 ng/ml, 4 h and 9310 ng.h/ml respectively. In this same study, the average concentration at a steady state was of 388 ng/ml. The absorption rates of glasdegib can be modified by the concomitant consumption of a high-fat, high-calorie meal. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Glasdegib reported volume of distribution in a dose of 50 mg is 225 L. The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Glasdegib is reported to be 91% protein bounded which is explained due to its high lipophilic profile. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): After oral administration, glasdegib was primarily metabolized by CYP3A4 with minor contributions of CYP2C8 and UGT1A9. The amount of unchanged glasdegib in plasma accounts only for 69% of the administered dose. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): From a single oral dose of 100 mg radiolabeled glasdegib, 49% is eliminated in the urine from which 17% is excreted as the unchanged form while 42% is eliminated in feces where 20% represents the unchanged form. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The reported half-life of glasdegib is of 17.4 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance rate of 50 mg of glasdegib is reported to be of 5.22 L/h. The geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following 100 mg once daily dosing in patients with hematologic malignancies. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, glasdegib can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of glasdegib in pregnant women to inform of a drug-associated risk of major birth defects and miscarriage. Glasdegib is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating treatment with glasdegib. Report pregnancy exposures to Pfizer at 1-800-438-1985. In animal embryo-fetal developmental toxicity studies, repeat-dose oral administration of glasdegib during organogenesis at maternal exposures that were less than the human exposure at the recommended dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Carcinogenicity studies have not been performed with glasdegib. Glasdegib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay in human lymphocytes. Glasdegib was not clastogenic or aneugenic in the rat micronucleus assay. Based on nonclinical safety findings, glasdegib has the potential to impair reproductive function in males. Men should seek advice on effective fertility preservation before treatment. In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses ≥50 mg/kg/day and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6 times (based on AUC) those associated with the observed human exposure at the 100 mg once daily dose. There is no specific antidote for DAURISMO. Management of DAURISMO overdose should include symptomatic treatment and ECG monitoring. Glasdegib has been administered in clinical studies up to a dose of 640 mg/day. At the highest dosage, the adverse reactions that were dose-limiting were nausea, vomiting, dehydration, hypotension, fatigue, and dizziness. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Daurismo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Glasdegib is a sonic hedgehog receptor inhibitor used to treat newly diagnosed acute myeloid leukemia in patients over 75 years who cannot receive intense chemotherapy. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. The severity of the interaction is moderate.

Does Abatacept and Glatiramer interact?

•Drug A: Abatacept •Drug B: Glatiramer •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Glatiramer. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Glatiramer acetate is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Glatiramer acetate is a mix of synthetic polypeptides that includes four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine. This drug is indicated for the treatment of relapsing multiple sclerosis (MS) due to its ability to modify immune processes involved in the pathogenesis of this disease. Intact and large fragments of glatiramer acetate are recognized by glatiramer acetate-reactive antibodies. In vitro and in vivo studies suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery. A fraction of intact or partially hydrolyzed glatiramer acetate enters lymphatic circulation and is able to reach the lymph nodes. Compared to placebo and IFNb-1a, patients with relapsing-remitting MS receiving 20 mg/mL of glatiramer acetate once a day had significantly lower annualized relapse rates. Similar outcomes were observed in MS patients taking 40 mg/mL of glatiramer acetate three times a week. Some of the patients treated with glatiramer acetate (approximately 16%) have developed immediate post-injection reactions. Most of these cases are transient and do not require treatment, but there have been reports of patients requiring emergency medical care. Patients taking glatiramer acetate may also experience chest pain, injection site side effects such as localized lipoatrophy and skin necrosis, and hepatic injury. Since glatiramer acetate modifies immune response, it may interfere with immune function. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism of action of glatiramer acetate has not been fully elucidated; however, it is thought to act by modifying immune processes involved in the pathogenesis of multiple sclerosis (MS). MS is characterized by damage to the myelin layer that covers nerve cells (demyelination) and axonal degeneration. Also, it has been suggested that the myelin basic protein (MBP), a myelin autoantigen, plays a role in the development of MS. Several mechanisms of action have been proposed. For instance, glatiramer acetate binds strongly to several major histocompatibility complex (MHC) class II molecules on MBP-specific antigen-presenting cells, preventing MBP from stimulating these cells. Glatiramer acetate also has the ability to shift the immune system from a pro-inflammatory to an anti-inflammatory pattern. It inhibits the secretion of pro-inflammatory cytokines (IL-2, IL-12, IFNγ, TNF) released by T helper 1 (Th1) cells, and induces T helper 2 (Th2) suppressor cells that are able to cross the blood-brain barrier and produce anti-inflammatory cytokines (IL-4, IL-5, IL-13, IL-10, TGF-β). It has also been suggested that glatiramer acetate induces the production of T-regulatory cells associated with the suppression of MS, such as CD4, CD8 and CD4 CD25 cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): After subcutaneous administration, most glatiramer acetate is rapidly absorbed and hydrolyzed locally. In 7 out of 9 healthy volunteers that received 60 mg of glatiramer acetate subcutaneously, the C max ranged from 69 to 126 ng/mL, while the other two subjects showed significantly higher values (605 and 301 ng/mL). AUC values showed great variability, ranging from 1,644 to 67,532 min⋅ng/mL. The T max of glatiramer acetate went from 15 to 30 min, and in all subjects, glatiramer acetate levels returned to baseline after 30-60 min. In healthy volunteers given 60 mg of glatiramer acetate subcutaneously, immunorecognizable fragments were no longer detected after 24 hours. The systemic bioavailability of glatiramer acetate is considered to be minimal. The pharmacokinetic parameters of glatiramer acetate in multiple sclerosis (MS) patients have not been determined. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Not available. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Glatiramer acetate is highly bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Glatiramer acetate ​​is a mixture of synthetic polypeptides hydrolyzed by proteases. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In vivo studies have shown that glatiramer acetate is mainly excreted through urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Not available. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Not available. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In mice given 60 mg/kg/day of glatiramer acetate subcutaneously (15 times the human therapeutic dose of 20 mg/day on a mg/m basis), glatiramer acetate did not increase systemic neoplasms. Similar results were obtained in rats given 30 mg/kg/day of glatiramer acetate subcutaneously (15 times the human therapeutic dose of 20 mg/day on a mg/m basis). In vitro studies suggest that glatiramer acetate is non-mutagenic. No adverse effects were observed on reproductive or developmental parameters during in vivo studies. Overdose information regarding glatiramer acetate is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as hepatic injury, lipoatrophy and skin necrosis at the injection site. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Copaxone, Glatect, Glatopa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Glatiramer is an immunomodulator used to reduce the frequency of relapses in Multiple Sclerosis (MS).

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Glatiramer interact? Information: •Drug A: Abatacept •Drug B: Glatiramer •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Glatiramer. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Glatiramer acetate is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Glatiramer acetate is a mix of synthetic polypeptides that includes four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine. This drug is indicated for the treatment of relapsing multiple sclerosis (MS) due to its ability to modify immune processes involved in the pathogenesis of this disease. Intact and large fragments of glatiramer acetate are recognized by glatiramer acetate-reactive antibodies. In vitro and in vivo studies suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery. A fraction of intact or partially hydrolyzed glatiramer acetate enters lymphatic circulation and is able to reach the lymph nodes. Compared to placebo and IFNb-1a, patients with relapsing-remitting MS receiving 20 mg/mL of glatiramer acetate once a day had significantly lower annualized relapse rates. Similar outcomes were observed in MS patients taking 40 mg/mL of glatiramer acetate three times a week. Some of the patients treated with glatiramer acetate (approximately 16%) have developed immediate post-injection reactions. Most of these cases are transient and do not require treatment, but there have been reports of patients requiring emergency medical care. Patients taking glatiramer acetate may also experience chest pain, injection site side effects such as localized lipoatrophy and skin necrosis, and hepatic injury. Since glatiramer acetate modifies immune response, it may interfere with immune function. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism of action of glatiramer acetate has not been fully elucidated; however, it is thought to act by modifying immune processes involved in the pathogenesis of multiple sclerosis (MS). MS is characterized by damage to the myelin layer that covers nerve cells (demyelination) and axonal degeneration. Also, it has been suggested that the myelin basic protein (MBP), a myelin autoantigen, plays a role in the development of MS. Several mechanisms of action have been proposed. For instance, glatiramer acetate binds strongly to several major histocompatibility complex (MHC) class II molecules on MBP-specific antigen-presenting cells, preventing MBP from stimulating these cells. Glatiramer acetate also has the ability to shift the immune system from a pro-inflammatory to an anti-inflammatory pattern. It inhibits the secretion of pro-inflammatory cytokines (IL-2, IL-12, IFNγ, TNF) released by T helper 1 (Th1) cells, and induces T helper 2 (Th2) suppressor cells that are able to cross the blood-brain barrier and produce anti-inflammatory cytokines (IL-4, IL-5, IL-13, IL-10, TGF-β). It has also been suggested that glatiramer acetate induces the production of T-regulatory cells associated with the suppression of MS, such as CD4, CD8 and CD4 CD25 cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): After subcutaneous administration, most glatiramer acetate is rapidly absorbed and hydrolyzed locally. In 7 out of 9 healthy volunteers that received 60 mg of glatiramer acetate subcutaneously, the C max ranged from 69 to 126 ng/mL, while the other two subjects showed significantly higher values (605 and 301 ng/mL). AUC values showed great variability, ranging from 1,644 to 67,532 min⋅ng/mL. The T max of glatiramer acetate went from 15 to 30 min, and in all subjects, glatiramer acetate levels returned to baseline after 30-60 min. In healthy volunteers given 60 mg of glatiramer acetate subcutaneously, immunorecognizable fragments were no longer detected after 24 hours. The systemic bioavailability of glatiramer acetate is considered to be minimal. The pharmacokinetic parameters of glatiramer acetate in multiple sclerosis (MS) patients have not been determined. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Not available. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Glatiramer acetate is highly bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Glatiramer acetate ​​is a mixture of synthetic polypeptides hydrolyzed by proteases. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In vivo studies have shown that glatiramer acetate is mainly excreted through urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Not available. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Not available. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In mice given 60 mg/kg/day of glatiramer acetate subcutaneously (15 times the human therapeutic dose of 20 mg/day on a mg/m basis), glatiramer acetate did not increase systemic neoplasms. Similar results were obtained in rats given 30 mg/kg/day of glatiramer acetate subcutaneously (15 times the human therapeutic dose of 20 mg/day on a mg/m basis). In vitro studies suggest that glatiramer acetate is non-mutagenic. No adverse effects were observed on reproductive or developmental parameters during in vivo studies. Overdose information regarding glatiramer acetate is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as hepatic injury, lipoatrophy and skin necrosis at the injection site. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Copaxone, Glatect, Glatopa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Glatiramer is an immunomodulator used to reduce the frequency of relapses in Multiple Sclerosis (MS). Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Gliclazide interact?

•Drug A: Abatacept •Drug B: Gliclazide •Severity: MODERATE •Description: The metabolism of Gliclazide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of NIDDM in conjunction with diet and exercise. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Based on the pharmacological properties, gliclazide is a second generation sulphonylurea which acts as a hypoglycemic agent. It stimulates β cells of the islet of Langerhans in the pancreas to release insulin. It also enhances peripheral insulin sensitivity. Overall, it potentiates insulin release and improves insulin dynamics. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Gliclazide binds to the β cell sulfonyl urea receptor (SUR1). This binding subsequently blocks the ATP sensitive potassium channels. The binding results in closure of the channels and leads to a resulting decrease in potassium efflux leads to depolarization of the β cells. This opens voltage-dependent calcium channels in the β cell resulting in calmodulin activation, which in turn leads to exocytosis of insulin containing secretorty granules. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly and well absorbed but may have wide inter- and intra-individual variability. Peak plasma concentrations occur within 4-6 hours of oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 94%, highly bound to plasma proteins •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Extensively metabolized in the liver. Less than 1% of the orally administered dose appears unchanged in the urine. Metabolites include oxidized and hydroxylated derivates, as well as glucuronic acid conjugates. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Metabolites and conjugates are eliminated primarily by the kidneys (60-70%) and also in the feces (10-20%). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 10.4 hours. Duration of action is 10-24 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 =3000 mg/kg (orally in mice). Gliclazide and its metabolites may accumulate in those with severe hepatic and/or renal dysfunction. Symptoms of hypoglycemia include: dizziness, lack of energy, drowsiness, headache and sweating. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Diamicron •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Gliclazida Gliclazide Gliclazidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Gliclazide is a sulfonylurea used to treat hyperglycemia in patients with type 2 diabetes mellitus.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Gliclazide interact? Information: •Drug A: Abatacept •Drug B: Gliclazide •Severity: MODERATE •Description: The metabolism of Gliclazide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of NIDDM in conjunction with diet and exercise. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Based on the pharmacological properties, gliclazide is a second generation sulphonylurea which acts as a hypoglycemic agent. It stimulates β cells of the islet of Langerhans in the pancreas to release insulin. It also enhances peripheral insulin sensitivity. Overall, it potentiates insulin release and improves insulin dynamics. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Gliclazide binds to the β cell sulfonyl urea receptor (SUR1). This binding subsequently blocks the ATP sensitive potassium channels. The binding results in closure of the channels and leads to a resulting decrease in potassium efflux leads to depolarization of the β cells. This opens voltage-dependent calcium channels in the β cell resulting in calmodulin activation, which in turn leads to exocytosis of insulin containing secretorty granules. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly and well absorbed but may have wide inter- and intra-individual variability. Peak plasma concentrations occur within 4-6 hours of oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 94%, highly bound to plasma proteins •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Extensively metabolized in the liver. Less than 1% of the orally administered dose appears unchanged in the urine. Metabolites include oxidized and hydroxylated derivates, as well as glucuronic acid conjugates. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Metabolites and conjugates are eliminated primarily by the kidneys (60-70%) and also in the feces (10-20%). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 10.4 hours. Duration of action is 10-24 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 =3000 mg/kg (orally in mice). Gliclazide and its metabolites may accumulate in those with severe hepatic and/or renal dysfunction. Symptoms of hypoglycemia include: dizziness, lack of energy, drowsiness, headache and sweating. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Diamicron •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Gliclazida Gliclazide Gliclazidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Gliclazide is a sulfonylurea used to treat hyperglycemia in patients with type 2 diabetes mellitus. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Glimepiride interact?

•Drug A: Abatacept •Drug B: Glimepiride •Severity: MODERATE •Description: The metabolism of Glimepiride can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Glimepiride is indicated for the management of type 2 diabetes in adults as an adjunct to diet and exercise to improve glycemic control as monotherapy. It may also be indicated for use in combination with metformin or insulin to lower blood glucose in patients with type 2 diabetes whose high blood sugar levels cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic (a drug used to lower blood sugar levels) agent alone. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Glimepiride stimulates the secretion of insulin granules from the pancreatic beta cells and improves the sensitivity of peripheral tissues to insulin to increase peripheral glucose uptake, thus reducing plasma blood glucose levels and glycated hemoglobin (HbA1C) levels. A multi-center, randomized, placebo-controlled clinical trial evaluated the efficacy of glimepiride (1–8 mg) as monotherapy titrated over 10 weeks compared with placebo in T2DM subjects who were not controlled by diet alone. In this study, there was a reduction in fasting plasma glucose (FPG) by 46 mg/dL, post-prandial glucose (PPG) by 72 mg/dL, and HbA1c by 1.4% more than the placebo. In another randomized study comprising of patients with T2DM receiving either placebo or one of the three doses (1, 4, or 8 mg) of glimepiride during a 14-week study period, all glimepiride regimens significantly reduced FPG, PPG, and HbA1c values (P < 0.001) compared to placebo by the end of the study period. The 4- and 8-mg doses of glimepiride were more effective than the 1-mg dose; however, the 4-mg dose provided a nearly maximal antihyperglycemic effect. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): ATP-sensitive potassium channels on pancreatic beta cells that are gated by intracellular ATP and ADP. The hetero-octomeric complex of the channel is composed of four pore-forming Kir6.2 subunits and four regulatory sulfonylurea receptor (SUR) subunits. Alternative splicing allows the formation of channels composed of varying subunit isoforms expressed at different concentrations in different tissues. In pancreatic beta cells, ATP-sensitive potassium channels play a role as essential metabolic sensors and regulators that couple membrane excitability with glucose-stimulated insulin secretion (GSIS). When there is a decrease in the ATP:ADP ratio, the channels are activated and open, leading to K+ efflux from the cell, membrane hyperpolarization, and suppression of insulin secretion. In contrast, increased uptake of glucose into the cell leads to elevated intracellular ATP:ADP ratio, leading to the closure of channels and membrane depolarization. Depolarization leads to activation and opening of the voltage-dependent Ca2+ channels and consequently an influx of calcium ions into the cell. Elevated intracellular calcium levels causes the contraction of the filaments of actomyosin responsible for the exocytosis of insulin granules stored in vesicles. Glimepiride blocks the ATP-sensitive potassium channel by binding non-specifically to the B sites of both sulfonylurea receptor-1 (SUR1) and sulfonylurea receptor-2A (SUR2A) subunits as well as the A site of SUR1 subunit of the channel to promote insulin secretion from the beta cell. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Glimepiride is completely absorbed after oral administration within 1 hour of administration with a linear pharmacokinetics profile. Following administration of a single oral dose of glimepiride in healthy subjects and with multiple oral doses with type 2 diabetes, the peak plasma concentrations (Cmax) were reached after 2 to 3 hours post-dose. Accumulation does not occur after multiple doses. When glimepiride was given with meals, the time to reach Cmax was increased by 12% while the mean and AUC (area under the curve) were decreased by 8 to 9%, respectively. In a pharmacokinetic study of Japanese patients with T2DM, Cmax value in once-daily dose was higher than those in twice-daily doses. The absolute bioavailability of glimepiride is reported to be complete following oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Following intravenous dosing in healthy subjects, the volume of distribution was 8.8 L (113 mL/kg). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of glimepiride is greater than 99.5%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Glimepiride is reported to undergo hepatic metabolism. Following either an intravenous or oral dose, glimepiride undergoes oxidative biotransformation mediated by CYP2C9 enzyme to form a major metabolite, cyclohexyl hydroxymethyl derivative (M1), that is pharmacologically active. M1 can be further metabolized to the inactive metabolite carboxyl derivative (M2) by one or several cytosolic enzymes. M1 retained approximately one third of the pharmacologic activity of its parent in an animal model, with a half-life of 3-6 hours. However, whether the glucose-lowering effect of M1 is clinically significant is not clear. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration of glimepiride in healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days, with M1 and M2 accounting for 80-90% of the total radioactivity recovered in the urine. The ratio of M1 to M2 was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces where M1 and M2 accounted for about 70% of the radioactivity and a ratio of M1 to M2 being 1:3. No parent drug was recovered from urine or feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of glimepiride is approximately 5 to 8 hours, which can increase up to 9 hours following multiple doses. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): A single-dose, crossover, dose-proportionality (1, 2, 4, and 8 mg) study in normal subjects and from a single- and multiple-dose, parallel, dose proportionality (4 and 8 mg) study in patients with type 2 diabetes (T2D) were performed. In these studies, the total body clearance was 52.1 +/- 16.0 mL/min, 48.5 +/- 29.3 mL/min in patients with T2D given a single oral dose, and 52.7 +/- 40.3 mL/min in patients with T2D given multiple oral doses. Following intravenous dosing in healthy subjects, the total body clearance was 47.8 mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD50 value in rats is > 10000 mg/kg. The intraperitoneal LD50 value in rats is reported to be 3950 mg/kg. Although glimepiride is reported to have fewer risks of hypoglycemia compared to other sulfonylureas such as glyburide, overdosage of glimepiride may result in severe hypoglycemia with coma, seizure, or other neurological impairment may occur. This can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary since hypoglycemia may recur after apparent clinical recovery. In a study of rats given doses of up to 5000 parts per million (ppm) in complete feed for 30 months, there were no signs of carcinogenesis. Meanwhile, the administration of glimepiride at a dose much higher than the maximum human recommended dose for 24 months in mice resulted in an increase in benign pancreatic adenoma formation in a dose-related manner, which was thought to be the result of chronic pancreatic stimulation. Glimepiride was non-mutagenic in in vitro and in vivo mutagenicity studies. In male and female rat studies, glimepiride was shown to have no effects on fertility. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Duetact, Tandemact •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Glimepiride is a sulfonylurea drug used to treat type 2 diabetes mellitus.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Glimepiride interact? Information: •Drug A: Abatacept •Drug B: Glimepiride •Severity: MODERATE •Description: The metabolism of Glimepiride can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Glimepiride is indicated for the management of type 2 diabetes in adults as an adjunct to diet and exercise to improve glycemic control as monotherapy. It may also be indicated for use in combination with metformin or insulin to lower blood glucose in patients with type 2 diabetes whose high blood sugar levels cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic (a drug used to lower blood sugar levels) agent alone. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Glimepiride stimulates the secretion of insulin granules from the pancreatic beta cells and improves the sensitivity of peripheral tissues to insulin to increase peripheral glucose uptake, thus reducing plasma blood glucose levels and glycated hemoglobin (HbA1C) levels. A multi-center, randomized, placebo-controlled clinical trial evaluated the efficacy of glimepiride (1–8 mg) as monotherapy titrated over 10 weeks compared with placebo in T2DM subjects who were not controlled by diet alone. In this study, there was a reduction in fasting plasma glucose (FPG) by 46 mg/dL, post-prandial glucose (PPG) by 72 mg/dL, and HbA1c by 1.4% more than the placebo. In another randomized study comprising of patients with T2DM receiving either placebo or one of the three doses (1, 4, or 8 mg) of glimepiride during a 14-week study period, all glimepiride regimens significantly reduced FPG, PPG, and HbA1c values (P < 0.001) compared to placebo by the end of the study period. The 4- and 8-mg doses of glimepiride were more effective than the 1-mg dose; however, the 4-mg dose provided a nearly maximal antihyperglycemic effect. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): ATP-sensitive potassium channels on pancreatic beta cells that are gated by intracellular ATP and ADP. The hetero-octomeric complex of the channel is composed of four pore-forming Kir6.2 subunits and four regulatory sulfonylurea receptor (SUR) subunits. Alternative splicing allows the formation of channels composed of varying subunit isoforms expressed at different concentrations in different tissues. In pancreatic beta cells, ATP-sensitive potassium channels play a role as essential metabolic sensors and regulators that couple membrane excitability with glucose-stimulated insulin secretion (GSIS). When there is a decrease in the ATP:ADP ratio, the channels are activated and open, leading to K+ efflux from the cell, membrane hyperpolarization, and suppression of insulin secretion. In contrast, increased uptake of glucose into the cell leads to elevated intracellular ATP:ADP ratio, leading to the closure of channels and membrane depolarization. Depolarization leads to activation and opening of the voltage-dependent Ca2+ channels and consequently an influx of calcium ions into the cell. Elevated intracellular calcium levels causes the contraction of the filaments of actomyosin responsible for the exocytosis of insulin granules stored in vesicles. Glimepiride blocks the ATP-sensitive potassium channel by binding non-specifically to the B sites of both sulfonylurea receptor-1 (SUR1) and sulfonylurea receptor-2A (SUR2A) subunits as well as the A site of SUR1 subunit of the channel to promote insulin secretion from the beta cell. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Glimepiride is completely absorbed after oral administration within 1 hour of administration with a linear pharmacokinetics profile. Following administration of a single oral dose of glimepiride in healthy subjects and with multiple oral doses with type 2 diabetes, the peak plasma concentrations (Cmax) were reached after 2 to 3 hours post-dose. Accumulation does not occur after multiple doses. When glimepiride was given with meals, the time to reach Cmax was increased by 12% while the mean and AUC (area under the curve) were decreased by 8 to 9%, respectively. In a pharmacokinetic study of Japanese patients with T2DM, Cmax value in once-daily dose was higher than those in twice-daily doses. The absolute bioavailability of glimepiride is reported to be complete following oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Following intravenous dosing in healthy subjects, the volume of distribution was 8.8 L (113 mL/kg). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of glimepiride is greater than 99.5%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Glimepiride is reported to undergo hepatic metabolism. Following either an intravenous or oral dose, glimepiride undergoes oxidative biotransformation mediated by CYP2C9 enzyme to form a major metabolite, cyclohexyl hydroxymethyl derivative (M1), that is pharmacologically active. M1 can be further metabolized to the inactive metabolite carboxyl derivative (M2) by one or several cytosolic enzymes. M1 retained approximately one third of the pharmacologic activity of its parent in an animal model, with a half-life of 3-6 hours. However, whether the glucose-lowering effect of M1 is clinically significant is not clear. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration of glimepiride in healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days, with M1 and M2 accounting for 80-90% of the total radioactivity recovered in the urine. The ratio of M1 to M2 was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces where M1 and M2 accounted for about 70% of the radioactivity and a ratio of M1 to M2 being 1:3. No parent drug was recovered from urine or feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of glimepiride is approximately 5 to 8 hours, which can increase up to 9 hours following multiple doses. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): A single-dose, crossover, dose-proportionality (1, 2, 4, and 8 mg) study in normal subjects and from a single- and multiple-dose, parallel, dose proportionality (4 and 8 mg) study in patients with type 2 diabetes (T2D) were performed. In these studies, the total body clearance was 52.1 +/- 16.0 mL/min, 48.5 +/- 29.3 mL/min in patients with T2D given a single oral dose, and 52.7 +/- 40.3 mL/min in patients with T2D given multiple oral doses. Following intravenous dosing in healthy subjects, the total body clearance was 47.8 mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD50 value in rats is > 10000 mg/kg. The intraperitoneal LD50 value in rats is reported to be 3950 mg/kg. Although glimepiride is reported to have fewer risks of hypoglycemia compared to other sulfonylureas such as glyburide, overdosage of glimepiride may result in severe hypoglycemia with coma, seizure, or other neurological impairment may occur. This can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary since hypoglycemia may recur after apparent clinical recovery. In a study of rats given doses of up to 5000 parts per million (ppm) in complete feed for 30 months, there were no signs of carcinogenesis. Meanwhile, the administration of glimepiride at a dose much higher than the maximum human recommended dose for 24 months in mice resulted in an increase in benign pancreatic adenoma formation in a dose-related manner, which was thought to be the result of chronic pancreatic stimulation. Glimepiride was non-mutagenic in in vitro and in vivo mutagenicity studies. In male and female rat studies, glimepiride was shown to have no effects on fertility. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Duetact, Tandemact •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Glimepiride is a sulfonylurea drug used to treat type 2 diabetes mellitus. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Glipizide interact?

•Drug A: Abatacept •Drug B: Glipizide •Severity: MODERATE •Description: The metabolism of Glipizide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Glipizide is a blood glucose-lowering agent. The initial onset of blood glucose-lowering effect occurs around 30 minutes post-administration with the duration of action lasting for about 12 to 24 hours. While the chronic use of glipizide does not result in elevations in the fasting insulin levels over time, the postprandial insulin response, or insulin response to a meal, is observed to be enhanced, even after 6 months of treatment. The main therapeutic actions of glipizide primarily occur at the pancreas where the insulin release is stimulated, but glipizide also mediates some extrapancreatic effects, such as the promotion of insulin signaling effects on the muscles, fat, or liver cells. Due to its action on the endogenous cells, sulfonylureas including glipizide is associated with a risk for developing hypoglycemia and weight gain in patients receiving the drug. Chronic administration of glipizide may result in down-regulation of the sulfonylurea receptors on pancreatic beta cells, which are molecular targets of the drug, leading to a reduced effect on insulin secretion. Like other sulfonylureas, glipizide may work on pancreatic delta (δ) cells and alpha (α) cells to stimulate the secretion of somatostatin and suppress the secretion of glucagon, which are peptide hormones that regulate neuroendocrine and metabolic pathways. Other than its primary action on the pancreas, glipizide also exerts other biological actions outside of the pancreas, or "extrapancreatic effects", which is similar to other members of the sulfonylurea drug class. Glipizide may enhance the glucose uptake into the skeletal muscles and potentiate the action of insulin in the liver. Other effects include inhibited lipolysis in the liver and adipose tissue, inhibited hepatic glucose output, and increased uptake and oxidation of glucose. It has also been demonstrated by several studies that the chronic therapeutic use of sulfonylureas may result in an increase in insulin receptors expressed on monocytes, adipocytes, and erythrocytes. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with increasing prevalence worldwide. Characterized by higher-than-normal levels of blood glucose, T2DM is a complex disorder that arises from the interaction between genetic, environmental and behavioral risk factors. Insulin is a peptide hormone that plays a critical role in regulating blood glucose levels. In response to high blood glucose levels, insulin promotes the uptake of glucose into the liver, muscle cells, and fat cells for storage. Although there are multiple events occurring that lead to the pathophysiology of T2DM, the disorder mainly involves insulin insensitivity as a result of insulin resistance, declining insulin production, and eventual failure of beta cells of pancreatic islets that normally produce insulin. Early management with lifestyle intervention, such as controlled diet and exercise, is critical in reducing the risk of long-term secondary complications, such as cardiovascular mortality. Glipizide, like other sulfonylurea drugs, is an insulin secretagogue, which works by stimulating the insulin release from the pancreatic beta cells thereby increasing the plasma concentrations of insulin. Thus, the main therapeutic action of the drug depends on the functional beta cells in the pancreatic islets. Sulfonylureas bind to the sulfonylurea receptor expressed on the pancreatic beta-cell plasma membrane, leading to the closure of the ATP-sensitive potassium channel and reduced potassium conductance. This results in depolarization of the pancreatic beta cell and opening of the voltage-sensitive calcium channels, promoting calcium ion influx. Increased intracellular concentrations of calcium ions in beta cells stimulates the secretion, or exocytosis, of insulin granules from the cells. Apart from this main mechanism of action, the blood-glucose-lowering effect of glipizide involves increased peripheral glucose utilization via stimulating hepatic gluconeogenesis and by increasing the number and sensitivity of insulin receptors. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Gastrointestinal absorption of glipizide is uniform, rapid, and essentially complete. The absolute bioavailability of glipizide in patients with type 2 diabetes receiving a single oral dose was 100%. The maximum plasma concentrations are expected to be reached within 6 to 12 hours following initial dosing. The steady-state plasma concentrations of glipizide from extended-release oral formulations are maintained over the 24-hour dosing interval. In healthy volunteers, the absorption of glipizide was delayed by the presence of food but the total absorption was unaffected. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean volume of distribution was approximately 10 L following administration of single intravenous doses in patients with type 2 diabetes mellitus. In mice and rat studies, the presence of the drug and its metabolites was none to minimal in the fetus of pregnant female animals. Other sulfonylurea drugs were shown to cross the placenta and enter breast milk thus the potential risk of glipizide in fetus or infants cannot be excluded. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Glipizide is about 98-99% bound to serum proteins, with albumin being the main plasma protein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Glipizide is subject to hepatic metabolism, in which its major metabolites are formed from aromatic hydroxylation. These major metabolites are glipizide are reported to be pharmacologically inactive. In contrast, an acetylaminoethyl benzine derivative is formed as a minor metabolite which accounts for less than 2% of the initial dose and is reported to have one-tenth to one-third as much hypoglycemic activity as the parent compound. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Glipizide is mainly eliminated by hepatic biotransformation, where less than 10% of the initial dose of the drug can be detected in the urine and feces as unchanged glipizide. About 80% of the metabolites of glipizide is excreted in the urine while 10% is excreted in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes mellitus. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean total body clearance of glipizide was approximately 3 L/hr following administration of single intravenous doses in patients with type 2 diabetes mellitus. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In rats, the oral LD 50 is reported to be greater than 4000 mg/kg and the intraperitoneal LD 50 is 1200 mg/kg. The lowest published toxic dose (TDLo) via oral route in child was 379 μg/kg. Symptoms of overdose in sulfonylureas, including glipizide, may be related to severe hypoglycemia and may include coma, seizure, or other neurological impairment. These are symptoms of severe hypoglycemia and require immediate treatment with glucagon or intravenous glucose and close monitoring for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated with oral glucose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Glucotrol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Glipizida Glipizide Glipizidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Glipizide is a sulfonylurea medication used in Type 2 Diabetes to sensitize pancreatic beta cells and stimulate insulin release.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Glipizide interact? Information: •Drug A: Abatacept •Drug B: Glipizide •Severity: MODERATE •Description: The metabolism of Glipizide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Glipizide is a blood glucose-lowering agent. The initial onset of blood glucose-lowering effect occurs around 30 minutes post-administration with the duration of action lasting for about 12 to 24 hours. While the chronic use of glipizide does not result in elevations in the fasting insulin levels over time, the postprandial insulin response, or insulin response to a meal, is observed to be enhanced, even after 6 months of treatment. The main therapeutic actions of glipizide primarily occur at the pancreas where the insulin release is stimulated, but glipizide also mediates some extrapancreatic effects, such as the promotion of insulin signaling effects on the muscles, fat, or liver cells. Due to its action on the endogenous cells, sulfonylureas including glipizide is associated with a risk for developing hypoglycemia and weight gain in patients receiving the drug. Chronic administration of glipizide may result in down-regulation of the sulfonylurea receptors on pancreatic beta cells, which are molecular targets of the drug, leading to a reduced effect on insulin secretion. Like other sulfonylureas, glipizide may work on pancreatic delta (δ) cells and alpha (α) cells to stimulate the secretion of somatostatin and suppress the secretion of glucagon, which are peptide hormones that regulate neuroendocrine and metabolic pathways. Other than its primary action on the pancreas, glipizide also exerts other biological actions outside of the pancreas, or "extrapancreatic effects", which is similar to other members of the sulfonylurea drug class. Glipizide may enhance the glucose uptake into the skeletal muscles and potentiate the action of insulin in the liver. Other effects include inhibited lipolysis in the liver and adipose tissue, inhibited hepatic glucose output, and increased uptake and oxidation of glucose. It has also been demonstrated by several studies that the chronic therapeutic use of sulfonylureas may result in an increase in insulin receptors expressed on monocytes, adipocytes, and erythrocytes. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with increasing prevalence worldwide. Characterized by higher-than-normal levels of blood glucose, T2DM is a complex disorder that arises from the interaction between genetic, environmental and behavioral risk factors. Insulin is a peptide hormone that plays a critical role in regulating blood glucose levels. In response to high blood glucose levels, insulin promotes the uptake of glucose into the liver, muscle cells, and fat cells for storage. Although there are multiple events occurring that lead to the pathophysiology of T2DM, the disorder mainly involves insulin insensitivity as a result of insulin resistance, declining insulin production, and eventual failure of beta cells of pancreatic islets that normally produce insulin. Early management with lifestyle intervention, such as controlled diet and exercise, is critical in reducing the risk of long-term secondary complications, such as cardiovascular mortality. Glipizide, like other sulfonylurea drugs, is an insulin secretagogue, which works by stimulating the insulin release from the pancreatic beta cells thereby increasing the plasma concentrations of insulin. Thus, the main therapeutic action of the drug depends on the functional beta cells in the pancreatic islets. Sulfonylureas bind to the sulfonylurea receptor expressed on the pancreatic beta-cell plasma membrane, leading to the closure of the ATP-sensitive potassium channel and reduced potassium conductance. This results in depolarization of the pancreatic beta cell and opening of the voltage-sensitive calcium channels, promoting calcium ion influx. Increased intracellular concentrations of calcium ions in beta cells stimulates the secretion, or exocytosis, of insulin granules from the cells. Apart from this main mechanism of action, the blood-glucose-lowering effect of glipizide involves increased peripheral glucose utilization via stimulating hepatic gluconeogenesis and by increasing the number and sensitivity of insulin receptors. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Gastrointestinal absorption of glipizide is uniform, rapid, and essentially complete. The absolute bioavailability of glipizide in patients with type 2 diabetes receiving a single oral dose was 100%. The maximum plasma concentrations are expected to be reached within 6 to 12 hours following initial dosing. The steady-state plasma concentrations of glipizide from extended-release oral formulations are maintained over the 24-hour dosing interval. In healthy volunteers, the absorption of glipizide was delayed by the presence of food but the total absorption was unaffected. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean volume of distribution was approximately 10 L following administration of single intravenous doses in patients with type 2 diabetes mellitus. In mice and rat studies, the presence of the drug and its metabolites was none to minimal in the fetus of pregnant female animals. Other sulfonylurea drugs were shown to cross the placenta and enter breast milk thus the potential risk of glipizide in fetus or infants cannot be excluded. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Glipizide is about 98-99% bound to serum proteins, with albumin being the main plasma protein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Glipizide is subject to hepatic metabolism, in which its major metabolites are formed from aromatic hydroxylation. These major metabolites are glipizide are reported to be pharmacologically inactive. In contrast, an acetylaminoethyl benzine derivative is formed as a minor metabolite which accounts for less than 2% of the initial dose and is reported to have one-tenth to one-third as much hypoglycemic activity as the parent compound. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Glipizide is mainly eliminated by hepatic biotransformation, where less than 10% of the initial dose of the drug can be detected in the urine and feces as unchanged glipizide. About 80% of the metabolites of glipizide is excreted in the urine while 10% is excreted in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes mellitus. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean total body clearance of glipizide was approximately 3 L/hr following administration of single intravenous doses in patients with type 2 diabetes mellitus. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In rats, the oral LD 50 is reported to be greater than 4000 mg/kg and the intraperitoneal LD 50 is 1200 mg/kg. The lowest published toxic dose (TDLo) via oral route in child was 379 μg/kg. Symptoms of overdose in sulfonylureas, including glipizide, may be related to severe hypoglycemia and may include coma, seizure, or other neurological impairment. These are symptoms of severe hypoglycemia and require immediate treatment with glucagon or intravenous glucose and close monitoring for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated with oral glucose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Glucotrol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Glipizida Glipizide Glipizidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Glipizide is a sulfonylurea medication used in Type 2 Diabetes to sensitize pancreatic beta cells and stimulate insulin release. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Gliquidone interact?

•Drug A: Abatacept •Drug B: Gliquidone •Severity: MODERATE •Description: The metabolism of Gliquidone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used in the treatment of diabetes mellitus type 2. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Gliquidone is an anti-diabetic drug in the sulfonylurea class. In patients with diabetes mellitus, there is a deficiency or absence of a hormone manufactured by the pancreas called insulin. Insulin is the main hormone responsible for the control of sugar in the blood. Gliquidone is an antidiabetic medication which is used in those patients with adult maturity onset or non-insulin dependent diabetes (NIDDM). It works by lowering blood sugar levels by stimulating the production and release of insulin from the pancreas. It also promotes the movement of sugar from the blood into the cells in the body which need it. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism of action of gliquidone in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells, and increasing sensitivity of peripheral tissues to insulin. Gliquidone likely binds to ATP-sensitive potassium channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Membrane depolarization stimulates calcium ion influx through voltage-sensitive calcium channels. This increase in intracellular calcium ion concentration induces the secretion of insulin. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean terminal half-life was approximately 8 hours (range 5.7-9.4 hours) •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Gliquidone is a sulfonylurea drug used in the management of diabetes mellitus type 2.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Gliquidone interact? Information: •Drug A: Abatacept •Drug B: Gliquidone •Severity: MODERATE •Description: The metabolism of Gliquidone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used in the treatment of diabetes mellitus type 2. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Gliquidone is an anti-diabetic drug in the sulfonylurea class. In patients with diabetes mellitus, there is a deficiency or absence of a hormone manufactured by the pancreas called insulin. Insulin is the main hormone responsible for the control of sugar in the blood. Gliquidone is an antidiabetic medication which is used in those patients with adult maturity onset or non-insulin dependent diabetes (NIDDM). It works by lowering blood sugar levels by stimulating the production and release of insulin from the pancreas. It also promotes the movement of sugar from the blood into the cells in the body which need it. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism of action of gliquidone in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells, and increasing sensitivity of peripheral tissues to insulin. Gliquidone likely binds to ATP-sensitive potassium channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Membrane depolarization stimulates calcium ion influx through voltage-sensitive calcium channels. This increase in intracellular calcium ion concentration induces the secretion of insulin. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The mean terminal half-life was approximately 8 hours (range 5.7-9.4 hours) •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Gliquidone is a sulfonylurea drug used in the management of diabetes mellitus type 2. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Glyburide interact?

•Drug A: Abatacept •Drug B: Glyburide •Severity: MODERATE •Description: The metabolism of Glyburide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Glyburide is indicated alone or as part of combination product with metformin, as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Glyburide is a second generation sulfonylurea that stimulates insulin secretion through the closure of ATP-sensitive potassium channels on beta cells, raising intracellular potassium and calcium ion concentrations. Glibenclamide has a long duration of action as it is given once daily, and a wide therapeutic index as patients are started at doses as low as 0.75mg but that can increase as high as 10mg or more. Patients taking glyburide should be cautioned regarding an increased risk of cardiovascular mortality as seen with tolbutamide, another sulfonylurea. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Glyburide belongs to a class of drugs known as sulfonylureas. These drugs act by closing ATP-sensitive potassium channels on pancreatic beta cells. The ATP-sensitive potassium channels on beta cells are known as sulfonylurea receptor 1 (SUR1). Under low glucose concentrations, SUR1 remains open, allowing for potassium ion efflux to create a -70mV membrane potential. Normally SUR1 closes in response to high glucose concentrations, the membrane potential of the cells becomes less negative, the cell depolarizes, voltage gated calcium channels open, calcium ions enter the cell, and the increased intracellular calcium concentration stimulates the release of insulin containing granules. Glyburide bypasses this process by forcing SUR1 closed and stimulating increased insulin secretion. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Elderly patients taking glyburide reached a C max of 211-315ng/mL with a T max of 0.9-1.0h, while younger patients reached a C max of 144-302ng/mL with a T max of 1.3-3.0h. Patients taking glyburide have and AUC of 348ng*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Elderly patients have a volume of distribution of 19.3-52.6L, while younger patients have a volume of distribution of 21.5-49.3L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Glyburide is 99.9% bound to protein in plasma with >98% accounted for by binding to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Glyburide is metabolized mainly by CYP3A4, followed by CYP2C9, CYP2C19, CYP3A7, and CYP3A5. These enzymes metabolize glyburide to 4-trans-hydroxycyclohexyl glyburide (M1), 4-cis-hydroxycyclohexyl glyburide (M2a), 3-cis-hydroxycyclohexyl glyburide (M2b), 3-trans-hydroxycyclohexyl glyburide (M3), 2-trans-hydroxycyclohexyl glyburide (M4), and ethylhydroxycyclohexyl glyburide (M5). The M1 and M2b metabolites are considered active, along with the parent molecule. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Unlike other sulfonylureas, glyburide is 50% excreted in the urine and 50% in the feces. Glyburide is mainly excreted as the metabolite 4-trans-hydroxyglyburide. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Elderly patients have a terminal elimination half life of 4.0-13.4h, while younger patients have a terminal elimination half life of 4.0-13.9h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Elderly patients have a clearance of 2.70-3.55L/h, while younger patients have a clearance of 2.47-4.11L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in rats is >3200mg/kg, in mice is >1500mg/kg, in rabbits is >10,000mg/kg, and in guinea pigs is >1500mg/kg. Patients experiencing an overdose may present with hypoglycemia. Mild hypoglycemia should be treated with oral glucose and adjustments to drug doses or meal schedules. Severe hypoglycemia may present with coma, seizure, and neurological impairment. This should be treated immediately in hospital with intravenous glucose and monitoring for 24-48 hours. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Diabeta, Glucovance, Glynase •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Glibenclamida Glibenclamide Glibenclamidum Glyburide •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Glyburide is a sulfonylurea used in the treatment of non insulin dependent diabetes mellitus.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Glyburide interact? Information: •Drug A: Abatacept •Drug B: Glyburide •Severity: MODERATE •Description: The metabolism of Glyburide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Glyburide is indicated alone or as part of combination product with metformin, as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Glyburide is a second generation sulfonylurea that stimulates insulin secretion through the closure of ATP-sensitive potassium channels on beta cells, raising intracellular potassium and calcium ion concentrations. Glibenclamide has a long duration of action as it is given once daily, and a wide therapeutic index as patients are started at doses as low as 0.75mg but that can increase as high as 10mg or more. Patients taking glyburide should be cautioned regarding an increased risk of cardiovascular mortality as seen with tolbutamide, another sulfonylurea. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Glyburide belongs to a class of drugs known as sulfonylureas. These drugs act by closing ATP-sensitive potassium channels on pancreatic beta cells. The ATP-sensitive potassium channels on beta cells are known as sulfonylurea receptor 1 (SUR1). Under low glucose concentrations, SUR1 remains open, allowing for potassium ion efflux to create a -70mV membrane potential. Normally SUR1 closes in response to high glucose concentrations, the membrane potential of the cells becomes less negative, the cell depolarizes, voltage gated calcium channels open, calcium ions enter the cell, and the increased intracellular calcium concentration stimulates the release of insulin containing granules. Glyburide bypasses this process by forcing SUR1 closed and stimulating increased insulin secretion. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Elderly patients taking glyburide reached a C max of 211-315ng/mL with a T max of 0.9-1.0h, while younger patients reached a C max of 144-302ng/mL with a T max of 1.3-3.0h. Patients taking glyburide have and AUC of 348ng*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Elderly patients have a volume of distribution of 19.3-52.6L, while younger patients have a volume of distribution of 21.5-49.3L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Glyburide is 99.9% bound to protein in plasma with >98% accounted for by binding to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Glyburide is metabolized mainly by CYP3A4, followed by CYP2C9, CYP2C19, CYP3A7, and CYP3A5. These enzymes metabolize glyburide to 4-trans-hydroxycyclohexyl glyburide (M1), 4-cis-hydroxycyclohexyl glyburide (M2a), 3-cis-hydroxycyclohexyl glyburide (M2b), 3-trans-hydroxycyclohexyl glyburide (M3), 2-trans-hydroxycyclohexyl glyburide (M4), and ethylhydroxycyclohexyl glyburide (M5). The M1 and M2b metabolites are considered active, along with the parent molecule. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Unlike other sulfonylureas, glyburide is 50% excreted in the urine and 50% in the feces. Glyburide is mainly excreted as the metabolite 4-trans-hydroxyglyburide. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Elderly patients have a terminal elimination half life of 4.0-13.4h, while younger patients have a terminal elimination half life of 4.0-13.9h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Elderly patients have a clearance of 2.70-3.55L/h, while younger patients have a clearance of 2.47-4.11L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in rats is >3200mg/kg, in mice is >1500mg/kg, in rabbits is >10,000mg/kg, and in guinea pigs is >1500mg/kg. Patients experiencing an overdose may present with hypoglycemia. Mild hypoglycemia should be treated with oral glucose and adjustments to drug doses or meal schedules. Severe hypoglycemia may present with coma, seizure, and neurological impairment. This should be treated immediately in hospital with intravenous glucose and monitoring for 24-48 hours. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Diabeta, Glucovance, Glynase •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Glibenclamida Glibenclamide Glibenclamidum Glyburide •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Glyburide is a sulfonylurea used in the treatment of non insulin dependent diabetes mellitus. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Golimumab interact?

•Drug A: Abatacept •Drug B: Golimumab •Severity: MAJOR •Description: The risk or severity of infection can be increased when Golimumab is combined with Abatacept. •Extended Description: Concomitant use of abatacept and TNF-α inhibitors, which are both immunosuppressive agents, increases the risk of serious infection with no therapeutic benefit. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used in adults (i) as an adjunct to methotrexate treatment in patients with moderate to severe active rheumatoid arthritis (RA), (ii) in patients 2 years old and above with active psoriatic arthritis (PsA), (iii) as a single agent in patients with active ankylosing spondylitis (AS) or in combination with methotrexate, and (iv) as a single agent in patients with moderate to severe ulcerative colitis (UC) who require chronic steroids or have experienced intolerance or only a partial response to previous medications. It is also indicated (v) for the treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years of age and older. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Golimumab inhibits the activity of the cytokine, tumor necrosis factor alpha (TNFα). In areas such as the joints and blood, increased TNFα is associated with chronic inflammation seen in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Thus golimumab decreases the inflammation in these conditions. Concerning ulcerative colitis, the physiological effects of golimumab has yet to be determined. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): As a human monoclonal antibody, golimumab binds and inhibits soluble and transmembrane human TNFα. Inhibition of TNFα prevents it binding to its receptors, which prevents both leukocyte infiltration through prevention of cell adhesion proteins such as E-selectin, ICAM-1 and VCAM-1, and pro-inflammatory cytokine secretion such as IL-6, IL-8, G-CSF and GM-CSF in vitro. Consequently, in patients with chronic inflammatory conditions, decreases in ICAM-1 and IL-6 as well as C-reactive protein (CRP), matrix metalloproteinase 3 (MMP-3), and vascular endothelial growth factor (VEGF) were observed. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): After subcutaneous administration, golimumab can achieve maximum serum concentrations in 2 to 6 days and has an approximate bioavailability of 53%. In healthy volunteers, the maximum average concentration reached was 3.2 ± 1.4 μg/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): After IV administration, golimumab has a volume of distribution of about 58 to 126 mL/kg. This means that golimumab stays mostly in the circulatory system. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding was not quantified. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of golimumab has yet to be determined. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The route of elimination for golimumab has yet to be determined. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Golimumab has a long half-life of about 2 weeks. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): After one IV dose of golimumab, the systemic clearance was about 4.9 to 6.7 mL/day/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The FDA label includes a black box warning of serious infections and malignancy. Specifically there have been hospitalizations or death from infections such as bacterial sepsis, tuberculosis (TB), and invasive fungal (histoplasmosis) and other opportunistic infections. Additionally in children and adolescents taking golimumab, there have been lymphoma and other malignancies observed. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Simponi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Golimumab is a TNFα inhibitor used in the symptomatic treatment of various active inflammatory disorders, such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis.

Concomitant use of abatacept and TNF-α inhibitors, which are both immunosuppressive agents, increases the risk of serious infection with no therapeutic benefit. The severity of the interaction is major.

Question: Does Abatacept and Golimumab interact? Information: •Drug A: Abatacept •Drug B: Golimumab •Severity: MAJOR •Description: The risk or severity of infection can be increased when Golimumab is combined with Abatacept. •Extended Description: Concomitant use of abatacept and TNF-α inhibitors, which are both immunosuppressive agents, increases the risk of serious infection with no therapeutic benefit. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used in adults (i) as an adjunct to methotrexate treatment in patients with moderate to severe active rheumatoid arthritis (RA), (ii) in patients 2 years old and above with active psoriatic arthritis (PsA), (iii) as a single agent in patients with active ankylosing spondylitis (AS) or in combination with methotrexate, and (iv) as a single agent in patients with moderate to severe ulcerative colitis (UC) who require chronic steroids or have experienced intolerance or only a partial response to previous medications. It is also indicated (v) for the treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years of age and older. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Golimumab inhibits the activity of the cytokine, tumor necrosis factor alpha (TNFα). In areas such as the joints and blood, increased TNFα is associated with chronic inflammation seen in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Thus golimumab decreases the inflammation in these conditions. Concerning ulcerative colitis, the physiological effects of golimumab has yet to be determined. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): As a human monoclonal antibody, golimumab binds and inhibits soluble and transmembrane human TNFα. Inhibition of TNFα prevents it binding to its receptors, which prevents both leukocyte infiltration through prevention of cell adhesion proteins such as E-selectin, ICAM-1 and VCAM-1, and pro-inflammatory cytokine secretion such as IL-6, IL-8, G-CSF and GM-CSF in vitro. Consequently, in patients with chronic inflammatory conditions, decreases in ICAM-1 and IL-6 as well as C-reactive protein (CRP), matrix metalloproteinase 3 (MMP-3), and vascular endothelial growth factor (VEGF) were observed. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): After subcutaneous administration, golimumab can achieve maximum serum concentrations in 2 to 6 days and has an approximate bioavailability of 53%. In healthy volunteers, the maximum average concentration reached was 3.2 ± 1.4 μg/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): After IV administration, golimumab has a volume of distribution of about 58 to 126 mL/kg. This means that golimumab stays mostly in the circulatory system. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding was not quantified. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of golimumab has yet to be determined. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The route of elimination for golimumab has yet to be determined. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Golimumab has a long half-life of about 2 weeks. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): After one IV dose of golimumab, the systemic clearance was about 4.9 to 6.7 mL/day/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The FDA label includes a black box warning of serious infections and malignancy. Specifically there have been hospitalizations or death from infections such as bacterial sepsis, tuberculosis (TB), and invasive fungal (histoplasmosis) and other opportunistic infections. Additionally in children and adolescents taking golimumab, there have been lymphoma and other malignancies observed. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Simponi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Golimumab is a TNFα inhibitor used in the symptomatic treatment of various active inflammatory disorders, such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis. Output: Concomitant use of abatacept and TNF-α inhibitors, which are both immunosuppressive agents, increases the risk of serious infection with no therapeutic benefit. The severity of the interaction is major.

Does Abatacept and Guselkumab interact?

•Drug A: Abatacept •Drug B: Guselkumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Guselkumab. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Guselkumab is shown to reduce serum levels of IL-17A, IL-17F and IL-22. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Guselkumab targets the p19 alpha subunit of IL-23. While IL-23 promotes the normal inflammatory and immune responses, the p19 and p40 subunits of IL-23 are found to be over-expressed in the condition of psoriasis and other autoimmune inflammatory skin diseases. Guselkumab selectively binds to the p19 subunit of IL-23 in dendritic cells and keratinocytes and blocks its interaction with IL-23 receptor, which further prevents the release of other pro-inflammatory cytokines and chemokines via stimulation of immune cells such as Th17 cells. Thus, guselkumab blocks the abnormally-heightened signalling of inflammatory cascades that promote epidermal abnormalities including keratinocyte hyperproliferation and psoriatic plaque formation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following a 100mg subcutaneous administration, the peak plasma concentration (Cmax) of guselkumab is 8.09 ± 3.68 mcg/mL which is reached after approximately 5.5 days. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution is 13.5 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Like other human IgG monoclonal antibodies, guselkumab is expected to be degraded into small peptides and amino acids via catabolic pathways. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Like other human IgG monoclonal antibodies, guselkumab is expected to be both renally and fecally excreted as smaller peptide units. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Mean half-life of guselkumab is approximately 15 to 18 days in subjects with plaque psoriasis. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Apparent clearance in subjects with plaque psoriasis is 0.516 L/day. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Animal studies to assess the effect of guselkumab on carcinogenesis, mutagenesis and impairment on fertility have not been conducted. When subcutaneously injected into guinea pigs, the doses of guselkumab up to 100mg/kg twice-weekly demonstrated no effects on fertility parameters. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tremfya •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Guselkumab is a monoclonal antibody used to treat moderate to severe plaque psoriasis.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Guselkumab interact? Information: •Drug A: Abatacept •Drug B: Guselkumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Guselkumab. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Guselkumab is shown to reduce serum levels of IL-17A, IL-17F and IL-22. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Guselkumab targets the p19 alpha subunit of IL-23. While IL-23 promotes the normal inflammatory and immune responses, the p19 and p40 subunits of IL-23 are found to be over-expressed in the condition of psoriasis and other autoimmune inflammatory skin diseases. Guselkumab selectively binds to the p19 subunit of IL-23 in dendritic cells and keratinocytes and blocks its interaction with IL-23 receptor, which further prevents the release of other pro-inflammatory cytokines and chemokines via stimulation of immune cells such as Th17 cells. Thus, guselkumab blocks the abnormally-heightened signalling of inflammatory cascades that promote epidermal abnormalities including keratinocyte hyperproliferation and psoriatic plaque formation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following a 100mg subcutaneous administration, the peak plasma concentration (Cmax) of guselkumab is 8.09 ± 3.68 mcg/mL which is reached after approximately 5.5 days. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution is 13.5 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Like other human IgG monoclonal antibodies, guselkumab is expected to be degraded into small peptides and amino acids via catabolic pathways. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Like other human IgG monoclonal antibodies, guselkumab is expected to be both renally and fecally excreted as smaller peptide units. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Mean half-life of guselkumab is approximately 15 to 18 days in subjects with plaque psoriasis. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Apparent clearance in subjects with plaque psoriasis is 0.516 L/day. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Animal studies to assess the effect of guselkumab on carcinogenesis, mutagenesis and impairment on fertility have not been conducted. When subcutaneously injected into guinea pigs, the doses of guselkumab up to 100mg/kg twice-weekly demonstrated no effects on fertility parameters. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tremfya •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Guselkumab is a monoclonal antibody used to treat moderate to severe plaque psoriasis. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Haemophilus influenzae type B strain 20752 capsular polysaccharide tetanus toxoid conjugate antigen interact?

•Drug A: Abatacept •Drug B: Haemophilus influenzae type B strain 20752 capsular polysaccharide tetanus toxoid conjugate antigen •Severity: MODERATE •Description: The therapeutic efficacy of Haemophilus influenzae type B strain 20752 capsular polysaccharide tetanus toxoid conjugate antigen can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found

Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Question: Does Abatacept and Haemophilus influenzae type B strain 20752 capsular polysaccharide tetanus toxoid conjugate antigen interact? Information: •Drug A: Abatacept •Drug B: Haemophilus influenzae type B strain 20752 capsular polysaccharide tetanus toxoid conjugate antigen •Severity: MODERATE •Description: The therapeutic efficacy of Haemophilus influenzae type B strain 20752 capsular polysaccharide tetanus toxoid conjugate antigen can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found Output: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Does Abatacept and Haloperidol interact?

•Drug A: Abatacept •Drug B: Haloperidol •Severity: MODERATE •Description: The metabolism of Haloperidol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Haloperidol is indicated for a number of conditions including for the treatment of schizophrenia, for the manifestations of psychotic disorders, for the control of tics and vocal utterances of Tourette’s Disorder in children and adults, for treatment of severe behavior problems in children of combative, explosive hyperexcitability (which cannot be accounted for by immediate provocation). Haloperidol is also indicated in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance. Haloperidol should be reserved for these two groups of children only after failure to respond to psychotherapy or medications other than antipsychotics. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Use of the first-generation antipsychotics (including haloperidol) is considered highly effective for the management of the "positive" symptoms of schizophrenia including hallucinations, hearing voices, aggression/hostility, disorganized speech, and psychomotor agitation. However, this class is limited by the development of movement disorders such as drug-induced parkinsonism, akathisia, dystonia, and tardive dyskinesia, and other side effects including sedation, weight gain, and prolactin changes. Compared to the lower-potency first-generation antipsychotics such as Chlorpromazine, Zuclopenthixol, Fluphenazine, and Methotrimeprazine, haloperidol typically demonstrates the least amount of side effects within class, but demonstrates a stronger disposition for causing extrapyramidal symptoms (EPS). Low‐potency medications have a lower affinity for dopamine receptors so that a higher dose is required to effectively treat symptoms of schizophrenia. In addition, they block many receptors other than the primary target (dopamine receptors), such as cholinergic or histaminergic receptors, resulting in a higher incidence of side effects such as sedation, weight gain, and hypotension. The balance between the wanted drug effects on psychotic symptoms and unwanted side effects are largely at play within dopaminergic brain pathways affected by haloperidol. Cortical dopamine-D2-pathways play an important role in regulating these effects and include the nigrostriatal pathway, which is responsible for causing extrapyramidal symptoms (EPS), the mesolimbic and mesocortical pathways, which are responsible for the improvement in positive schizophrenic symptoms, and the tuberoinfundibular dopamine pathway, which is responsible for hyperprolactinemia. A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol. Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): While haloperidol has demonstrated pharmacologic activity at a number of receptors in the brain, it exerts its antipsychotic effect through its strong antagonism of the dopamine receptor (mainly D2), particularly within the mesolimbic and mesocortical systems of the brain. Schizophrenia is theorized to be caused by a hyperdopaminergic state within the limbic system of the brain. Dopamine-antagonizing medications such as haloperidol, therefore, are thought to improve psychotic symptoms by halting this over-production of dopamine. The optimal clinical efficacy of antipsychotics is associated with the blockade of approximately 60 % - 80 % of D2 receptors in the brain. While the exact mechanism is not entirely understood, haloperidol is known to inhibit the effects of dopamine and increase its turnover. Traditional antipsychotics, such as haloperidol, bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. It is believed that haloperidol competitively blocks post-synaptic dopamine (D2) receptors in the brain, eliminating dopamine neurotransmission and leading to the relief of delusions and hallucinations that are commonly associated with psychosis. It acts primarily on the D2-receptors and has some effect on 5-HT2 and α1-receptors, with negligible effects on dopamine D1-receptors. The drug also exerts some blockade of α-adrenergic receptors of the autonomic system. Antagonistic activity regulated through dopamine D2 receptors in the chemoreceptive trigger zone (CTZ) of the brain renders its antiemetic activity. Of the three D2-like receptors, only the D2 receptor is blocked by antipsychotic drugs in direct relation to their clinical antipsychotic abilities. Clinical brain-imaging findings show that haloperidol remains tightly bound to D2 dopamine receptors in humans undergoing 2 positron emission tomography (PET) scans with a 24h pause in between scans. A common adverse effect of this drug is the development of extrapyramidal symptoms (EPS), due to this tight binding of haloperidol to the dopamine D2 receptor. Due to the risk of unpleasant and sometimes lifelong extrapyramidal symptoms, newer antipsychotic medications than haloperidol have been discovered and formulated. Rapid dissociation of drugs from dopamine D2 receptors is a plausible explanation for the improved EPS profile of atypical antipsychotics such as Risperidone. This is also consistent with the theory of a lower affinity for D2 receptors for these drugs. As mentioned above, haloperidol binds tightly to the dopamine receptor, potentiating the risk of extrapyramidal symptoms, and therefore should only been used when necessary. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Haloperidol is a highly lipophilic compound and is extensively metabolized in humans, which may cause a large interindividual variability in its pharmacokinetics. Studies have found a wide variance in pharmacokinetic values for orally administered haloperidol with 1.7-6.1 hours reported for time to peak plasma concentration (tmax), 14.5-36.7 hours reported for half-life (t1⁄2), and 43.73 μg/L•h [range 14.89-120.96 μg/L•h] reported for AUC. Haloperidol is well-absorbed from the gastrointestinal tract when ingested orally, however, the first-pass hepatic metabolism decreases its oral bioavailability to 40 - 75%. After intramuscular administration, the time to peak plasma concentration (tmax) is 20 minutes in healthy individuals or 33.8 minutes in patients with schizophrenia, with a mean half-life of 20.7 hours. Bioavailability following intramuscular administration is higher than that for oral administration. Administration of haloperidol decanoate (the depot form of haloperidol for long-term treatment) in sesame oil results in slow release of the drug for long-term effects. The plasma concentrations of haloperidol gradually rise, reaching its peak concentration at about 6 days after the injection, with an apparent half-life of about 21 days. Steady-state plasma concentrations are achieved after the third or fourth dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution was found to range from 9.5-21.7 L/kg. This high volume of distribution is in accordance with its lipophilicity, which also suggests free movement through various tissues including the blood-brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Studies have found that free fraction of haloperidol in human plasma is 7.5-11.6%. This was found to be comparable among healthy adults, young adults, elderly patients with schizophrenia, and even in patients with liver cirrhosis. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Haloperidol is extensively metabolised in the liver with only about 1% of the administered dose excreted unchanged in urine. In humans, haloperidol is biotransformed to various metabolites, including p-fluorobenzoylpropionic acid, 4-(4-chlorophenyl)-4-hydroxypiperidine, reduced haloperidol, pyridinium metabolites, and haloperidol glucuronide. In psychiatric patients treated regularly with haloperidol, the concentration of haloperidol glucuronide in plasma is the highest among the metabolites, followed, in rank order, by unchanged haloperidol, reduced haloperidol and reduced haloperidol glucuronide. The drug is thought to be metabolized primarily by oxidative N-dealkylation of the piperidine nitrogen to form fluorophenylcarbonic acids and piperidine metabolites (which appear to be inactive), and by reduction of the butyrophenone carbonyl to the carbinol, forming hydroxyhaloperidol. The enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP) including CYP3A4 and CYP2D6, carbonyl reductase and uridine di-phosphoglucose glucuronosyltransferase enzymes. The greatest proportion of the intrinsic hepatic clearance of haloperidol is performed by glucuronidation and followed by the reduction of haloperidol to reduced haloperidol and by CYP-mediated oxidation. In studies of cytochrome-mediated disposition in vitro, CYP3A4 appears to be the major isoform of the enzyme responsible for the metabolism of haloperidol in humans. The intrinsic clearance of the back-oxidation of reduced haloperidol to the parent compound, oxidative N-dealkylation and pyridinium formation are of the same order of magnitude. This suggests that the same enzyme system is responsible for the above three metabolic reactions. In vivo human studies on haloperidol metabolism have shown that the glucuronidation of haloperidol accounts for 50 to 60% of haloperidol biotransformation and that approximately 23% of the biotransformation was accounted for by the reduction pathway. The remaining 20 to 30% ofthe biotransformation of haloperidol would be via N-dealkylation and pyridinium formation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In radiolabeling studies, approximately 30% of the radioactivity is excreted in the urine following a single oral administration of 14C-labelled haloperidol, while 18% is excreted in the urine as haloperidol glucuronide, demonstrating that haloperidol glucuronide is a major metabolite in the urine as well as in plasma in humans. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Following oral administration, the half-life was found to be 14.5-36.7 hours. Following intramuscular injection, mean half-life was found to be 20.7 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Following intravenous administration, the plasma or serum clearance (CL) was found to be 0.39-0.708 L/h/kg (6.5 to 11.8 ml/min/kg). Following oral administration, clearance was found to be 141.65 L/h (range 41.34 to 335.80 L/h). Haloperidol clearance after extravascular administration ranges from 0.9-1.5 l/h/kg, however this rate is reduced in poor metabolizers of C YP2D6 enzyme. Reduced CYP2D6 enzyme activity may result in increased concentrations of haloperidol. The inter-subject variability (coefficient of variation, %) in haloperidol clearance was estimated to be 44% in a population pharmacokinetic analysis in patients with schizophrenia. Genetic polymorphism of CYP2D6 has been demonstrated to be an important source of inter-patient variability in the pharmacokinetics of haloperidol and may affect therapeutic response and incidence of adverse effects. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Acute oral toxicity (LD50): 71 mg/kg in rats. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Haldol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Haloperidol Haloperidolum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Haloperidol is an antipsychotic agent used to treat schizophrenia and other psychoses, as well as symptoms of agitation, irritability, and delirium.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Haloperidol interact? Information: •Drug A: Abatacept •Drug B: Haloperidol •Severity: MODERATE •Description: The metabolism of Haloperidol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Haloperidol is indicated for a number of conditions including for the treatment of schizophrenia, for the manifestations of psychotic disorders, for the control of tics and vocal utterances of Tourette’s Disorder in children and adults, for treatment of severe behavior problems in children of combative, explosive hyperexcitability (which cannot be accounted for by immediate provocation). Haloperidol is also indicated in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance. Haloperidol should be reserved for these two groups of children only after failure to respond to psychotherapy or medications other than antipsychotics. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Use of the first-generation antipsychotics (including haloperidol) is considered highly effective for the management of the "positive" symptoms of schizophrenia including hallucinations, hearing voices, aggression/hostility, disorganized speech, and psychomotor agitation. However, this class is limited by the development of movement disorders such as drug-induced parkinsonism, akathisia, dystonia, and tardive dyskinesia, and other side effects including sedation, weight gain, and prolactin changes. Compared to the lower-potency first-generation antipsychotics such as Chlorpromazine, Zuclopenthixol, Fluphenazine, and Methotrimeprazine, haloperidol typically demonstrates the least amount of side effects within class, but demonstrates a stronger disposition for causing extrapyramidal symptoms (EPS). Low‐potency medications have a lower affinity for dopamine receptors so that a higher dose is required to effectively treat symptoms of schizophrenia. In addition, they block many receptors other than the primary target (dopamine receptors), such as cholinergic or histaminergic receptors, resulting in a higher incidence of side effects such as sedation, weight gain, and hypotension. The balance between the wanted drug effects on psychotic symptoms and unwanted side effects are largely at play within dopaminergic brain pathways affected by haloperidol. Cortical dopamine-D2-pathways play an important role in regulating these effects and include the nigrostriatal pathway, which is responsible for causing extrapyramidal symptoms (EPS), the mesolimbic and mesocortical pathways, which are responsible for the improvement in positive schizophrenic symptoms, and the tuberoinfundibular dopamine pathway, which is responsible for hyperprolactinemia. A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol. Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): While haloperidol has demonstrated pharmacologic activity at a number of receptors in the brain, it exerts its antipsychotic effect through its strong antagonism of the dopamine receptor (mainly D2), particularly within the mesolimbic and mesocortical systems of the brain. Schizophrenia is theorized to be caused by a hyperdopaminergic state within the limbic system of the brain. Dopamine-antagonizing medications such as haloperidol, therefore, are thought to improve psychotic symptoms by halting this over-production of dopamine. The optimal clinical efficacy of antipsychotics is associated with the blockade of approximately 60 % - 80 % of D2 receptors in the brain. While the exact mechanism is not entirely understood, haloperidol is known to inhibit the effects of dopamine and increase its turnover. Traditional antipsychotics, such as haloperidol, bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. It is believed that haloperidol competitively blocks post-synaptic dopamine (D2) receptors in the brain, eliminating dopamine neurotransmission and leading to the relief of delusions and hallucinations that are commonly associated with psychosis. It acts primarily on the D2-receptors and has some effect on 5-HT2 and α1-receptors, with negligible effects on dopamine D1-receptors. The drug also exerts some blockade of α-adrenergic receptors of the autonomic system. Antagonistic activity regulated through dopamine D2 receptors in the chemoreceptive trigger zone (CTZ) of the brain renders its antiemetic activity. Of the three D2-like receptors, only the D2 receptor is blocked by antipsychotic drugs in direct relation to their clinical antipsychotic abilities. Clinical brain-imaging findings show that haloperidol remains tightly bound to D2 dopamine receptors in humans undergoing 2 positron emission tomography (PET) scans with a 24h pause in between scans. A common adverse effect of this drug is the development of extrapyramidal symptoms (EPS), due to this tight binding of haloperidol to the dopamine D2 receptor. Due to the risk of unpleasant and sometimes lifelong extrapyramidal symptoms, newer antipsychotic medications than haloperidol have been discovered and formulated. Rapid dissociation of drugs from dopamine D2 receptors is a plausible explanation for the improved EPS profile of atypical antipsychotics such as Risperidone. This is also consistent with the theory of a lower affinity for D2 receptors for these drugs. As mentioned above, haloperidol binds tightly to the dopamine receptor, potentiating the risk of extrapyramidal symptoms, and therefore should only been used when necessary. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Haloperidol is a highly lipophilic compound and is extensively metabolized in humans, which may cause a large interindividual variability in its pharmacokinetics. Studies have found a wide variance in pharmacokinetic values for orally administered haloperidol with 1.7-6.1 hours reported for time to peak plasma concentration (tmax), 14.5-36.7 hours reported for half-life (t1⁄2), and 43.73 μg/L•h [range 14.89-120.96 μg/L•h] reported for AUC. Haloperidol is well-absorbed from the gastrointestinal tract when ingested orally, however, the first-pass hepatic metabolism decreases its oral bioavailability to 40 - 75%. After intramuscular administration, the time to peak plasma concentration (tmax) is 20 minutes in healthy individuals or 33.8 minutes in patients with schizophrenia, with a mean half-life of 20.7 hours. Bioavailability following intramuscular administration is higher than that for oral administration. Administration of haloperidol decanoate (the depot form of haloperidol for long-term treatment) in sesame oil results in slow release of the drug for long-term effects. The plasma concentrations of haloperidol gradually rise, reaching its peak concentration at about 6 days after the injection, with an apparent half-life of about 21 days. Steady-state plasma concentrations are achieved after the third or fourth dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution was found to range from 9.5-21.7 L/kg. This high volume of distribution is in accordance with its lipophilicity, which also suggests free movement through various tissues including the blood-brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Studies have found that free fraction of haloperidol in human plasma is 7.5-11.6%. This was found to be comparable among healthy adults, young adults, elderly patients with schizophrenia, and even in patients with liver cirrhosis. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Haloperidol is extensively metabolised in the liver with only about 1% of the administered dose excreted unchanged in urine. In humans, haloperidol is biotransformed to various metabolites, including p-fluorobenzoylpropionic acid, 4-(4-chlorophenyl)-4-hydroxypiperidine, reduced haloperidol, pyridinium metabolites, and haloperidol glucuronide. In psychiatric patients treated regularly with haloperidol, the concentration of haloperidol glucuronide in plasma is the highest among the metabolites, followed, in rank order, by unchanged haloperidol, reduced haloperidol and reduced haloperidol glucuronide. The drug is thought to be metabolized primarily by oxidative N-dealkylation of the piperidine nitrogen to form fluorophenylcarbonic acids and piperidine metabolites (which appear to be inactive), and by reduction of the butyrophenone carbonyl to the carbinol, forming hydroxyhaloperidol. The enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP) including CYP3A4 and CYP2D6, carbonyl reductase and uridine di-phosphoglucose glucuronosyltransferase enzymes. The greatest proportion of the intrinsic hepatic clearance of haloperidol is performed by glucuronidation and followed by the reduction of haloperidol to reduced haloperidol and by CYP-mediated oxidation. In studies of cytochrome-mediated disposition in vitro, CYP3A4 appears to be the major isoform of the enzyme responsible for the metabolism of haloperidol in humans. The intrinsic clearance of the back-oxidation of reduced haloperidol to the parent compound, oxidative N-dealkylation and pyridinium formation are of the same order of magnitude. This suggests that the same enzyme system is responsible for the above three metabolic reactions. In vivo human studies on haloperidol metabolism have shown that the glucuronidation of haloperidol accounts for 50 to 60% of haloperidol biotransformation and that approximately 23% of the biotransformation was accounted for by the reduction pathway. The remaining 20 to 30% ofthe biotransformation of haloperidol would be via N-dealkylation and pyridinium formation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In radiolabeling studies, approximately 30% of the radioactivity is excreted in the urine following a single oral administration of 14C-labelled haloperidol, while 18% is excreted in the urine as haloperidol glucuronide, demonstrating that haloperidol glucuronide is a major metabolite in the urine as well as in plasma in humans. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Following oral administration, the half-life was found to be 14.5-36.7 hours. Following intramuscular injection, mean half-life was found to be 20.7 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Following intravenous administration, the plasma or serum clearance (CL) was found to be 0.39-0.708 L/h/kg (6.5 to 11.8 ml/min/kg). Following oral administration, clearance was found to be 141.65 L/h (range 41.34 to 335.80 L/h). Haloperidol clearance after extravascular administration ranges from 0.9-1.5 l/h/kg, however this rate is reduced in poor metabolizers of C YP2D6 enzyme. Reduced CYP2D6 enzyme activity may result in increased concentrations of haloperidol. The inter-subject variability (coefficient of variation, %) in haloperidol clearance was estimated to be 44% in a population pharmacokinetic analysis in patients with schizophrenia. Genetic polymorphism of CYP2D6 has been demonstrated to be an important source of inter-patient variability in the pharmacokinetics of haloperidol and may affect therapeutic response and incidence of adverse effects. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Acute oral toxicity (LD50): 71 mg/kg in rats. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Haldol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Haloperidol Haloperidolum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Haloperidol is an antipsychotic agent used to treat schizophrenia and other psychoses, as well as symptoms of agitation, irritability, and delirium. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Halothane interact?

•Drug A: Abatacept •Drug B: Halothane •Severity: MODERATE •Description: The metabolism of Halothane can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the induction and maintenance of general anesthesia •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Halothane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It reduces the blood pressure and frequently decreases the pulse rate and depresses respiration. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Halothane causes general anaethesia due to its actions on multiple ion channels, which ultimately depresses nerve conduction, breathing, cardiac contractility. Its immobilizing effects have been attributed to its binding to potassium channels in cholinergic neurons. Halothane's effect are also likely due to binding to NMDA and calcium channels, causing hyperpolarization. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Halothane is metabolized in the liver, primarily by CYP2E1, and to a lesser extent by CYP3A4 and CYP2A6. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Toxic effects of halothane include malignant hyperthermia and hepatitis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alotano Bromochlorotrifluoroethane Halotano Halothane Halothanum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Halothane is a general inhalation anesthetic used for the induction and maintenance of general anesthesia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Halothane interact? Information: •Drug A: Abatacept •Drug B: Halothane •Severity: MODERATE •Description: The metabolism of Halothane can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the induction and maintenance of general anesthesia •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Halothane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It reduces the blood pressure and frequently decreases the pulse rate and depresses respiration. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Halothane causes general anaethesia due to its actions on multiple ion channels, which ultimately depresses nerve conduction, breathing, cardiac contractility. Its immobilizing effects have been attributed to its binding to potassium channels in cholinergic neurons. Halothane's effect are also likely due to binding to NMDA and calcium channels, causing hyperpolarization. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Halothane is metabolized in the liver, primarily by CYP2E1, and to a lesser extent by CYP3A4 and CYP2A6. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Toxic effects of halothane include malignant hyperthermia and hepatitis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alotano Bromochlorotrifluoroethane Halotano Halothane Halothanum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Halothane is a general inhalation anesthetic used for the induction and maintenance of general anesthesia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Does Abatacept and Hepatitis A Vaccine interact?

•Drug A: Abatacept •Drug B: Hepatitis A Vaccine •Severity: MODERATE •Description: The therapeutic efficacy of Hepatitis A Vaccine can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found

Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Question: Does Abatacept and Hepatitis A Vaccine interact? Information: •Drug A: Abatacept •Drug B: Hepatitis A Vaccine •Severity: MODERATE •Description: The therapeutic efficacy of Hepatitis A Vaccine can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found Output: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Does Abatacept and Hepatitis B Vaccine (Recombinant) interact?

•Drug A: Abatacept •Drug B: Hepatitis B Vaccine (Recombinant) •Severity: MODERATE •Description: The therapeutic efficacy of Hepatitis B Vaccine (Recombinant) can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found

Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Question: Does Abatacept and Hepatitis B Vaccine (Recombinant) interact? Information: •Drug A: Abatacept •Drug B: Hepatitis B Vaccine (Recombinant) •Severity: MODERATE •Description: The therapeutic efficacy of Hepatitis B Vaccine (Recombinant) can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found Output: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Does Abatacept and Hydrocodone interact?

•Drug A: Abatacept •Drug B: Hydrocodone •Severity: MODERATE •Description: The metabolism of Hydrocodone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Hydrocodone is indicated for the management of acute pain, sometimes in combination with acetaminophen or ibuprofen, as well as the symptomatic treatment of the common cold and allergic rhinitis in combination with decongestants, antihistamines, and expectorants. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydrocodone inhibits pain signaling in both the spinal cord and brain. Its actions in the brain also produce euphoria, respiratory depression, and sedation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Hydrocodone binds to the mu opioid receptor (MOR) with the highest affinity followed by the delta opioid receptors (DOR). Hydrocodone's agonist effect at the MOR is considered to contribute the most to its analgesic effects. Both MOR and DOR are Gi/o coupled and and produces its signal through activation of inward rectifier potassium (GIRK) channels, inhibition of voltage gated calcium channel opening, and decreased adenylyl cyclase activity. In the dorsal horn of the spinal cord, activation of pre-synaptic MOR on primary afferents the inhibition of calcium channel opening and increased activity of GIRK channels hyperpolarizes the neuron and prevents release of neurotransmitters. Post-synaptic MOR can also prevent activation of neurons by glutamate through the aforementioned mechanisms. Hydrocodone can also produce several actions in the brain similarly to other opioids. Activation of MOR in the periaquaductal gray (PAG) inhibits the GABAergic tone on medulo-spinal neurons. This allows these neurons, which project to the dorsal horn of the spinal cord, to suppress pain signalling in secondary afferents by activating inhibitory interneurons. MOR can also inhibit GABAergic neurons in the ventral tegmental area, removing the inhibitory tone on dopaminergic neurons in the nucleus accumbens and contributing to the activation of the brain's reward and addiction pathway. The inhibitory action or MOR likely contributes to respiratory depression, sedation, and suppression of the cough reflex. Activation of DOR may contribute to analgesia through the above mechanisms but has not been well studied. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability of hydrocodone has not been characterized due to lack of an IV formulation. The liquid formulations of hydrocodone have a Tmax of 0.83-1.33 h. The extended release tablet formulations have a Tmax of 14-16 h. The Cmax remains dose proportional over the range of 2.5-10 mg in liquid formulations and 20-120 mg in extended release formulations. Administration with food increases Cmax by about 27% while Tmax and AUC remain the same. Administration with 40% ethanol has been observed to increase Cmax 2-fold with an approximate 20% increase in AUC with no change in Tmax. 20% alcohol produces no significant effect. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution ranges widely in published literature. The official FDA labeling reports a value of 402 L. Pharmacokinetic studies report values from 210-714 L with higher values associated with higher doses or single dose studies and lower values associated with lower doses and multiple dose studies. Hydrocodone has been observed in human breast milk at levels equivalent to 1.6% of the maternal dosage. Only 12 of the 30 women studied had detectable concentrations of hydromorphone at mean levels of 0.3 mcg/kg/day. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Hydrocodone is 36% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hydrocodone undergoes oxidative O-demethylation to form hydromorphone, a more potent active metabolite. Though hydromorphone is active it is not present in sufficient quantities to contribute significantly to hydrocodone's therapeutic effects. Both hydrocodone and hydromorphone form 6-α- and 6-β-hydroxy metabolites through 6-ketoreduction. The hydroxy metabolites and hydromorphone can form glucuronide conjugates. Hydrocodone also undergoes oxidative N-demthylation to norhydrocodone. O-demethylation is primarily catalyzed by CYP2D6 while N-demethylation is primarily CYP3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Most hydrocodone appears to be eliminated via a non-renal route as renal clearance is substantially lower than total apparent clearance. Hepatic metabolism may account for a portion of this, however the slight increase in serum concentration and AUC seen in hepatic impairment indicates a different primary route of elimination. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life of elimination reported for hydrocodone is 7-9 h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Official FDA labeling reports an apparent clearance of 83 L/h. Pharmacokinetic studies report values ranging from 24.5-58.8 L/h largely dependent on CYP2D6 metabolizer status. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Overdosage with hydrocodone presents as opioid intoxication including respiratory depression, somnolence, coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. In case of oversdosage the foremost priority is the maintenance of a patent and protected airway with the provision of assisted ventilation if necessary. Supportive measures such as IV fluids, supplemental oxygen, and vasopressors may be used to manage circulatory shock. Advanced life support may be necessary in the case of cardiac arrest or arrhythmias. Opioid antagonists such as naloxone may be used to reverse the respiratory and circulatory effects of hydrocodone. Emergency monitoring is still required after naloxone administration as the opioid effects may reappear. Additionally, if used in an opioid tolerant patient, naloxone may produce opioid withdrawal symptoms. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Dalmacol, Hycet, Hycodan, Hydromet, Hysingla, Lorcet, Lortab, Norco, Obredon, Reprexain, Tussicaps, Tussionex, Vicoprofen, Xodol, Zamicet, Zohydro, Zydone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dihydrocodeinone Hidrocodona Hydrocodon Hydrocodone Hydrocodonum Hydrocone Hydroconum Idrocodone •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydrocodone is an opioid agonist used as an analgesic and antitussive agent.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Hydrocodone interact? Information: •Drug A: Abatacept •Drug B: Hydrocodone •Severity: MODERATE •Description: The metabolism of Hydrocodone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Hydrocodone is indicated for the management of acute pain, sometimes in combination with acetaminophen or ibuprofen, as well as the symptomatic treatment of the common cold and allergic rhinitis in combination with decongestants, antihistamines, and expectorants. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydrocodone inhibits pain signaling in both the spinal cord and brain. Its actions in the brain also produce euphoria, respiratory depression, and sedation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Hydrocodone binds to the mu opioid receptor (MOR) with the highest affinity followed by the delta opioid receptors (DOR). Hydrocodone's agonist effect at the MOR is considered to contribute the most to its analgesic effects. Both MOR and DOR are Gi/o coupled and and produces its signal through activation of inward rectifier potassium (GIRK) channels, inhibition of voltage gated calcium channel opening, and decreased adenylyl cyclase activity. In the dorsal horn of the spinal cord, activation of pre-synaptic MOR on primary afferents the inhibition of calcium channel opening and increased activity of GIRK channels hyperpolarizes the neuron and prevents release of neurotransmitters. Post-synaptic MOR can also prevent activation of neurons by glutamate through the aforementioned mechanisms. Hydrocodone can also produce several actions in the brain similarly to other opioids. Activation of MOR in the periaquaductal gray (PAG) inhibits the GABAergic tone on medulo-spinal neurons. This allows these neurons, which project to the dorsal horn of the spinal cord, to suppress pain signalling in secondary afferents by activating inhibitory interneurons. MOR can also inhibit GABAergic neurons in the ventral tegmental area, removing the inhibitory tone on dopaminergic neurons in the nucleus accumbens and contributing to the activation of the brain's reward and addiction pathway. The inhibitory action or MOR likely contributes to respiratory depression, sedation, and suppression of the cough reflex. Activation of DOR may contribute to analgesia through the above mechanisms but has not been well studied. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability of hydrocodone has not been characterized due to lack of an IV formulation. The liquid formulations of hydrocodone have a Tmax of 0.83-1.33 h. The extended release tablet formulations have a Tmax of 14-16 h. The Cmax remains dose proportional over the range of 2.5-10 mg in liquid formulations and 20-120 mg in extended release formulations. Administration with food increases Cmax by about 27% while Tmax and AUC remain the same. Administration with 40% ethanol has been observed to increase Cmax 2-fold with an approximate 20% increase in AUC with no change in Tmax. 20% alcohol produces no significant effect. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution ranges widely in published literature. The official FDA labeling reports a value of 402 L. Pharmacokinetic studies report values from 210-714 L with higher values associated with higher doses or single dose studies and lower values associated with lower doses and multiple dose studies. Hydrocodone has been observed in human breast milk at levels equivalent to 1.6% of the maternal dosage. Only 12 of the 30 women studied had detectable concentrations of hydromorphone at mean levels of 0.3 mcg/kg/day. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Hydrocodone is 36% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hydrocodone undergoes oxidative O-demethylation to form hydromorphone, a more potent active metabolite. Though hydromorphone is active it is not present in sufficient quantities to contribute significantly to hydrocodone's therapeutic effects. Both hydrocodone and hydromorphone form 6-α- and 6-β-hydroxy metabolites through 6-ketoreduction. The hydroxy metabolites and hydromorphone can form glucuronide conjugates. Hydrocodone also undergoes oxidative N-demthylation to norhydrocodone. O-demethylation is primarily catalyzed by CYP2D6 while N-demethylation is primarily CYP3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Most hydrocodone appears to be eliminated via a non-renal route as renal clearance is substantially lower than total apparent clearance. Hepatic metabolism may account for a portion of this, however the slight increase in serum concentration and AUC seen in hepatic impairment indicates a different primary route of elimination. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life of elimination reported for hydrocodone is 7-9 h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Official FDA labeling reports an apparent clearance of 83 L/h. Pharmacokinetic studies report values ranging from 24.5-58.8 L/h largely dependent on CYP2D6 metabolizer status. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Overdosage with hydrocodone presents as opioid intoxication including respiratory depression, somnolence, coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. In case of oversdosage the foremost priority is the maintenance of a patent and protected airway with the provision of assisted ventilation if necessary. Supportive measures such as IV fluids, supplemental oxygen, and vasopressors may be used to manage circulatory shock. Advanced life support may be necessary in the case of cardiac arrest or arrhythmias. Opioid antagonists such as naloxone may be used to reverse the respiratory and circulatory effects of hydrocodone. Emergency monitoring is still required after naloxone administration as the opioid effects may reappear. Additionally, if used in an opioid tolerant patient, naloxone may produce opioid withdrawal symptoms. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Dalmacol, Hycet, Hycodan, Hydromet, Hysingla, Lorcet, Lortab, Norco, Obredon, Reprexain, Tussicaps, Tussionex, Vicoprofen, Xodol, Zamicet, Zohydro, Zydone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dihydrocodeinone Hidrocodona Hydrocodon Hydrocodone Hydrocodonum Hydrocone Hydroconum Idrocodone •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydrocodone is an opioid agonist used as an analgesic and antitussive agent. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Does Abatacept and Hydrocortisone acetate interact?

•Drug A: Abatacept •Drug B: Hydrocortisone acetate •Severity: MODERATE •Description: The metabolism of Hydrocortisone acetate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Also used to treat endocrine (hormonal) disorders (adrenal insufficiency, Addisons disease). It is also used to treat many immune and allergic disorders, such as arthritis, lupus, severe psoriasis, severe asthma, ulcerative colitis, and Crohn's disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydrocortisone is the most important human glucocorticoid. It is essential for life and regulates or supports a variety of important cardiovascular, metabolic, immunologic and homeostatic functions. Topical hydrocortisone is used for its anti-inflammatory or immunosuppressive properties to treat inflammation due to corticosteroid-responsive dermatoses. Glucocorticoids are a class of steroid hormones characterised by an ability to bind with the cortisol receptor and trigger a variety of important cardiovascular, metabolic, immunologic and homeostatic effects. Glucocorticoids are distinguished from mineralocorticoids and sex steroids by having different receptors, target cells, and effects. Technically, the term corticosteroid refers to both glucocorticoids and mineralocorticoids, but is often used as a synonym for glucocorticoid. Glucocorticoids suppress cell-mediated immunity. They act by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and TNF-alpha, the most important of which is the IL-2. Reduced cytokine production limits T cell proliferation. Glucocorticoids also suppress humoral immunity, causing B cells to express lower amounts of IL-2 and IL-2 receptors. This diminishes both B cell clonal expansion and antibody synthesis. The diminished amounts of IL-2 also leads to fewer T lymphocyte cells being activated. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Hydrocortisone binds to the cytosolic glucocorticoid receptor. After binding the receptor the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. The anti-inflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. Specifically glucocorticoids induce lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In other words, the two main products in inflammation Prostaglandins and Leukotrienes are inhibited by the action of Glucocorticoids. Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines etc.) from neutrophils, macrophages and mastocytes. Additionally the immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic via CYP3A4 •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 6-8 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects include inhibition of bone formation, suppression of calcium absorption and delayed wound healing •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alcortin A, Analpram HC, Anodan-HC, Anucort-HC, Anusol, Anusol HC, Cortifoam, Cortisporin, Cortisporin-TC, Diphen, Egozinc, Epifoam, Fucidin, Micort-HC, Neo-polycin HC, Nucort, Pramosone, Procort 1.85/1.15, Proctocort, Proctodan-HC, Proctofoam-HC, Rectacort-HC, Rectogel, Riva-sol HC, U-cort, Vagisil, Vytone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydrocortisone acetate is a corticosteroid used to treat inflammatory and pruritic corticosteroid-responsive dermatoses and ulcerative colitis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Hydrocortisone acetate interact? Information: •Drug A: Abatacept •Drug B: Hydrocortisone acetate •Severity: MODERATE •Description: The metabolism of Hydrocortisone acetate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Also used to treat endocrine (hormonal) disorders (adrenal insufficiency, Addisons disease). It is also used to treat many immune and allergic disorders, such as arthritis, lupus, severe psoriasis, severe asthma, ulcerative colitis, and Crohn's disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydrocortisone is the most important human glucocorticoid. It is essential for life and regulates or supports a variety of important cardiovascular, metabolic, immunologic and homeostatic functions. Topical hydrocortisone is used for its anti-inflammatory or immunosuppressive properties to treat inflammation due to corticosteroid-responsive dermatoses. Glucocorticoids are a class of steroid hormones characterised by an ability to bind with the cortisol receptor and trigger a variety of important cardiovascular, metabolic, immunologic and homeostatic effects. Glucocorticoids are distinguished from mineralocorticoids and sex steroids by having different receptors, target cells, and effects. Technically, the term corticosteroid refers to both glucocorticoids and mineralocorticoids, but is often used as a synonym for glucocorticoid. Glucocorticoids suppress cell-mediated immunity. They act by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and TNF-alpha, the most important of which is the IL-2. Reduced cytokine production limits T cell proliferation. Glucocorticoids also suppress humoral immunity, causing B cells to express lower amounts of IL-2 and IL-2 receptors. This diminishes both B cell clonal expansion and antibody synthesis. The diminished amounts of IL-2 also leads to fewer T lymphocyte cells being activated. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Hydrocortisone binds to the cytosolic glucocorticoid receptor. After binding the receptor the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. The anti-inflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. Specifically glucocorticoids induce lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In other words, the two main products in inflammation Prostaglandins and Leukotrienes are inhibited by the action of Glucocorticoids. Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines etc.) from neutrophils, macrophages and mastocytes. Additionally the immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic via CYP3A4 •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 6-8 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects include inhibition of bone formation, suppression of calcium absorption and delayed wound healing •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alcortin A, Analpram HC, Anodan-HC, Anucort-HC, Anusol, Anusol HC, Cortifoam, Cortisporin, Cortisporin-TC, Diphen, Egozinc, Epifoam, Fucidin, Micort-HC, Neo-polycin HC, Nucort, Pramosone, Procort 1.85/1.15, Proctocort, Proctodan-HC, Proctofoam-HC, Rectacort-HC, Rectogel, Riva-sol HC, U-cort, Vagisil, Vytone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydrocortisone acetate is a corticosteroid used to treat inflammatory and pruritic corticosteroid-responsive dermatoses and ulcerative colitis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Hydrocortisone butyrate interact?

•Drug A: Abatacept •Drug B: Hydrocortisone butyrate •Severity: MODERATE •Description: The metabolism of Hydrocortisone butyrate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Also used to treat endocrine (hormonal) disorders (adrenal insufficiency, Addisons disease). It is also used to treat many immune and allergic disorders, such as arthritis, lupus, severe psoriasis, severe asthma, ulcerative colitis, and Crohn's disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydrocortisone is the most important human glucocorticoid. It is essential for life and regulates or supports a variety of important cardiovascular, metabolic, immunologic and homeostatic functions. Topical hydrocortisone is used for its anti-inflammatory or immunosuppressive properties to treat inflammation due to corticosteroid-responsive dermatoses. Glucocorticoids are a class of steroid hormones characterised by an ability to bind with the cortisol receptor and trigger a variety of important cardiovascular, metabolic, immunologic and homeostatic effects. Glucocorticoids are distinguished from mineralocorticoids and sex steroids by having different receptors, target cells, and effects. Technically, the term corticosteroid refers to both glucocorticoids and mineralocorticoids, but is often used as a synonym for glucocorticoid. Glucocorticoids suppress cell-mediated immunity. They act by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and TNF-alpha, the most important of which is the IL-2. Reduced cytokine production limits T cell proliferation. Glucocorticoids also suppress humoral immunity, causing B cells to express lower amounts of IL-2 and IL-2 receptors. This diminishes both B cell clonal expansion and antibody synthesis. The diminished amounts of IL-2 also leads to fewer T lymphocyte cells being activated. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Hydrocortisone binds to the cytosolic glucocorticoid receptor. After binding the receptor the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. The anti-inflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. Specifically glucocorticoids induce lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In other words, the two main products in inflammation Prostaglandins and Leukotrienes are inhibited by the action of Glucocorticoids. Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines etc.) from neutrophils, macrophages and mastocytes. Additionally the immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic via CYP3A4 •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 6-8 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects include inhibition of bone formation, suppression of calcium absorption and delayed wound healing •Brand Names (Drug A): Orencia •Brand Names (Drug B): Locoid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 17-O-butyrylcortisol Cortisol 17-butyrate Hydrocortisone butyrate •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydrocortisone butyrate is a corticosteroid used to treat inflammatory and pruritic corticosteroid-responsive dermatoses.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Hydrocortisone butyrate interact? Information: •Drug A: Abatacept •Drug B: Hydrocortisone butyrate •Severity: MODERATE •Description: The metabolism of Hydrocortisone butyrate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Also used to treat endocrine (hormonal) disorders (adrenal insufficiency, Addisons disease). It is also used to treat many immune and allergic disorders, such as arthritis, lupus, severe psoriasis, severe asthma, ulcerative colitis, and Crohn's disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydrocortisone is the most important human glucocorticoid. It is essential for life and regulates or supports a variety of important cardiovascular, metabolic, immunologic and homeostatic functions. Topical hydrocortisone is used for its anti-inflammatory or immunosuppressive properties to treat inflammation due to corticosteroid-responsive dermatoses. Glucocorticoids are a class of steroid hormones characterised by an ability to bind with the cortisol receptor and trigger a variety of important cardiovascular, metabolic, immunologic and homeostatic effects. Glucocorticoids are distinguished from mineralocorticoids and sex steroids by having different receptors, target cells, and effects. Technically, the term corticosteroid refers to both glucocorticoids and mineralocorticoids, but is often used as a synonym for glucocorticoid. Glucocorticoids suppress cell-mediated immunity. They act by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and TNF-alpha, the most important of which is the IL-2. Reduced cytokine production limits T cell proliferation. Glucocorticoids also suppress humoral immunity, causing B cells to express lower amounts of IL-2 and IL-2 receptors. This diminishes both B cell clonal expansion and antibody synthesis. The diminished amounts of IL-2 also leads to fewer T lymphocyte cells being activated. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Hydrocortisone binds to the cytosolic glucocorticoid receptor. After binding the receptor the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. The anti-inflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. Specifically glucocorticoids induce lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In other words, the two main products in inflammation Prostaglandins and Leukotrienes are inhibited by the action of Glucocorticoids. Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines etc.) from neutrophils, macrophages and mastocytes. Additionally the immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic via CYP3A4 •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 6-8 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects include inhibition of bone formation, suppression of calcium absorption and delayed wound healing •Brand Names (Drug A): Orencia •Brand Names (Drug B): Locoid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 17-O-butyrylcortisol Cortisol 17-butyrate Hydrocortisone butyrate •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydrocortisone butyrate is a corticosteroid used to treat inflammatory and pruritic corticosteroid-responsive dermatoses. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Hydrocortisone phosphate interact?

•Drug A: Abatacept •Drug B: Hydrocortisone phosphate •Severity: MODERATE •Description: The metabolism of Hydrocortisone phosphate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Also used to treat endocrine (hormonal) disorders (adrenal insufficiency, Addisons disease). It is also used to treat many immune and allergic disorders, such as arthritis, lupus, severe psoriasis, severe asthma, ulcerative colitis, and Crohn's disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydrocortisone is the most important human glucocorticoid. It is essential for life and regulates or supports a variety of important cardiovascular, metabolic, immunologic and homeostatic functions. Topical hydrocortisone is used for its anti-inflammatory or immunosuppressive properties to treat inflammation due to corticosteroid-responsive dermatoses. Glucocorticoids are a class of steroid hormones characterised by an ability to bind with the cortisol receptor and trigger a variety of important cardiovascular, metabolic, immunologic and homeostatic effects. Glucocorticoids are distinguished from mineralocorticoids and sex steroids by having different receptors, target cells, and effects. Technically, the term corticosteroid refers to both glucocorticoids and mineralocorticoids, but is often used as a synonym for glucocorticoid. Glucocorticoids suppress cell-mediated immunity. They act by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and TNF-alpha, the most important of which is the IL-2. Reduced cytokine production limits T cell proliferation. Glucocorticoids also suppress humoral immunity, causing B cells to express lower amounts of IL-2 and IL-2 receptors. This diminishes both B cell clonal expansion and antibody synthesis. The diminished amounts of IL-2 also leads to fewer T lymphocyte cells being activated. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Hydrocortisone binds to the cytosolic glucocorticoid receptor. After binding the receptor the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. The anti-inflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. Specifically glucocorticoids induce lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In other words, the two main products in inflammation Prostaglandins and Leukotrienes are inhibited by the action of Glucocorticoids. Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines etc.) from neutrophils, macrophages and mastocytes. Additionally the immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic via CYP3A4 •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 6-8 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects include inhibition of bone formation, suppression of calcium absorption and delayed wound healing •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydrocortisone phosphate is a corticosteroid used to treat congenital adrenal hyperplasia, for emergency asthma treatment, hypersensitivity, and inflammation.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Hydrocortisone phosphate interact? Information: •Drug A: Abatacept •Drug B: Hydrocortisone phosphate •Severity: MODERATE •Description: The metabolism of Hydrocortisone phosphate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Also used to treat endocrine (hormonal) disorders (adrenal insufficiency, Addisons disease). It is also used to treat many immune and allergic disorders, such as arthritis, lupus, severe psoriasis, severe asthma, ulcerative colitis, and Crohn's disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydrocortisone is the most important human glucocorticoid. It is essential for life and regulates or supports a variety of important cardiovascular, metabolic, immunologic and homeostatic functions. Topical hydrocortisone is used for its anti-inflammatory or immunosuppressive properties to treat inflammation due to corticosteroid-responsive dermatoses. Glucocorticoids are a class of steroid hormones characterised by an ability to bind with the cortisol receptor and trigger a variety of important cardiovascular, metabolic, immunologic and homeostatic effects. Glucocorticoids are distinguished from mineralocorticoids and sex steroids by having different receptors, target cells, and effects. Technically, the term corticosteroid refers to both glucocorticoids and mineralocorticoids, but is often used as a synonym for glucocorticoid. Glucocorticoids suppress cell-mediated immunity. They act by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and TNF-alpha, the most important of which is the IL-2. Reduced cytokine production limits T cell proliferation. Glucocorticoids also suppress humoral immunity, causing B cells to express lower amounts of IL-2 and IL-2 receptors. This diminishes both B cell clonal expansion and antibody synthesis. The diminished amounts of IL-2 also leads to fewer T lymphocyte cells being activated. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Hydrocortisone binds to the cytosolic glucocorticoid receptor. After binding the receptor the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. The anti-inflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. Specifically glucocorticoids induce lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In other words, the two main products in inflammation Prostaglandins and Leukotrienes are inhibited by the action of Glucocorticoids. Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines etc.) from neutrophils, macrophages and mastocytes. Additionally the immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic via CYP3A4 •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 6-8 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Side effects include inhibition of bone formation, suppression of calcium absorption and delayed wound healing •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydrocortisone phosphate is a corticosteroid used to treat congenital adrenal hyperplasia, for emergency asthma treatment, hypersensitivity, and inflammation. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Hydrocortisone succinate interact?

•Drug A: Abatacept •Drug B: Hydrocortisone succinate •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Hydrocortisone succinate. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Solu-cortef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cortisol succinate Hydrocortisone hydrogen succinate Hydrocortisone succinate Hydroxycortisone succinate •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydrocortisone succinate is a corticosteroid used to treat severe allergic reactions, dermatologic diseases, endocrine disorders, gastrointestinal diseases, hematological disorders, neoplastic diseases, nervous system conditions, ophthalmic diseases, renal diseases, respiratory diseases, and rheumatic disorders.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Hydrocortisone succinate interact? Information: •Drug A: Abatacept •Drug B: Hydrocortisone succinate •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Hydrocortisone succinate. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Solu-cortef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cortisol succinate Hydrocortisone hydrogen succinate Hydrocortisone succinate Hydroxycortisone succinate •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydrocortisone succinate is a corticosteroid used to treat severe allergic reactions, dermatologic diseases, endocrine disorders, gastrointestinal diseases, hematological disorders, neoplastic diseases, nervous system conditions, ophthalmic diseases, renal diseases, respiratory diseases, and rheumatic disorders. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Hydrocortisone interact?

•Drug A: Abatacept •Drug B: Hydrocortisone •Severity: MODERATE •Description: The metabolism of Hydrocortisone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Otic solutions are indicated for infections of the external auditory canal caused by susceptible organisms and with inflammation. Hydrocortisone tablets are indicated for certain endocrine, rheumatic, collagen, allergic, ophthalmic, respiratory, hematologic, neoplastic, edematous, gastrointestinal, and other conditions. A hydrocortisone enema is indicated for ulcerative colitis, a topical ointment with antibiotics is indicated for corticosteroid responsive dermatoses with infections, and a topical cream with acyclovir is indicated to treat cold sores. Oral granules of hydrocortisone are used as a replacement therapy for Adrenocortical Insufficiency (AI) in children under 17 years of age. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydrocortisone binds to the glucocorticoid receptor leading to downstream effects such as inhibition of phospholipase A2, NF-kappa B, other inflammatory transcription factors, and the promotion of anti-inflammatory genes. Hydrocortisone has a wide therapeutic index and a moderate duration of action. Patients should stop taking the medication if irritation or sensitization occurs. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Oral hydrocortisone at a dose of 0.2-0.3mg/kg/day reached a mean C max of 32.69nmol/L with a mean AUC of 90.63h*nmol/L A 0.4-0.6mg/kg/day dose reached a mean C max of 70.81nmol/L with a mean AUC of 199.11h*nmol/L. However, the pharmacokinetics of hydrocortisone can vary by 10 times from patient to patient. Topical hydrocortisone cream is 4-19% bioavailable with a T max of 24h. Hydrocortisone retention enemas are have a bioavailability of 0.810 for slow absorbers and 0.502 in rapid absorbers. Slow absorbers take up hydrocortisone at a rate of 0.361±0.255/h while fast absorbers take up hydrocortisone at a rate of 1.05±0.255/h. A 20mg IV dose of hydrocortisone has an AUC of 1163±277ng*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Total hydrocortisone has a volume of distribution of 39.82L, while the free fraction has a volume of distribution of 474.38L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Corticosteroids are generally bound to corticosteroid binding globulin and serum albumin in plasma. Hydrocortisone is 90.1% bound to proteins in plasma, with 56.2% bound to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hydrocortisone is metabolised to 6-beta hydrocortisol via CYP3A, 5-beta tetrahydrocortisol via 3-oxo-5-beta-steroid 4-dehydrogenase, 5-alpha tetrahydrocortisol via 3-oxo-5-alpha-steroid 4-dehydrogenase 2, cortisone via Corticosteroid 11-beta-dehydrogenase isozyme 1 and Corticosteroid 11-beta-dehydrogenase isozyme 2, and glucuronide products. Cortisone is further metabolized to tetrahydrocortisone and dihydrocortisol. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Corticosteroids are eliminated predominantly in the urine. However, data regarding the exact proportion is not readily available. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Total hydrocortisone via the oral route has a half life of 2.15h while the free fraction has a half life of 1.39h. A 20mg IV dose of hydrocortisone has a terminal half life of 1.9±0.4h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Total hydrocortisone by the oral route has a mean clearance of 12.85L/h, while the free fraction has a mean clearance of 235.78L/h. A 20mg IV dose of hydrocortisone has a clearance of 18.2±4.2L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Data regarding acute overdoses of glucocorticoids are rare. Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency. Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ala-cort, Ala-scalp, Alcortin, Alkindi, Anusol HC, Aquanil HC, Casporyn HC, Cipro, Cipro HC, Colocort, Cortaid, Cortane-B, Cortef, Cortenema, Cortisporin, Cortizone-10, Dermacort, Dermarest Eczema, Dermazene, Home Papkit, Hydroskin, Monistat Itch Relief, Preparation H Hydrocortisone, Procto-med, Procto-pak, Proctocort, Proctol, Proctosedyl, Proctosol, Proctozone HC, Scalpicin Itch Relief, Texacort, Vanoxide-HC, Xerese •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 11beta-hydrocortisone 17-Hydroxycorticosterone Cortisol Hidrocortisona Hydrocortisone Hydrocortisonum Kendall's compound F Reichstein's substance M •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydrocortisone is a glucocorticoid used to treat corticosteroid-responsive dermatoses, endocrine disorders, immune conditions, and allergic disorders.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Hydrocortisone interact? Information: •Drug A: Abatacept •Drug B: Hydrocortisone •Severity: MODERATE •Description: The metabolism of Hydrocortisone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Otic solutions are indicated for infections of the external auditory canal caused by susceptible organisms and with inflammation. Hydrocortisone tablets are indicated for certain endocrine, rheumatic, collagen, allergic, ophthalmic, respiratory, hematologic, neoplastic, edematous, gastrointestinal, and other conditions. A hydrocortisone enema is indicated for ulcerative colitis, a topical ointment with antibiotics is indicated for corticosteroid responsive dermatoses with infections, and a topical cream with acyclovir is indicated to treat cold sores. Oral granules of hydrocortisone are used as a replacement therapy for Adrenocortical Insufficiency (AI) in children under 17 years of age. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydrocortisone binds to the glucocorticoid receptor leading to downstream effects such as inhibition of phospholipase A2, NF-kappa B, other inflammatory transcription factors, and the promotion of anti-inflammatory genes. Hydrocortisone has a wide therapeutic index and a moderate duration of action. Patients should stop taking the medication if irritation or sensitization occurs. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Oral hydrocortisone at a dose of 0.2-0.3mg/kg/day reached a mean C max of 32.69nmol/L with a mean AUC of 90.63h*nmol/L A 0.4-0.6mg/kg/day dose reached a mean C max of 70.81nmol/L with a mean AUC of 199.11h*nmol/L. However, the pharmacokinetics of hydrocortisone can vary by 10 times from patient to patient. Topical hydrocortisone cream is 4-19% bioavailable with a T max of 24h. Hydrocortisone retention enemas are have a bioavailability of 0.810 for slow absorbers and 0.502 in rapid absorbers. Slow absorbers take up hydrocortisone at a rate of 0.361±0.255/h while fast absorbers take up hydrocortisone at a rate of 1.05±0.255/h. A 20mg IV dose of hydrocortisone has an AUC of 1163±277ng*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Total hydrocortisone has a volume of distribution of 39.82L, while the free fraction has a volume of distribution of 474.38L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Corticosteroids are generally bound to corticosteroid binding globulin and serum albumin in plasma. Hydrocortisone is 90.1% bound to proteins in plasma, with 56.2% bound to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hydrocortisone is metabolised to 6-beta hydrocortisol via CYP3A, 5-beta tetrahydrocortisol via 3-oxo-5-beta-steroid 4-dehydrogenase, 5-alpha tetrahydrocortisol via 3-oxo-5-alpha-steroid 4-dehydrogenase 2, cortisone via Corticosteroid 11-beta-dehydrogenase isozyme 1 and Corticosteroid 11-beta-dehydrogenase isozyme 2, and glucuronide products. Cortisone is further metabolized to tetrahydrocortisone and dihydrocortisol. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Corticosteroids are eliminated predominantly in the urine. However, data regarding the exact proportion is not readily available. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Total hydrocortisone via the oral route has a half life of 2.15h while the free fraction has a half life of 1.39h. A 20mg IV dose of hydrocortisone has a terminal half life of 1.9±0.4h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Total hydrocortisone by the oral route has a mean clearance of 12.85L/h, while the free fraction has a mean clearance of 235.78L/h. A 20mg IV dose of hydrocortisone has a clearance of 18.2±4.2L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Data regarding acute overdoses of glucocorticoids are rare. Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency. Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ala-cort, Ala-scalp, Alcortin, Alkindi, Anusol HC, Aquanil HC, Casporyn HC, Cipro, Cipro HC, Colocort, Cortaid, Cortane-B, Cortef, Cortenema, Cortisporin, Cortizone-10, Dermacort, Dermarest Eczema, Dermazene, Home Papkit, Hydroskin, Monistat Itch Relief, Preparation H Hydrocortisone, Procto-med, Procto-pak, Proctocort, Proctol, Proctosedyl, Proctosol, Proctozone HC, Scalpicin Itch Relief, Texacort, Vanoxide-HC, Xerese •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 11beta-hydrocortisone 17-Hydroxycorticosterone Cortisol Hidrocortisona Hydrocortisone Hydrocortisonum Kendall's compound F Reichstein's substance M •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydrocortisone is a glucocorticoid used to treat corticosteroid-responsive dermatoses, endocrine disorders, immune conditions, and allergic disorders. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Hydromorphone interact?

•Drug A: Abatacept •Drug B: Hydromorphone •Severity: MODERATE •Description: The metabolism of Hydromorphone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Hydromorphone is indicated for the management of moderate to severe acute pain and severe chronic pain. Due to its addictive potential and overdose risk, hydromorphone is only prescribed when other first-line treatments have failed. The WHO has proposed a three-step ladder for the management of pain in which it is suggested to start with a non-opioid medication followed by addition of weak opioids to the non-opioid treatment for moderate pain and finishing in the use of strong opioids such as hydromorphone along with the existing regimen for cases of severe pain. Off-label, hydromorphone can be administered for the suppression of refractory cough. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In clinical trials, hydromorphone has been shown to be suitable for pain relief in patients that do not tolerate the side effects of morphine or that suffer from renal failure or asthma. It has been shown to be 5-7 times more potent than morphine with a shorter duration of analgesia. Some of the observed effects of the consumption of hydromorphone for acute pain are complete and longlasting pain relief when compared to other pain relief agents such as meperidine, morphine, diamorphine, bupivacaine, indomethacin, and fentanyl. On the same trials, hydromorphone was shown to produce respiratory depression, lower cognitive function, miosis, mydriasis, constipation, hypotension, and vertigo but to present a reduced incidence of pruritus (which indicates a lower release of histamine) and nausea. The respiratory depression is known to be caused by the effect on the brain stem respiratory centers as well as to a reduction in the responsiveness of this brain stems to increase carbon dioxide tension. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Hydromorphone is an opioid agonist that can bind to different types of opioid receptors. Its analgesic effect is suggested to be related to the effect on the mu-opioid receptors. It has been reported to also have a minor affinity for the delta and kappa receptor. On the other hand, it is known to act at the level of the medulla which allows it to depress the respiratory drive and suppress cough. The onset of action of the immediate release form of hydromorphone is achieved in 15-20 minutes and having a lasting effect for 3-4 hours while the extended-release form onset of action is of 6 hours lasting for about 13 hours. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The immediate release version of hydromorphone reaches its peak concentration after 30-60 minutes while the extended-release version reaches the peak concentration after 9 hours. When administered orally, hydromorphone is absorbed mainly in the upper small intestine with a bioavailability of 60% due to intensive first-pass metabolism. In the controlled-release version of hydromorphone, the absorption follows a biphasic pharmacokinetic profile. However, even though there are clear distinctions in the absorption pathway of hydromorphone, the AUC of both versions is reported to be of 34 ng.h/ml which indicates an equivalence. The parenteral administration of hydromorphone, which is the most common pathway, presents an almost immediate absorption as observed by the presence of peak plasma concentration almost immediately. This peak plasma concentration declines rapidly due to fast redistribution into liver, spleen, kidney and skeletal muscle. In the parenteral route, the pharmacokinetic profile is log-linear and dose-dependent and to present a higher bioavailability of 78%. Other administration routes such as rectal, nasal, intraspinal and transdermal present lower bioavailability and changes in their pharmacokinetic profile. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of hydromorphone is reported to be of 4 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein-bound form of hydromorphone corresponds to about 8-19% of the administered dose. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of hydromorphone is mainly hepatic and it is represented by the generation of hydromorphone-3-glucuronide through glucuronidation reactions. This primary metabolic pathway is done by the activity of the UDP-glucuronosyltransferase-2B7. The first-pass hepatic metabolism is so large that it represents 62% of the initial administered dose. On the other hand, hydromorphone is also characterized by the presence of minor metabolic pathways such as the CYP3A4- and CYP2C9-driven generation of norhydromorphone. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The main elimination route of hydromorphone is through the urine in the form of the main metabolite hydromorphone-3-glucuronide. The elimination of the parent compound represents 7% of the urine elimination and 1% of the fecal elimination. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life of hydromorphone immediate-release is of 2-3 hour while the extended release can range from 8-15 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean plasma clearance of hydromorphone is reported to be of 105.7 ml/min. The systemic clearance is reported to be of 1.96 L/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The reported LD50 of hydromorphone in the mouse was of 104 mg/kg when given intravenously and 84 mg/kg when given orally. The reports of overdose with hydromorphone are characterized by respiratory depression, somnolence, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, myosis, mydriasis, bradycardia, hypotension, apnea, circulatory collapse, cardiac arrest, and even death. The management of an overdose might require assisted ventilation, supportive measures, as well as cardiac massage and defibrillation. It can be recommended the use of naloxone solely in the cases of respiratory depression. The use of opioid antagonist should be restricted to patients that present respiratory depression as they can produce acute abstinence symptoms. Hydromorphone was not shown to be mutagenic nor clastogenic and long-term studies of carcinogenicity studies have not been performed. On the other hand, reduced implantation sites and viable fetuses were noted at a 2X normal concentration. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Dilaudid, Exalgo, Hydromorph Contin, Hydromorphone Hp Forte •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 7,8-Dihydromorphinone Dihydromorfinon Dihydromorphinone Dimorphone Hidromorfona Hydromorfona Hydromorphone Hydromorphonum Idromorfone •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydromorphone is an opioid analgesic used to treat moderate to severe pain when the use of an opioid is indicated.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Hydromorphone interact? Information: •Drug A: Abatacept •Drug B: Hydromorphone •Severity: MODERATE •Description: The metabolism of Hydromorphone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Hydromorphone is indicated for the management of moderate to severe acute pain and severe chronic pain. Due to its addictive potential and overdose risk, hydromorphone is only prescribed when other first-line treatments have failed. The WHO has proposed a three-step ladder for the management of pain in which it is suggested to start with a non-opioid medication followed by addition of weak opioids to the non-opioid treatment for moderate pain and finishing in the use of strong opioids such as hydromorphone along with the existing regimen for cases of severe pain. Off-label, hydromorphone can be administered for the suppression of refractory cough. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In clinical trials, hydromorphone has been shown to be suitable for pain relief in patients that do not tolerate the side effects of morphine or that suffer from renal failure or asthma. It has been shown to be 5-7 times more potent than morphine with a shorter duration of analgesia. Some of the observed effects of the consumption of hydromorphone for acute pain are complete and longlasting pain relief when compared to other pain relief agents such as meperidine, morphine, diamorphine, bupivacaine, indomethacin, and fentanyl. On the same trials, hydromorphone was shown to produce respiratory depression, lower cognitive function, miosis, mydriasis, constipation, hypotension, and vertigo but to present a reduced incidence of pruritus (which indicates a lower release of histamine) and nausea. The respiratory depression is known to be caused by the effect on the brain stem respiratory centers as well as to a reduction in the responsiveness of this brain stems to increase carbon dioxide tension. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Hydromorphone is an opioid agonist that can bind to different types of opioid receptors. Its analgesic effect is suggested to be related to the effect on the mu-opioid receptors. It has been reported to also have a minor affinity for the delta and kappa receptor. On the other hand, it is known to act at the level of the medulla which allows it to depress the respiratory drive and suppress cough. The onset of action of the immediate release form of hydromorphone is achieved in 15-20 minutes and having a lasting effect for 3-4 hours while the extended-release form onset of action is of 6 hours lasting for about 13 hours. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The immediate release version of hydromorphone reaches its peak concentration after 30-60 minutes while the extended-release version reaches the peak concentration after 9 hours. When administered orally, hydromorphone is absorbed mainly in the upper small intestine with a bioavailability of 60% due to intensive first-pass metabolism. In the controlled-release version of hydromorphone, the absorption follows a biphasic pharmacokinetic profile. However, even though there are clear distinctions in the absorption pathway of hydromorphone, the AUC of both versions is reported to be of 34 ng.h/ml which indicates an equivalence. The parenteral administration of hydromorphone, which is the most common pathway, presents an almost immediate absorption as observed by the presence of peak plasma concentration almost immediately. This peak plasma concentration declines rapidly due to fast redistribution into liver, spleen, kidney and skeletal muscle. In the parenteral route, the pharmacokinetic profile is log-linear and dose-dependent and to present a higher bioavailability of 78%. Other administration routes such as rectal, nasal, intraspinal and transdermal present lower bioavailability and changes in their pharmacokinetic profile. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of hydromorphone is reported to be of 4 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein-bound form of hydromorphone corresponds to about 8-19% of the administered dose. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of hydromorphone is mainly hepatic and it is represented by the generation of hydromorphone-3-glucuronide through glucuronidation reactions. This primary metabolic pathway is done by the activity of the UDP-glucuronosyltransferase-2B7. The first-pass hepatic metabolism is so large that it represents 62% of the initial administered dose. On the other hand, hydromorphone is also characterized by the presence of minor metabolic pathways such as the CYP3A4- and CYP2C9-driven generation of norhydromorphone. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The main elimination route of hydromorphone is through the urine in the form of the main metabolite hydromorphone-3-glucuronide. The elimination of the parent compound represents 7% of the urine elimination and 1% of the fecal elimination. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life of hydromorphone immediate-release is of 2-3 hour while the extended release can range from 8-15 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean plasma clearance of hydromorphone is reported to be of 105.7 ml/min. The systemic clearance is reported to be of 1.96 L/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The reported LD50 of hydromorphone in the mouse was of 104 mg/kg when given intravenously and 84 mg/kg when given orally. The reports of overdose with hydromorphone are characterized by respiratory depression, somnolence, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, myosis, mydriasis, bradycardia, hypotension, apnea, circulatory collapse, cardiac arrest, and even death. The management of an overdose might require assisted ventilation, supportive measures, as well as cardiac massage and defibrillation. It can be recommended the use of naloxone solely in the cases of respiratory depression. The use of opioid antagonist should be restricted to patients that present respiratory depression as they can produce acute abstinence symptoms. Hydromorphone was not shown to be mutagenic nor clastogenic and long-term studies of carcinogenicity studies have not been performed. On the other hand, reduced implantation sites and viable fetuses were noted at a 2X normal concentration. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Dilaudid, Exalgo, Hydromorph Contin, Hydromorphone Hp Forte •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 7,8-Dihydromorphinone Dihydromorfinon Dihydromorphinone Dimorphone Hidromorfona Hydromorfona Hydromorphone Hydromorphonum Idromorfone •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydromorphone is an opioid analgesic used to treat moderate to severe pain when the use of an opioid is indicated. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Hydroxychloroquine interact?

•Drug A: Abatacept •Drug B: Hydroxychloroquine •Severity: MODERATE •Description: The metabolism of Hydroxychloroquine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Hydroxychloroquine is indicated for the prophylaxis of malaria where chloroquine resistance is not reported, treatment of uncomplicated malaria (caused by P. falciparum, P. malariae, P. ovale, or P. vivax ), chronic discoid lupus erythematosus, systemic lupus erythematosus, acute rheumatoid arthritis, and chronic rheumatoid arthritis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydroxychloroquine affects the function of lysosomes in humans as well as plasmodia. Altering the pH of the lysosomes reduces low-affinity self-antigen presentation in autoimmune diseases and interferes with the ability of plasmodia to proteolyze hemoglobin for their energy requirements. Hydroxychloroquine has a long duration of action as it may be taken on a weekly basis for some indications. Hydroxychloroquine may lead to severe hypoglycemia and so diabetic patients are advised to monitor their blood glucose levels. Hydroxychloroquine is active against the erythrocytic forms of chloroquine-sensitive strains of P. falciparum, P. malariae, P. vivax, and P. ovale. Hydroxychloroquine is not active against the gametocytes and exoerythrocytic forms including the hypnozoite liver stage forms of P. vivax and P. ovale. Hydroxychloroquine is not effective against malaria in areas where chloroquine resistance has been reported. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The exact mechanisms of hydroxychloroquine are unknown. It has been shown that hydroxychloroquine accumulates in the lysosomes of the malaria parasite, raising the pH of the vacuole. This activity interferes with the parasite's ability to proteolyse hemoglobin, preventing the normal growth and replication of the parasite. Hydroxychloroquine can also interfere with the action of parasitic heme polymerase, an enzyme that uses ferriprotoporphyrin IX (FP) released from hemoglobin as a substrate to form beta-hematin. By reducing the activity of heme polymerase without inhibiting the release of FP, hydroxychloroquine leads to the accumulation of FP in a toxic form. Hydroxychloroquine accumulation in human organelles also raise their pH, which inhibits antigen processing, prevents the alpha and beta chains of the major histocompatibility complex (MHC) class II from dimerizing, inhibits antigen presentation of the cell, and reduces the inflammatory response. Elevated pH in the vesicles may alter the recycling of MHC complexes so that only the high affinity complexes are presented on the cell surface. Self peptides bind to MHC complexes with low affinity and so they will be less likely to be presented to autoimmune T cells. Hydroxychloroquine also reduces the release of cytokines like interleukin-1 and tumor necrosis factor, possibly through inhibition of Toll-like receptors. The raised pH in endosomes, prevent virus particles (such as SARS-CoV and SARS-CoV-2) from utilizing their activity for fusion and entry into the cell. Hydroxychloroquine inhibits terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry. ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Hydroxychloroquine is 67-74% bioavailable. Bioavailability of the R and S enantiomers were not significantly different. Following a single 200 mg oral dose of hydroxychloroquine to healthy male volunteers, whole blood hydroxychloroquine C max was 129.6 ng/mL (plasma C max was 50.3 ng/mL) with T max of 3.3 hours (plasma T max 3.7 hours). Following a single oral hydroxychloroquine dose of 200 mg, the mean fraction of the dose absorbed was 0.74 (compared to the administration of 155 mg of hydroxychloroquine intravenous infusion). Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxychloroquine. After administration of single 155 mg and 310 mg intravenous doses, peak blood concentrations ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL) following the 155 mg infusion and 6 months following the 310 mg infusion. Pharmacokinetic parameters were not significantly different over the therapeutic dose range of 155 mg and 310 mg indicating linear kinetics. In patients with rheumatoid arthritis, there was large variability as to the fraction of the dose absorbed (i.e. 30 to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Hydroxychloroquine is extensively distributed to tissues; it has a volume of distribution of 5522L from blood and 44,257L from plasma. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The S enantiomer of hydroxychloroquine is 64% protein bound in plasma. It is 50% bound to serum albumin and 29% bound to alpha-1-acid glycoprotein. The R enantiomer is 37% protein bound in plasma. It is 29% bound to serum albumin and 41% bound to alpha-1-acid glycoprotein. In total, hydroxychloroquine is 50% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hydroxychloroquine is N-dealkylated by CYP3A4 to the active metabolite desethylhydroxychloroquine, as well as the inactive metabolites desethylchloroquine and bidesethylchloroquine. Desethylhydroxychloroquine is the major metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 40-50% of hydroxychloroquine is excreted renally, while only 16-21% of a dose is excreted in the urine as unchanged drug. 5% of a dose is sloughed off in skin and 24-25% is eliminated through the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): A half-life of 123.5 days in plasma was observed following a single 200 mg oral PLAQUENIL dose to healthy male volunteers. Urine hydroxychloroquine levels were still detectable after 3 months with approximately 10% of the dose excreted as the parent drug. Results following a single dose of a 200 mg tablet versus i.v. infusion (155 mg), demonstrated a half-life of about 40 days and a large volume of distribution. Following chronic oral administration of hydroxychloroquine, the absorption half-life was approximately 3 to 4 hours and the terminal half-life ranged from 40 to 50 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance of hydroxychloroquine is 96mL/min. Renal clearance of unchanged drug was approximately 16% to 30%. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Patients experiencing an overdose may present with headache, drowsiness, visual disturbances, cardiovascular collapse, convulsions, hypokalemia, rhythm and conduction disorders including QT prolongation, torsades de pointes, ventricular tachycardia, and ventricular fibrillation. This may progress to sudden respiratory and cardiac arrest. Overdose should be treated with immediate gastric lavage and activated charcoal at a dose of at least 5 times the hydroxychloroquine dose within 30 minutes. Parenteral diazepam may be given to treat cardiotoxicity, transfusion may reduce serum concentrations of drug, patients should be monitored for at least 6 hours, fluids should be given, and ammonium chloride should be given to acidify urine and promote urinary excretion. Patients may also be given epinephrine. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Plaquenil, Sovuna •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Hidroxicloroquina Hydroxychloroquine Hydroxychloroquinum Oxichlorochine Oxichloroquine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydroxychloroquine is an antimalarial medication used to treat uncomplicated cases of malaria and for chemoprophylaxis in specific regions. Also a disease modifying anti-rheumatic drug (DMARD) indicated for treatment of rheumatoid arthritis and lupus erythematosus.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Hydroxychloroquine interact? Information: •Drug A: Abatacept •Drug B: Hydroxychloroquine •Severity: MODERATE •Description: The metabolism of Hydroxychloroquine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Hydroxychloroquine is indicated for the prophylaxis of malaria where chloroquine resistance is not reported, treatment of uncomplicated malaria (caused by P. falciparum, P. malariae, P. ovale, or P. vivax ), chronic discoid lupus erythematosus, systemic lupus erythematosus, acute rheumatoid arthritis, and chronic rheumatoid arthritis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydroxychloroquine affects the function of lysosomes in humans as well as plasmodia. Altering the pH of the lysosomes reduces low-affinity self-antigen presentation in autoimmune diseases and interferes with the ability of plasmodia to proteolyze hemoglobin for their energy requirements. Hydroxychloroquine has a long duration of action as it may be taken on a weekly basis for some indications. Hydroxychloroquine may lead to severe hypoglycemia and so diabetic patients are advised to monitor their blood glucose levels. Hydroxychloroquine is active against the erythrocytic forms of chloroquine-sensitive strains of P. falciparum, P. malariae, P. vivax, and P. ovale. Hydroxychloroquine is not active against the gametocytes and exoerythrocytic forms including the hypnozoite liver stage forms of P. vivax and P. ovale. Hydroxychloroquine is not effective against malaria in areas where chloroquine resistance has been reported. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The exact mechanisms of hydroxychloroquine are unknown. It has been shown that hydroxychloroquine accumulates in the lysosomes of the malaria parasite, raising the pH of the vacuole. This activity interferes with the parasite's ability to proteolyse hemoglobin, preventing the normal growth and replication of the parasite. Hydroxychloroquine can also interfere with the action of parasitic heme polymerase, an enzyme that uses ferriprotoporphyrin IX (FP) released from hemoglobin as a substrate to form beta-hematin. By reducing the activity of heme polymerase without inhibiting the release of FP, hydroxychloroquine leads to the accumulation of FP in a toxic form. Hydroxychloroquine accumulation in human organelles also raise their pH, which inhibits antigen processing, prevents the alpha and beta chains of the major histocompatibility complex (MHC) class II from dimerizing, inhibits antigen presentation of the cell, and reduces the inflammatory response. Elevated pH in the vesicles may alter the recycling of MHC complexes so that only the high affinity complexes are presented on the cell surface. Self peptides bind to MHC complexes with low affinity and so they will be less likely to be presented to autoimmune T cells. Hydroxychloroquine also reduces the release of cytokines like interleukin-1 and tumor necrosis factor, possibly through inhibition of Toll-like receptors. The raised pH in endosomes, prevent virus particles (such as SARS-CoV and SARS-CoV-2) from utilizing their activity for fusion and entry into the cell. Hydroxychloroquine inhibits terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry. ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Hydroxychloroquine is 67-74% bioavailable. Bioavailability of the R and S enantiomers were not significantly different. Following a single 200 mg oral dose of hydroxychloroquine to healthy male volunteers, whole blood hydroxychloroquine C max was 129.6 ng/mL (plasma C max was 50.3 ng/mL) with T max of 3.3 hours (plasma T max 3.7 hours). Following a single oral hydroxychloroquine dose of 200 mg, the mean fraction of the dose absorbed was 0.74 (compared to the administration of 155 mg of hydroxychloroquine intravenous infusion). Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxychloroquine. After administration of single 155 mg and 310 mg intravenous doses, peak blood concentrations ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL) following the 155 mg infusion and 6 months following the 310 mg infusion. Pharmacokinetic parameters were not significantly different over the therapeutic dose range of 155 mg and 310 mg indicating linear kinetics. In patients with rheumatoid arthritis, there was large variability as to the fraction of the dose absorbed (i.e. 30 to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Hydroxychloroquine is extensively distributed to tissues; it has a volume of distribution of 5522L from blood and 44,257L from plasma. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The S enantiomer of hydroxychloroquine is 64% protein bound in plasma. It is 50% bound to serum albumin and 29% bound to alpha-1-acid glycoprotein. The R enantiomer is 37% protein bound in plasma. It is 29% bound to serum albumin and 41% bound to alpha-1-acid glycoprotein. In total, hydroxychloroquine is 50% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hydroxychloroquine is N-dealkylated by CYP3A4 to the active metabolite desethylhydroxychloroquine, as well as the inactive metabolites desethylchloroquine and bidesethylchloroquine. Desethylhydroxychloroquine is the major metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 40-50% of hydroxychloroquine is excreted renally, while only 16-21% of a dose is excreted in the urine as unchanged drug. 5% of a dose is sloughed off in skin and 24-25% is eliminated through the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): A half-life of 123.5 days in plasma was observed following a single 200 mg oral PLAQUENIL dose to healthy male volunteers. Urine hydroxychloroquine levels were still detectable after 3 months with approximately 10% of the dose excreted as the parent drug. Results following a single dose of a 200 mg tablet versus i.v. infusion (155 mg), demonstrated a half-life of about 40 days and a large volume of distribution. Following chronic oral administration of hydroxychloroquine, the absorption half-life was approximately 3 to 4 hours and the terminal half-life ranged from 40 to 50 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance of hydroxychloroquine is 96mL/min. Renal clearance of unchanged drug was approximately 16% to 30%. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Patients experiencing an overdose may present with headache, drowsiness, visual disturbances, cardiovascular collapse, convulsions, hypokalemia, rhythm and conduction disorders including QT prolongation, torsades de pointes, ventricular tachycardia, and ventricular fibrillation. This may progress to sudden respiratory and cardiac arrest. Overdose should be treated with immediate gastric lavage and activated charcoal at a dose of at least 5 times the hydroxychloroquine dose within 30 minutes. Parenteral diazepam may be given to treat cardiotoxicity, transfusion may reduce serum concentrations of drug, patients should be monitored for at least 6 hours, fluids should be given, and ammonium chloride should be given to acidify urine and promote urinary excretion. Patients may also be given epinephrine. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Plaquenil, Sovuna •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Hidroxicloroquina Hydroxychloroquine Hydroxychloroquinum Oxichlorochine Oxichloroquine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydroxychloroquine is an antimalarial medication used to treat uncomplicated cases of malaria and for chemoprophylaxis in specific regions. Also a disease modifying anti-rheumatic drug (DMARD) indicated for treatment of rheumatoid arthritis and lupus erythematosus. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Hydroxyprogesterone caproate interact?

•Drug A: Abatacept •Drug B: Hydroxyprogesterone caproate •Severity: MODERATE •Description: The metabolism of Hydroxyprogesterone caproate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Hydroxyprogesterone caproate was previously indicated in the US for the prevention of spontaneous preterm births in singleton pregnancies in women with a history of spontaneous preterm birth. This indication was revoked by the FDA in April 2023. Hydroxyprogesterone caproate remains indicated in other jurisdictions for the management of primary and secondary amenorrhea, corpus luteum insufficiency, and for the prevention of preterm birth. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No specific pharmacodynamic studies have been performed to assess hydroxyprogesterone caproate injections. However, the mechanism of action is likely related to increased interaction between progesterone and progesterone receptors. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism by which progesterone prevents preterm birth is not well understood, but many pathways are likely involved. Progesterone plays a vital role in regulation of the female reproductive system and is important for successful implantation of the embryo and maintenance of pregnancy. It acts by binding to progesterone receptors in the uterus, ovaries, breasts and in the central nervous system. These receptors exist in 2 isoforms, PR-A and PR-B. Progesterone binding to these receptors ultimately leads to regulation of gene transcription. This results in an anti-inflammatory effect which blunts the proinflammatory state that occurs with initiation of labor, and maintains uterine queiscence by stabilizing progesterone acting on the myometrium. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption of 17-hydroxyprogesteron caproate is slow, occurring over a long period of time. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Hydroxyprogesterone caproate has a high volume of distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Hydroxyprogesterone caproate is extensively protein bound in the plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The main enzymes involved in metabolism of hydroxyprogesterone caproate are cytochrome P450 (CYP) 3A4 and to a lesser extent CYP3A5. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following intramuscular injection, approximately 50% of hydroxyprogesterone caproate metabolites are eliminated in the feces, while approximately 30% of metabolites are eliminated in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Half-life = 16 days (±6 days). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Clearance is highly variable from patient to patient. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Injection site pain is the most common adverse effect associated with hydroxyprogesterone caproate. Other commonly reported adverse effects include: injection site swelling, urticaria, pruritus, injection site pruritus, nausea, injection site nodule, and diarrhea. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Makena •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Caproate d'hydroxyprogesterone Caproato de hidroxiprogesterona Hydroxyprogesterone caproate Hydroxyprogesterone hexanoate •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydroxyprogesterone caproate is a synthetic progestin used for the prevention of spontaneous preterm births in singleton pregnancies in women who have previously had a spontaneous preterm birth.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Hydroxyprogesterone caproate interact? Information: •Drug A: Abatacept •Drug B: Hydroxyprogesterone caproate •Severity: MODERATE •Description: The metabolism of Hydroxyprogesterone caproate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Hydroxyprogesterone caproate was previously indicated in the US for the prevention of spontaneous preterm births in singleton pregnancies in women with a history of spontaneous preterm birth. This indication was revoked by the FDA in April 2023. Hydroxyprogesterone caproate remains indicated in other jurisdictions for the management of primary and secondary amenorrhea, corpus luteum insufficiency, and for the prevention of preterm birth. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No specific pharmacodynamic studies have been performed to assess hydroxyprogesterone caproate injections. However, the mechanism of action is likely related to increased interaction between progesterone and progesterone receptors. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The mechanism by which progesterone prevents preterm birth is not well understood, but many pathways are likely involved. Progesterone plays a vital role in regulation of the female reproductive system and is important for successful implantation of the embryo and maintenance of pregnancy. It acts by binding to progesterone receptors in the uterus, ovaries, breasts and in the central nervous system. These receptors exist in 2 isoforms, PR-A and PR-B. Progesterone binding to these receptors ultimately leads to regulation of gene transcription. This results in an anti-inflammatory effect which blunts the proinflammatory state that occurs with initiation of labor, and maintains uterine queiscence by stabilizing progesterone acting on the myometrium. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption of 17-hydroxyprogesteron caproate is slow, occurring over a long period of time. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Hydroxyprogesterone caproate has a high volume of distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Hydroxyprogesterone caproate is extensively protein bound in the plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The main enzymes involved in metabolism of hydroxyprogesterone caproate are cytochrome P450 (CYP) 3A4 and to a lesser extent CYP3A5. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following intramuscular injection, approximately 50% of hydroxyprogesterone caproate metabolites are eliminated in the feces, while approximately 30% of metabolites are eliminated in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Half-life = 16 days (±6 days). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Clearance is highly variable from patient to patient. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Injection site pain is the most common adverse effect associated with hydroxyprogesterone caproate. Other commonly reported adverse effects include: injection site swelling, urticaria, pruritus, injection site pruritus, nausea, injection site nodule, and diarrhea. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Makena •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Caproate d'hydroxyprogesterone Caproato de hidroxiprogesterona Hydroxyprogesterone caproate Hydroxyprogesterone hexanoate •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydroxyprogesterone caproate is a synthetic progestin used for the prevention of spontaneous preterm births in singleton pregnancies in women who have previously had a spontaneous preterm birth. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Hydroxyurea interact?

•Drug A: Abatacept •Drug B: Hydroxyurea •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Hydroxyurea is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Hydroxyurea is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult and pediatric patients, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): The correlation between hydroxyurea concentrations, reduction of crisis rate, and increase in HbF, is not known. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in rat and human tissue cultures lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis, by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. Hydroxyurea probably acts by decreasing the rate of conversion of ribonucleotides and deoxyribonucleotides. This effect is particularly apparent in cells with a high rate of proliferation. Particularly, hydroxyurea reduces the tyrosyl free radical at the active site of the M2 via a one-electron transfer reaction through the –NH2-OH moiety. Three mechanisms have been postulated for the potentiation of the therapeutic effects of irradiation by hydroxyurea on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea is lethal to normally radioresistant S-stage cells and holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells: it appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; there is no alteration of RNA and protein syntheses. Another proposed mechanism of action of hydroxyurea is the elevation of HbF concentrations in Sickle Cell Disease patients. HbF interferes with the polymerization of HbS (sickle haemoglobin) and thus impedes the sickling of red blood cell. Recently, hydroxyurea has shown to be associated with the generation of nitric oxide, suggesting that nitric oxide stimulates cyclic guanosine monophosphates (cGMP) production, which then activates a protein kinase and increases the production of HbF. Other known pharmacological effects of hydroxycarbamide which may contribute to its beneficial effects in Sickle Cell Disease include decrease of neutrophils, improved deformability of sickled cells, and altered adhesion of red blood cells to the endothelium. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): After oral administration hydroxyurea is readily absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 2 hours and by 24 hours the serum concentrations are virtually zero. Bioavailability is complete or nearly complete in cancer patients. After oral administration of 20 mg/kg of hydroxyurea, a rapid absorption is observed with peak plasma levels of about 30 mg/L occurring after 0.75 and 1.2 h in children and adult patients with sickle cell syndrome, respectively. The total exposure up to 24 h post-dose is 124 mg.h/L in children and adolescents and 135 mg.h/L in adult patients. The oral bioavailability of hydroxyurea is almost complete as assessed in indications other than sickle cell syndrome. In a comparative bioavailability study in healthy adult volunteers (n=28), 500 mg of hydroxyurea oral solution was demonstrated to be bioequivalent to the reference 500 mg capsule, with respect to both the peak concentration and area under the curve. There was a statistically significant reduction in time to peak concentration with hydroxyurea oral solution compared to the reference 500 mg capsule (0.5 versus 0.75 hours, p = 0.0467), indicating a faster rate of absorption.[L47137 In a study of children with Sickle Cell Disease, liquid and capsule formulations resulted in similar area under the curve, peak concentrations, and half-life. The largest difference in the pharmacokinetic profile was a trend towards a shorter time to peak concentration following ingestion of the liquid compared with the capsule, but that difference did not reach statistical significance (0.74 versus 0.97 hours, p = 0.14). •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Hydroxyurea distributes rapidly throughout the human body, enters the cerebrospinal fluid, appears in peritoneal fluid and ascites, and concentrates in leukocytes and erythrocytes. The estimated volume of distribution of hydroxycarbamide approximates total body water. The volume of distribution following oral dosing of hydroxycarbamide is approximately equal to total body water: adult values of 0.48 – 0.90 L/kg have been reported, whilst in children a population estimate of 0.7 L/kg has been reported. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The extent of protein binding of hydroxyurea is unknown. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation to acetohydroxamic acid by urease found in intestinal bacteria. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): A significant fraction of hydroxycarbamide is eliminated by nonrenal (mainly hepatic) mechanisms. In adults, the urinary recovery of unchanged drug is reported to be approximately 37% of the oral dose when renal function is normal. In children, the fraction of hydroxyurea excreted unchanged into the urine comprised about 50%. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In adult cancer patients, hydroxyurea was eliminated with a half-life of approximately 2-3 hours. In a single-dose study in children with Sickle Cell Disease, the mean half-life was reported to be 1.7 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The total body clearance of hydroxyurea in adult patients with Sickle Cell Disease is 0.17 L/h/kg. The respective value in children was similar, 0.22 L/h/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral, mouse: LD 50 = 7330 mg/kg; Oral, rat: LD 50 = 5760 mg/kg Hydroxyurea can cause fetal harm based on findings from animal studies and the drug’s mechanism of action. There are no studies on the use of Hydroxyurea in pregnant women and limited available data on SIKLOS use during pregnancy are insufficient to inform drug-associated risks. Drugs that affect DNA synthesis, such as hydroxyurea, may be potential mutagenic agents. In animal reproduction studies, administration of hydroxyurea to pregnant rats and rabbits during organogenesis produced embryotoxic and teratogenic effects at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m² basis. In rats and rabbits, fetal malformations were observed with partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, and missing lumbar vertebrae. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Advise pregnant women of the potential risk to a fetus. Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at doses several times above the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hand and feet, severe generalized hyperpigmentation of the skin, and stomatitis have been observed. In patients with sickle cell anemia, neutropenia was reported in isolated cases of hydroxyurea overdose (1.43 times and 8.57 times the maximum recommended dose of 35 mg/kg b.w./day). Monitor blood counts weekly until recovery. Treatment of overdose consists of gastric lavage, followed by symptomatic treatment and control of bone marrow function. Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, hydroxyurea is presumed to be a transspecies carcinogen. Intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months in female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype. Hydroxyurea administered to male rats at 60 mg/kg /day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Droxia, Hydrea, Siklos •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydroxyurea is an antimetabolite used to treat sickle cell anemia crisis, resistant chronic myeloid leukemia, and Locally advanced squamous cell carcinomas of the head and neck (excluding the lip).

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Hydroxyurea interact? Information: •Drug A: Abatacept •Drug B: Hydroxyurea •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Hydroxyurea is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Hydroxyurea is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult and pediatric patients, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): The correlation between hydroxyurea concentrations, reduction of crisis rate, and increase in HbF, is not known. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in rat and human tissue cultures lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis, by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. Hydroxyurea probably acts by decreasing the rate of conversion of ribonucleotides and deoxyribonucleotides. This effect is particularly apparent in cells with a high rate of proliferation. Particularly, hydroxyurea reduces the tyrosyl free radical at the active site of the M2 via a one-electron transfer reaction through the –NH2-OH moiety. Three mechanisms have been postulated for the potentiation of the therapeutic effects of irradiation by hydroxyurea on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea is lethal to normally radioresistant S-stage cells and holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells: it appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; there is no alteration of RNA and protein syntheses. Another proposed mechanism of action of hydroxyurea is the elevation of HbF concentrations in Sickle Cell Disease patients. HbF interferes with the polymerization of HbS (sickle haemoglobin) and thus impedes the sickling of red blood cell. Recently, hydroxyurea has shown to be associated with the generation of nitric oxide, suggesting that nitric oxide stimulates cyclic guanosine monophosphates (cGMP) production, which then activates a protein kinase and increases the production of HbF. Other known pharmacological effects of hydroxycarbamide which may contribute to its beneficial effects in Sickle Cell Disease include decrease of neutrophils, improved deformability of sickled cells, and altered adhesion of red blood cells to the endothelium. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): After oral administration hydroxyurea is readily absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 2 hours and by 24 hours the serum concentrations are virtually zero. Bioavailability is complete or nearly complete in cancer patients. After oral administration of 20 mg/kg of hydroxyurea, a rapid absorption is observed with peak plasma levels of about 30 mg/L occurring after 0.75 and 1.2 h in children and adult patients with sickle cell syndrome, respectively. The total exposure up to 24 h post-dose is 124 mg.h/L in children and adolescents and 135 mg.h/L in adult patients. The oral bioavailability of hydroxyurea is almost complete as assessed in indications other than sickle cell syndrome. In a comparative bioavailability study in healthy adult volunteers (n=28), 500 mg of hydroxyurea oral solution was demonstrated to be bioequivalent to the reference 500 mg capsule, with respect to both the peak concentration and area under the curve. There was a statistically significant reduction in time to peak concentration with hydroxyurea oral solution compared to the reference 500 mg capsule (0.5 versus 0.75 hours, p = 0.0467), indicating a faster rate of absorption.[L47137 In a study of children with Sickle Cell Disease, liquid and capsule formulations resulted in similar area under the curve, peak concentrations, and half-life. The largest difference in the pharmacokinetic profile was a trend towards a shorter time to peak concentration following ingestion of the liquid compared with the capsule, but that difference did not reach statistical significance (0.74 versus 0.97 hours, p = 0.14). •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Hydroxyurea distributes rapidly throughout the human body, enters the cerebrospinal fluid, appears in peritoneal fluid and ascites, and concentrates in leukocytes and erythrocytes. The estimated volume of distribution of hydroxycarbamide approximates total body water. The volume of distribution following oral dosing of hydroxycarbamide is approximately equal to total body water: adult values of 0.48 – 0.90 L/kg have been reported, whilst in children a population estimate of 0.7 L/kg has been reported. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The extent of protein binding of hydroxyurea is unknown. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation to acetohydroxamic acid by urease found in intestinal bacteria. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): A significant fraction of hydroxycarbamide is eliminated by nonrenal (mainly hepatic) mechanisms. In adults, the urinary recovery of unchanged drug is reported to be approximately 37% of the oral dose when renal function is normal. In children, the fraction of hydroxyurea excreted unchanged into the urine comprised about 50%. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In adult cancer patients, hydroxyurea was eliminated with a half-life of approximately 2-3 hours. In a single-dose study in children with Sickle Cell Disease, the mean half-life was reported to be 1.7 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The total body clearance of hydroxyurea in adult patients with Sickle Cell Disease is 0.17 L/h/kg. The respective value in children was similar, 0.22 L/h/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral, mouse: LD 50 = 7330 mg/kg; Oral, rat: LD 50 = 5760 mg/kg Hydroxyurea can cause fetal harm based on findings from animal studies and the drug’s mechanism of action. There are no studies on the use of Hydroxyurea in pregnant women and limited available data on SIKLOS use during pregnancy are insufficient to inform drug-associated risks. Drugs that affect DNA synthesis, such as hydroxyurea, may be potential mutagenic agents. In animal reproduction studies, administration of hydroxyurea to pregnant rats and rabbits during organogenesis produced embryotoxic and teratogenic effects at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m² basis. In rats and rabbits, fetal malformations were observed with partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, and missing lumbar vertebrae. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Advise pregnant women of the potential risk to a fetus. Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at doses several times above the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed by scaling of hand and feet, severe generalized hyperpigmentation of the skin, and stomatitis have been observed. In patients with sickle cell anemia, neutropenia was reported in isolated cases of hydroxyurea overdose (1.43 times and 8.57 times the maximum recommended dose of 35 mg/kg b.w./day). Monitor blood counts weekly until recovery. Treatment of overdose consists of gastric lavage, followed by symptomatic treatment and control of bone marrow function. Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However, hydroxyurea is presumed to be a transspecies carcinogen. Intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months in female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic phenotype. Hydroxyurea administered to male rats at 60 mg/kg /day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate females. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Droxia, Hydrea, Siklos •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydroxyurea is an antimetabolite used to treat sickle cell anemia crisis, resistant chronic myeloid leukemia, and Locally advanced squamous cell carcinomas of the head and neck (excluding the lip). Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Hydroxyzine interact?

•Drug A: Abatacept •Drug B: Hydroxyzine •Severity: MODERATE •Description: The metabolism of Hydroxyzine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Hydroxyzine is indicated for the symptomatic relief of anxiety and tension associated with psychoneuroses, and as an adjunct in organic disease states in which anxiety is manifested. It is also indicated in the treatment of histamine-mediated pruritus and pruritus due to allergic conditions such as chronic urticaria. Canadian labeling states that hydroxyzine is also indicated in adults and children as a premedication prior to medical procedures, such as dental surgery. It is also used in the control of nausea and vomiting, excluding nausea and vomiting of pregnancy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydroxyzine blocks the activity of histamine to relieve allergic symptoms such as pruritus. Activity at off-targets also allows for its use as a sedative anxiolytic and an antiemetic in certain disease states. Hydroxyzine is relatively fast-acting, with an onset of effect that occurs between 15 and 60 minutes and a duration of action between 4-6 hours. Hydroxyzine may potentiate the effects of central nervous system (CNS) depressants following general anesthesia - patients maintained on hydroxyzine should receive reduced doses of any CNS depressants required. Hydroxyzine is reported to prolong the QT/QTc interval based on postmarketing reports of rare events of Torsade de Pointes, cardiac arrest, and sudden death, and should be used with caution in patients with an increased baseline risk for QTc prolongation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The H 1 histamine receptor is responsible for mediating hypersensitivity and allergic reactions. Exposure to an allergen results in degranulation of mast cells and basophils, which then release histamine and other inflammatory mediators. Histamine binds to, and activates, H 1 receptors, which results in the further release of pro-inflammatory cytokines, such as interleukins, from basophils and mast cells. These downstream effects of histamine binding are responsible for a wide variety of allergic symptoms, such as pruritus, rhinorrhea, and watery eyes. Hydroxyzine is a potent inverse agonist of histamine H 1 -receptors - inverse agonists are agents that are considered to have a "negative efficacy", so rather than simply blocking activity at a receptor they actively dampen its activity. Inverse agonism at these receptors is responsible for hydroxyzine's efficacy in the treatment of histaminic edema, flare, and pruritus. Hydroxyzine is not a cortical depressant, so its sedative properties likely occur at the subcortical level of the CNS. These sedative properties allow activity as an anxiolytic. Antiemetic efficacy is likely secondary to activity at off-targets. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability of hydroxyzine has not been ascertained, as intravenous formulations are unavailable due to a risk of hemolysis. Hydroxyzine is rapidly absorbed from the gastrointestinal tract upon oral administration, reaching its maximum plasma concentration (T max ) approximately 2 hours following administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean volume of distribution is 16.0 ± 3.0 L/kg. Higher concentrations are found in the skin than in the plasma. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Hydroxyzine has been shown to bind to human albumin in vitro, but the extent of protein binding in plasma has not been evaluated. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hydroxyzine is metabolized in the liver by CYP3A4 and CYP3A5. While the precise metabolic fate of hydroxyzine is unclear, its main and active metabolite (~45 to 60% of an orally administered dose), generated by oxidation of its alcohol moiety to a carboxylic acid, is the second-generation antihistamine cetirizine. Hydroxyzine is likely broken down into several other metabolites, though specific structures and pathways have not been elucidated in humans. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 70% of hydroxyzine's active metabolite, cetirizine, is excreted unchanged in the urine. The precise extent of renal and fecal excretion in humans has not been determined. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life of hydroxyzine is reportedly 14-25 hours, and appears to be, on average, shorter in children (~7.1 hours) than in adults (~20 hours). Elimination half-life is prolonged in the elderly, averaging approximately 29 hours, and is likely to be similarly prolonged in patients with renal or hepatic impairment. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Clearance of hydroxyzine has been reported to be 31.1 ± 11.1 mL/min/kg in children and 9.8 ± 3.3 mL/min/kg in adults. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 is 840 mg/kg in rats and 400 mg/kg in mice. Overdose from hydroxyzine is most commonly characterized by hypersedation, but may also manifest as convulsions, stupor, nausea, and vomiting. In cases of overdose, consider the induction of vomiting and the use of gastric lavage. Other treatment should involve general symptomatic and supportive care. Hypotension may be controlled by intravenous fluids and pressors, and caffeine and sodium benzoate injection may be used to counteract any observed CNS depressant effects. Hemodialysis is unlikely to provide any benefit in the treatment hydroxyzine overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Atarax, Vistaril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydroxyzine is an antihistamine used to treat anxiety and tension associated with psychoneuroses, as well as allergic conditions such as pruritus and chronic urticaria.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Hydroxyzine interact? Information: •Drug A: Abatacept •Drug B: Hydroxyzine •Severity: MODERATE •Description: The metabolism of Hydroxyzine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Hydroxyzine is indicated for the symptomatic relief of anxiety and tension associated with psychoneuroses, and as an adjunct in organic disease states in which anxiety is manifested. It is also indicated in the treatment of histamine-mediated pruritus and pruritus due to allergic conditions such as chronic urticaria. Canadian labeling states that hydroxyzine is also indicated in adults and children as a premedication prior to medical procedures, such as dental surgery. It is also used in the control of nausea and vomiting, excluding nausea and vomiting of pregnancy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Hydroxyzine blocks the activity of histamine to relieve allergic symptoms such as pruritus. Activity at off-targets also allows for its use as a sedative anxiolytic and an antiemetic in certain disease states. Hydroxyzine is relatively fast-acting, with an onset of effect that occurs between 15 and 60 minutes and a duration of action between 4-6 hours. Hydroxyzine may potentiate the effects of central nervous system (CNS) depressants following general anesthesia - patients maintained on hydroxyzine should receive reduced doses of any CNS depressants required. Hydroxyzine is reported to prolong the QT/QTc interval based on postmarketing reports of rare events of Torsade de Pointes, cardiac arrest, and sudden death, and should be used with caution in patients with an increased baseline risk for QTc prolongation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The H 1 histamine receptor is responsible for mediating hypersensitivity and allergic reactions. Exposure to an allergen results in degranulation of mast cells and basophils, which then release histamine and other inflammatory mediators. Histamine binds to, and activates, H 1 receptors, which results in the further release of pro-inflammatory cytokines, such as interleukins, from basophils and mast cells. These downstream effects of histamine binding are responsible for a wide variety of allergic symptoms, such as pruritus, rhinorrhea, and watery eyes. Hydroxyzine is a potent inverse agonist of histamine H 1 -receptors - inverse agonists are agents that are considered to have a "negative efficacy", so rather than simply blocking activity at a receptor they actively dampen its activity. Inverse agonism at these receptors is responsible for hydroxyzine's efficacy in the treatment of histaminic edema, flare, and pruritus. Hydroxyzine is not a cortical depressant, so its sedative properties likely occur at the subcortical level of the CNS. These sedative properties allow activity as an anxiolytic. Antiemetic efficacy is likely secondary to activity at off-targets. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability of hydroxyzine has not been ascertained, as intravenous formulations are unavailable due to a risk of hemolysis. Hydroxyzine is rapidly absorbed from the gastrointestinal tract upon oral administration, reaching its maximum plasma concentration (T max ) approximately 2 hours following administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean volume of distribution is 16.0 ± 3.0 L/kg. Higher concentrations are found in the skin than in the plasma. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Hydroxyzine has been shown to bind to human albumin in vitro, but the extent of protein binding in plasma has not been evaluated. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hydroxyzine is metabolized in the liver by CYP3A4 and CYP3A5. While the precise metabolic fate of hydroxyzine is unclear, its main and active metabolite (~45 to 60% of an orally administered dose), generated by oxidation of its alcohol moiety to a carboxylic acid, is the second-generation antihistamine cetirizine. Hydroxyzine is likely broken down into several other metabolites, though specific structures and pathways have not been elucidated in humans. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 70% of hydroxyzine's active metabolite, cetirizine, is excreted unchanged in the urine. The precise extent of renal and fecal excretion in humans has not been determined. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life of hydroxyzine is reportedly 14-25 hours, and appears to be, on average, shorter in children (~7.1 hours) than in adults (~20 hours). Elimination half-life is prolonged in the elderly, averaging approximately 29 hours, and is likely to be similarly prolonged in patients with renal or hepatic impairment. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Clearance of hydroxyzine has been reported to be 31.1 ± 11.1 mL/min/kg in children and 9.8 ± 3.3 mL/min/kg in adults. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 is 840 mg/kg in rats and 400 mg/kg in mice. Overdose from hydroxyzine is most commonly characterized by hypersedation, but may also manifest as convulsions, stupor, nausea, and vomiting. In cases of overdose, consider the induction of vomiting and the use of gastric lavage. Other treatment should involve general symptomatic and supportive care. Hypotension may be controlled by intravenous fluids and pressors, and caffeine and sodium benzoate injection may be used to counteract any observed CNS depressant effects. Hemodialysis is unlikely to provide any benefit in the treatment hydroxyzine overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Atarax, Vistaril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Hydroxyzine is an antihistamine used to treat anxiety and tension associated with psychoneuroses, as well as allergic conditions such as pruritus and chronic urticaria. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Ibritumomab tiuxetan interact?

•Drug A: Abatacept •Drug B: Ibritumomab tiuxetan •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Ibritumomab tiuxetan is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For treatment of non-Hodgkin's lymphoma •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ibritumomab is a murine monoclonal antibody against CD20 that has been radiolabeled with yttrium-90. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The Fab segment of the antibody targets the CD20 epitope on B-cells, allowing the radioactive yttrium to destroy the cell via production of beta particles. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Binding observed on lymphoid cells of the bone marrow, lymph node, thymus, red and white pulp of the spleen, lymphoid follicles of the tonsil, and lymphoid nodules of other organs (e.g., large and small intestines) •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Most likely removed by opsonization via the reticuloendothelial system when bound to B cells, or by human antimurine antibody production •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 0.8 hours (mammalian reticulocytes, in vitro) •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Approximately 7.2% of injected dose of yttrium Y 90 ibritumomab tiuxetan is excreted in urine within 7 days. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Zevalin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ibritumomab tiuxetan is a monoclonal anti-CD20 antibody used to treat B-cell non-Hodgkin's lymphoma via a conjugated radioactive isotope.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Ibritumomab tiuxetan interact? Information: •Drug A: Abatacept •Drug B: Ibritumomab tiuxetan •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Ibritumomab tiuxetan is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For treatment of non-Hodgkin's lymphoma •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ibritumomab is a murine monoclonal antibody against CD20 that has been radiolabeled with yttrium-90. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The Fab segment of the antibody targets the CD20 epitope on B-cells, allowing the radioactive yttrium to destroy the cell via production of beta particles. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Binding observed on lymphoid cells of the bone marrow, lymph node, thymus, red and white pulp of the spleen, lymphoid follicles of the tonsil, and lymphoid nodules of other organs (e.g., large and small intestines) •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Most likely removed by opsonization via the reticuloendothelial system when bound to B cells, or by human antimurine antibody production •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 0.8 hours (mammalian reticulocytes, in vitro) •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Approximately 7.2% of injected dose of yttrium Y 90 ibritumomab tiuxetan is excreted in urine within 7 days. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Zevalin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ibritumomab tiuxetan is a monoclonal anti-CD20 antibody used to treat B-cell non-Hodgkin's lymphoma via a conjugated radioactive isotope. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Ibrutinib interact?

•Drug A: Abatacept •Drug B: Ibrutinib •Severity: MODERATE •Description: The metabolism of Ibrutinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ibrutinib is indicated for the treatment of the following conditions. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) In the US, it is used in adult patients with or without 17p deletion. In Europe and Canada, it is used as a single agent or combined with rituximab, obinutuzumab, or venetoclax in previously untreated CLL patients. In patients who have received at least one prior therapy, it is used as a single agent or in combination with bendamustine and rituximab. Waldenström's macroglobulinemia It is used alone or with rituximab. In Europe, it is approved for patients who have received at least one prior therapy or in first-line treatment for patients unsuitable for chemoimmunotherapy. Chronic graft-versus-host disease (cGVHD) In the US, it is approved in patients aged one year and older after the prior failure of one or more lines of systemic therapy. In Canada, it is approved in adults with steroid-dependent or refractory cGVHD. Mantle cell lymphoma (MCL) In Europe and Canada, ibrutinib is also indicated to treat relapsed or refractory MCL in adults. Marginal zone lymphoma (MZL) In Canada, it is approved for adults who require systemic therapy and have received at least one prior anti-CD20-based therapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In vitro studies have shown an induction of CLL cell apoptosis even in presence of prosurvival factors. It has also been reported an inhibition of CLL cell survival and proliferation as well as an impaired in cell migration and a reduction in the secretion of chemokines such as CCL3 and CCL4. The latter effect has been shown to produce regression in xenograft mouse models. Clinical studies for relapsed/refractory CLL in phase I and II showed an approximate 71% of overall response rate.. In the case of relapsed/refractory mantle cell lymphoma, approximately 70% of the tested patients presented a partial or complete response.. In clinical trials for relapsed/refractory diffuse large B-cell lymphoma, a partial response was found in between 15-20% of the patients studied; while for patients with relapsed/refractory Waldenstrom's macroglobulinemia, a partial response was observed in over 75% of the patients tested. Finally, for patients with relapsed/refractory follicular lymphoma, a partial to complete response was obtained in approximately 54% of the patients. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). It forms a covalent bond with a cysteine residue in the active site of BTK (Cys481), leading to its inhibition. The inhibition of BTK plays a role in the B-cell receptor signaling and thus, the presence of ibrutinib prevents the phosphorylation of downstream substrates such as PLC-γ. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Ibrutinib is rapidly absorbed after oral administration and it presents a Cmax, tmax and AUC of approximately 35 ng/ml, 1-2 hour and 953 mg.h/ml respectively. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution at steady-state of ibrutinib is in approximately 10,000 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Irreversible plasma protein binding increases gradually over time and reaches 25% of the administered dose 8 hours after initial administration. From the plasma proteins, ibrutinib has been shown to be mainly bound to albumin and to bind to α1 AGP. The irreversible protein binding of ibrutinib to plasma proteins can account for 97.3% of the administered dose. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Three metabolic pathways have been identified according to the possible metabolites. These pathways are the hydroxylation of the phenyl group (M35), the opening of the piperidine with a reduction of the primary alcohol (M34) and the oxidation to a carboxylic acid and epoxidation of the ethylene followed by a hydrolysis to the formation of dihydrodiol (PCI-45227). The latter metabolite presents also 15 times lower inhibitory activity against BTK. The metabolism of ibrutinib is mainly performed by CYP3A5 and CYP3A4. and in a minor extent it is seen to be performed by CYP2D6. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The cumulative excretion of ibrutinib in urine is of about 7.8% of the administered dose and most of this excretion is found during the first 24 hours after administration. In feces, the cumulative excretion accounts for 80% of the administered dose and the excretion occurs within 48 hours of the initial administration. The total excretion of ibrutinib during the first 168 hours after initial administration accounts for 88.5% of the administered dose. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of ibrutinib is of approximately 4-6 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In patients with normal renal function, the clearance rate is in the range of 112-159 ml/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Ibrutinib was not showed to present a mutagenic potential in bacterial assays, nor clastogenic in chromosome aberration assays in mammalian cells or in bone marrow micronucleus assays in mice. Carcinogenicity or effects on fertility have not been determined. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Imbruvica •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ibrutinib •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ibrutinib is an antineoplastic agent used to treat chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's Macroglobulinemia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Ibrutinib interact? Information: •Drug A: Abatacept •Drug B: Ibrutinib •Severity: MODERATE •Description: The metabolism of Ibrutinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ibrutinib is indicated for the treatment of the following conditions. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) In the US, it is used in adult patients with or without 17p deletion. In Europe and Canada, it is used as a single agent or combined with rituximab, obinutuzumab, or venetoclax in previously untreated CLL patients. In patients who have received at least one prior therapy, it is used as a single agent or in combination with bendamustine and rituximab. Waldenström's macroglobulinemia It is used alone or with rituximab. In Europe, it is approved for patients who have received at least one prior therapy or in first-line treatment for patients unsuitable for chemoimmunotherapy. Chronic graft-versus-host disease (cGVHD) In the US, it is approved in patients aged one year and older after the prior failure of one or more lines of systemic therapy. In Canada, it is approved in adults with steroid-dependent or refractory cGVHD. Mantle cell lymphoma (MCL) In Europe and Canada, ibrutinib is also indicated to treat relapsed or refractory MCL in adults. Marginal zone lymphoma (MZL) In Canada, it is approved for adults who require systemic therapy and have received at least one prior anti-CD20-based therapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In vitro studies have shown an induction of CLL cell apoptosis even in presence of prosurvival factors. It has also been reported an inhibition of CLL cell survival and proliferation as well as an impaired in cell migration and a reduction in the secretion of chemokines such as CCL3 and CCL4. The latter effect has been shown to produce regression in xenograft mouse models. Clinical studies for relapsed/refractory CLL in phase I and II showed an approximate 71% of overall response rate.. In the case of relapsed/refractory mantle cell lymphoma, approximately 70% of the tested patients presented a partial or complete response.. In clinical trials for relapsed/refractory diffuse large B-cell lymphoma, a partial response was found in between 15-20% of the patients studied; while for patients with relapsed/refractory Waldenstrom's macroglobulinemia, a partial response was observed in over 75% of the patients tested. Finally, for patients with relapsed/refractory follicular lymphoma, a partial to complete response was obtained in approximately 54% of the patients. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). It forms a covalent bond with a cysteine residue in the active site of BTK (Cys481), leading to its inhibition. The inhibition of BTK plays a role in the B-cell receptor signaling and thus, the presence of ibrutinib prevents the phosphorylation of downstream substrates such as PLC-γ. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Ibrutinib is rapidly absorbed after oral administration and it presents a Cmax, tmax and AUC of approximately 35 ng/ml, 1-2 hour and 953 mg.h/ml respectively. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution at steady-state of ibrutinib is in approximately 10,000 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Irreversible plasma protein binding increases gradually over time and reaches 25% of the administered dose 8 hours after initial administration. From the plasma proteins, ibrutinib has been shown to be mainly bound to albumin and to bind to α1 AGP. The irreversible protein binding of ibrutinib to plasma proteins can account for 97.3% of the administered dose. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Three metabolic pathways have been identified according to the possible metabolites. These pathways are the hydroxylation of the phenyl group (M35), the opening of the piperidine with a reduction of the primary alcohol (M34) and the oxidation to a carboxylic acid and epoxidation of the ethylene followed by a hydrolysis to the formation of dihydrodiol (PCI-45227). The latter metabolite presents also 15 times lower inhibitory activity against BTK. The metabolism of ibrutinib is mainly performed by CYP3A5 and CYP3A4. and in a minor extent it is seen to be performed by CYP2D6. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The cumulative excretion of ibrutinib in urine is of about 7.8% of the administered dose and most of this excretion is found during the first 24 hours after administration. In feces, the cumulative excretion accounts for 80% of the administered dose and the excretion occurs within 48 hours of the initial administration. The total excretion of ibrutinib during the first 168 hours after initial administration accounts for 88.5% of the administered dose. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of ibrutinib is of approximately 4-6 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In patients with normal renal function, the clearance rate is in the range of 112-159 ml/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Ibrutinib was not showed to present a mutagenic potential in bacterial assays, nor clastogenic in chromosome aberration assays in mammalian cells or in bone marrow micronucleus assays in mice. Carcinogenicity or effects on fertility have not been determined. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Imbruvica •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ibrutinib •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ibrutinib is an antineoplastic agent used to treat chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's Macroglobulinemia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Ibuprofen interact?

•Drug A: Abatacept •Drug B: Ibuprofen •Severity: MODERATE •Description: The metabolism of Ibuprofen can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ibuprofen is the most commonly used and prescribed NSAID. It is a very common over-the-counter medication widely used as an analgesic, anti-inflammatory and antipyretic. The use of ibuprofen and its enantiomer Dexibuprofen in a racemic mix is common for the management of mild to moderate pain related to dysmenorrhea, headache, migraine, postoperative dental pain, spondylitis, osteoarthritis, rheumatoid arthritis, and soft tissue disorder. Due to its activity against prostaglandin and thromboxane synthesis, ibuprofen has been attributed to alteration of platelet function and prolongation of gestation and labour. As ibuprofen is a widely used medication, the main therapeutic indications are: Patent Ductus Arteriosus - it is a neonatal condition wherein the ductus arteriosus (blood vessel that connects the main pulmonary artery to the proximal descending aorta) fails to close after birth causing severe risk of heart failure. The prostaglandin inhibition of ibuprofen has been studied for the treatment of this condition as it is known that prostaglandin E2 is responsible for keeping the ductus arteriosus open. Rheumatoid- and osteo-arthritis - ibuprofen is very commonly used in the symptomatic treatment of inflammatory, musculoskeletal and rheumatic disorders. Cystic fibrosis - the use of high dosages of ibuprofen has been proven to decrease inflammation and decreasing polymorphonuclear cell influx in the lungs. Orthostatic hypotension - ibuprofen can induce sodium retention and antagonize the effect of diuretics which has been reported to be beneficial for patients with severe orthostatic hypotension. Dental pain - ibuprofen is used to manage acute and chronic orofacial pain. Pain - ibuprofen is widely used to reduce minor aches and pains as well as to reduce fever and manage dysmenorrhea. It is very commonly used for the relief of acute indications such as fever and tension headaches. It is also used to manage mild to moderate pain and moderate to severe pain as an adjunct to opioid analgesics. Investigational uses - efforts have been put into developing ibuprofen for the prophylaxis of Alzheimer's disease, Parkinson disease, and breast cancer. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ibuprofen has multiple actions in different inflammatory pathways involved in acute and chronic inflammation. The main effects reported in ibuprofen are related to the control of pain, fever and acute inflammation by the inhibition of the synthesis of prostanoids by COX-1 and COX-2. Pain relief is attributed to peripheral affected regions and central nervous system effects in the pain transmission mediated by the dorsal horn and higher spinothalamic tract. Some reports have tried to link the pain regulation with a possible enhancement on the synthesis of endogenous cannabinoids and action on the NMDA receptors. The effect on pain has been shown to be related to the cortically evoked potentials. The antipyretic effect is reported to be linked to the effect on the prostanoid synthesis due to the fact that the prostanoids are the main signaling mediator of pyresis in the hypothalamic-preoptic region. The use of ibuprofen in dental procedures is attributed to the local inhibition of prostanoid production as well as to anti-oedemic activity and an increase of plasma beta-endorphins. Some reports have suggested a rapid local reduction of the expression of COX-2 in dental pulp derived by the administration of ibuprofen. The administration of ibuprofen in patients with rheumatic diseases has shown to control joint symptoms. Ibuprofen is largely used in OTC products such as an agent for the management of dysmenorrhea which has been proven to reduce the amount of menstrual prostanoids and to produce a reduction in the uterine hypercontractility. As well, it has been reported to reduce significantly the fever and the pain caused by migraines. This effect is thought to be related to the effect on platelet activation and thromboxane A2 production which produces local vascular effects in the affected regions. This effect is viable as ibuprofen can enter in the central nervous system. In the investigational uses of ibuprofen, it has been reported to reduce neurodegeneration when given in low doses over a long time. On the other hand, its use in Parkinson disease is related to the importance of inflammation and oxidative stress in the pathology of this condition. The use of ibuprofen for breast cancer is related to a study that shows a decrease of 50% in the rate of breast cancer. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The exact mechanism of action of ibuprofen is unknown. However, ibuprofen is considered an NSAID and thus it is a non-selective inhibitor of cyclooxygenase, which is an enzyme involved in prostaglandin (mediators of pain and fever) and thromboxane (stimulators of blood clotting) synthesis via the arachidonic acid pathway. Ibuprofen is a non-selective COX inhibitor and hence, it inhibits the activity of both COX-1 and COX-2. The inhibition of COX-2 activity decreases the synthesis of prostaglandins involved in mediating inflammation, pain, fever, and swelling while the inhibition of COX-1 is thought to cause some of the side effects of ibuprofen including GI ulceration. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): It is very well absorbed orally and the peak serum concentration can be attained in 1 to 2 hours after extravascular administration. When ibuprofen is administered immediately after a meal there is a slight reduction in the absorption rate but there is no change in the extent of the absorption. When orally administered, the absorption of ibuprofen in adults is very rapidly done in the upper GI tract. The average Cmax, Tmax and AUC ranges around 20 mcg/ml, 2 h and 70 mcg.h/ml. These parameters can vary depending on the enantiomer form, route, and dose of administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of ibuprofen is of 0.1 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Ibuprofen dosage is more than 99% bound to plasma proteins and site II of purified albumin, binding appears to be saturable and becomes non-linear at concentrations exceeding 20 mcg/ml. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ibuprofen is rapidly metabolized and biotransformed in the liver to the formation of major metabolites which are the hydroxylated and carboxylated derivatives. As soon as it is absorbed, the R-enantiomer undergoes extensive enantiomeric conversion (53-65%) to the more active S-enantiomer in vivo by the activity of alpha-methylacyl-CoA racemase. Ibuprofen metabolism can be divided in phase I which is represented by the hydroxylation of the isobutyl chains for the formation of 2 or 3-hydroxy derivatives followed by oxidation to 2-carboxy-ibuprofen and p-carboxy-2-propionate. These oxidative reactions are performed by the activity of the cytochrome P450 isoforms CYP 2C9, CYP 2C19 and CYP 2C8. Therefore, these enzymes participate in the oxidation of the alkyl side chain to hydroxyl and carboxyl derivatives. From this enzymes, the major catalyst in the formation of oxidative metabolites is the isoform CYP 2C9. The metabolic phase I is followed by a phase II in which the oxidative metabolites may be conjugated to glucuronide prior to excretion. This activity forms phenolic and acyl glucuronides. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Ibuprofen is rapidly metabolized and eliminated in the urine thus, this via accounts for more than 90% of the administered dose. It is completely eliminated in 24 hours after the last dose and almost all the administered dose goes through metabolism, representing about 99% of the eliminated dose. The biliary excretion of unchanged drug and active phase II metabolites represents 1% of the administered dose. In summary, ibuprofen is excreted as metabolites or their conjugates. The elimination of ibuprofen is not impaired by old age or the presence of renal impairment. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The serum half-life of ibuprofen is 1.2-2 hours. In patients with a compromised liver function, the half-life can be prolonged to 3.1-3.4 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance rate ranges between 3-13 L/h depending on the route of administration, enantiomer type and dosage. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The symptoms of overdose are presented in individuals that consumed more than 99 mg/kg. Most common symptoms of overdose are abdominal pain, nausea, vomiting, lethargy, vertigo, drowsiness (somnolence), dizziness and insomnia. Other symptoms of overdose include headache, loss of consciousness, tinnitus, CNS depression, convulsions and seizures. May rarely cause metabolic acidosis, abnormal hepatic function, hyperkalemia, renal failure, dyspnea, respiratory depression, coma, acute renal failure, and apnea (primarily in very young pediatric patients). The reported LD50 of ibuprofen is of 636 mg/kg in rat, 740 mg/kg in mouse and 495 mg/kg in guinea pig. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Addaprin, Advil, Advil Cold and Sinus, Advil Congestion Relief, Advil PM, Advil Sinus Congestion and Pain, Alivio, Caldolor, Cedaprin, Children's Ibuprofen, Combogesic, Diphen, Duexis, Ibu, Ibutab, Junior Strength Motrin, Motrin, Motrin PM, Neoprofen, Nuprin, Pedea, Proprinal, Reprexain, Sudafed PE Head Congestion Plus Pain, Vicoprofen, Wal-profen Congestion Relief and Pain •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ibuprofen Ibuprofene Ibuprofeno Ibuprofenum Ibuprophen •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ibuprofen is an NSAID and non-selective COX inhibitor used to treat mild-moderate pain, fever, and inflammation.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Ibuprofen interact? Information: •Drug A: Abatacept •Drug B: Ibuprofen •Severity: MODERATE •Description: The metabolism of Ibuprofen can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ibuprofen is the most commonly used and prescribed NSAID. It is a very common over-the-counter medication widely used as an analgesic, anti-inflammatory and antipyretic. The use of ibuprofen and its enantiomer Dexibuprofen in a racemic mix is common for the management of mild to moderate pain related to dysmenorrhea, headache, migraine, postoperative dental pain, spondylitis, osteoarthritis, rheumatoid arthritis, and soft tissue disorder. Due to its activity against prostaglandin and thromboxane synthesis, ibuprofen has been attributed to alteration of platelet function and prolongation of gestation and labour. As ibuprofen is a widely used medication, the main therapeutic indications are: Patent Ductus Arteriosus - it is a neonatal condition wherein the ductus arteriosus (blood vessel that connects the main pulmonary artery to the proximal descending aorta) fails to close after birth causing severe risk of heart failure. The prostaglandin inhibition of ibuprofen has been studied for the treatment of this condition as it is known that prostaglandin E2 is responsible for keeping the ductus arteriosus open. Rheumatoid- and osteo-arthritis - ibuprofen is very commonly used in the symptomatic treatment of inflammatory, musculoskeletal and rheumatic disorders. Cystic fibrosis - the use of high dosages of ibuprofen has been proven to decrease inflammation and decreasing polymorphonuclear cell influx in the lungs. Orthostatic hypotension - ibuprofen can induce sodium retention and antagonize the effect of diuretics which has been reported to be beneficial for patients with severe orthostatic hypotension. Dental pain - ibuprofen is used to manage acute and chronic orofacial pain. Pain - ibuprofen is widely used to reduce minor aches and pains as well as to reduce fever and manage dysmenorrhea. It is very commonly used for the relief of acute indications such as fever and tension headaches. It is also used to manage mild to moderate pain and moderate to severe pain as an adjunct to opioid analgesics. Investigational uses - efforts have been put into developing ibuprofen for the prophylaxis of Alzheimer's disease, Parkinson disease, and breast cancer. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ibuprofen has multiple actions in different inflammatory pathways involved in acute and chronic inflammation. The main effects reported in ibuprofen are related to the control of pain, fever and acute inflammation by the inhibition of the synthesis of prostanoids by COX-1 and COX-2. Pain relief is attributed to peripheral affected regions and central nervous system effects in the pain transmission mediated by the dorsal horn and higher spinothalamic tract. Some reports have tried to link the pain regulation with a possible enhancement on the synthesis of endogenous cannabinoids and action on the NMDA receptors. The effect on pain has been shown to be related to the cortically evoked potentials. The antipyretic effect is reported to be linked to the effect on the prostanoid synthesis due to the fact that the prostanoids are the main signaling mediator of pyresis in the hypothalamic-preoptic region. The use of ibuprofen in dental procedures is attributed to the local inhibition of prostanoid production as well as to anti-oedemic activity and an increase of plasma beta-endorphins. Some reports have suggested a rapid local reduction of the expression of COX-2 in dental pulp derived by the administration of ibuprofen. The administration of ibuprofen in patients with rheumatic diseases has shown to control joint symptoms. Ibuprofen is largely used in OTC products such as an agent for the management of dysmenorrhea which has been proven to reduce the amount of menstrual prostanoids and to produce a reduction in the uterine hypercontractility. As well, it has been reported to reduce significantly the fever and the pain caused by migraines. This effect is thought to be related to the effect on platelet activation and thromboxane A2 production which produces local vascular effects in the affected regions. This effect is viable as ibuprofen can enter in the central nervous system. In the investigational uses of ibuprofen, it has been reported to reduce neurodegeneration when given in low doses over a long time. On the other hand, its use in Parkinson disease is related to the importance of inflammation and oxidative stress in the pathology of this condition. The use of ibuprofen for breast cancer is related to a study that shows a decrease of 50% in the rate of breast cancer. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The exact mechanism of action of ibuprofen is unknown. However, ibuprofen is considered an NSAID and thus it is a non-selective inhibitor of cyclooxygenase, which is an enzyme involved in prostaglandin (mediators of pain and fever) and thromboxane (stimulators of blood clotting) synthesis via the arachidonic acid pathway. Ibuprofen is a non-selective COX inhibitor and hence, it inhibits the activity of both COX-1 and COX-2. The inhibition of COX-2 activity decreases the synthesis of prostaglandins involved in mediating inflammation, pain, fever, and swelling while the inhibition of COX-1 is thought to cause some of the side effects of ibuprofen including GI ulceration. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): It is very well absorbed orally and the peak serum concentration can be attained in 1 to 2 hours after extravascular administration. When ibuprofen is administered immediately after a meal there is a slight reduction in the absorption rate but there is no change in the extent of the absorption. When orally administered, the absorption of ibuprofen in adults is very rapidly done in the upper GI tract. The average Cmax, Tmax and AUC ranges around 20 mcg/ml, 2 h and 70 mcg.h/ml. These parameters can vary depending on the enantiomer form, route, and dose of administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of ibuprofen is of 0.1 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Ibuprofen dosage is more than 99% bound to plasma proteins and site II of purified albumin, binding appears to be saturable and becomes non-linear at concentrations exceeding 20 mcg/ml. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ibuprofen is rapidly metabolized and biotransformed in the liver to the formation of major metabolites which are the hydroxylated and carboxylated derivatives. As soon as it is absorbed, the R-enantiomer undergoes extensive enantiomeric conversion (53-65%) to the more active S-enantiomer in vivo by the activity of alpha-methylacyl-CoA racemase. Ibuprofen metabolism can be divided in phase I which is represented by the hydroxylation of the isobutyl chains for the formation of 2 or 3-hydroxy derivatives followed by oxidation to 2-carboxy-ibuprofen and p-carboxy-2-propionate. These oxidative reactions are performed by the activity of the cytochrome P450 isoforms CYP 2C9, CYP 2C19 and CYP 2C8. Therefore, these enzymes participate in the oxidation of the alkyl side chain to hydroxyl and carboxyl derivatives. From this enzymes, the major catalyst in the formation of oxidative metabolites is the isoform CYP 2C9. The metabolic phase I is followed by a phase II in which the oxidative metabolites may be conjugated to glucuronide prior to excretion. This activity forms phenolic and acyl glucuronides. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Ibuprofen is rapidly metabolized and eliminated in the urine thus, this via accounts for more than 90% of the administered dose. It is completely eliminated in 24 hours after the last dose and almost all the administered dose goes through metabolism, representing about 99% of the eliminated dose. The biliary excretion of unchanged drug and active phase II metabolites represents 1% of the administered dose. In summary, ibuprofen is excreted as metabolites or their conjugates. The elimination of ibuprofen is not impaired by old age or the presence of renal impairment. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The serum half-life of ibuprofen is 1.2-2 hours. In patients with a compromised liver function, the half-life can be prolonged to 3.1-3.4 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance rate ranges between 3-13 L/h depending on the route of administration, enantiomer type and dosage. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The symptoms of overdose are presented in individuals that consumed more than 99 mg/kg. Most common symptoms of overdose are abdominal pain, nausea, vomiting, lethargy, vertigo, drowsiness (somnolence), dizziness and insomnia. Other symptoms of overdose include headache, loss of consciousness, tinnitus, CNS depression, convulsions and seizures. May rarely cause metabolic acidosis, abnormal hepatic function, hyperkalemia, renal failure, dyspnea, respiratory depression, coma, acute renal failure, and apnea (primarily in very young pediatric patients). The reported LD50 of ibuprofen is of 636 mg/kg in rat, 740 mg/kg in mouse and 495 mg/kg in guinea pig. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Addaprin, Advil, Advil Cold and Sinus, Advil Congestion Relief, Advil PM, Advil Sinus Congestion and Pain, Alivio, Caldolor, Cedaprin, Children's Ibuprofen, Combogesic, Diphen, Duexis, Ibu, Ibutab, Junior Strength Motrin, Motrin, Motrin PM, Neoprofen, Nuprin, Pedea, Proprinal, Reprexain, Sudafed PE Head Congestion Plus Pain, Vicoprofen, Wal-profen Congestion Relief and Pain •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ibuprofen Ibuprofene Ibuprofeno Ibuprofenum Ibuprophen •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ibuprofen is an NSAID and non-selective COX inhibitor used to treat mild-moderate pain, fever, and inflammation. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Idarubicin interact?

•Drug A: Abatacept •Drug B: Idarubicin •Severity: MODERATE •Description: The metabolism of Idarubicin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of acute myeloid leukemia (AML) in adults. This includes French-American-British (FAB) classifications M1 through M7. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Idarubicin is an antineoplastic in the anthracycline class. General properties of drugs in this class include: interaction with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and antibiotics. However, they lack the specificity of the antimicrobial antibiotics and thus produce significant toxicity. The anthracyclines are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemia. Idarubicin may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA. Idarubicin possesses an antitumor effect against a wide spectrum of tumors, either grafted or spontaneous. The anthracyclines are cell cycle-nonspecific. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Idarubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Idarubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 97% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The drug is eliminated predominately by biliary and to a lesser extent by renal excretion, mostly in the form of idarubicinol. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 22 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Idamycin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 4-Demethoxydaunorubicin Idarubicin Idarubicina Idarubicine Idarubicinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Idarubicin is an anthracycline antineoplastic agent used to treat acute myeloid leukemia (AML) in adults.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Idarubicin interact? Information: •Drug A: Abatacept •Drug B: Idarubicin •Severity: MODERATE •Description: The metabolism of Idarubicin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of acute myeloid leukemia (AML) in adults. This includes French-American-British (FAB) classifications M1 through M7. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Idarubicin is an antineoplastic in the anthracycline class. General properties of drugs in this class include: interaction with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and antibiotics. However, they lack the specificity of the antimicrobial antibiotics and thus produce significant toxicity. The anthracyclines are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemia. Idarubicin may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA. Idarubicin possesses an antitumor effect against a wide spectrum of tumors, either grafted or spontaneous. The anthracyclines are cell cycle-nonspecific. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Idarubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Idarubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 97% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The drug is eliminated predominately by biliary and to a lesser extent by renal excretion, mostly in the form of idarubicinol. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 22 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Idamycin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 4-Demethoxydaunorubicin Idarubicin Idarubicina Idarubicine Idarubicinum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Idarubicin is an anthracycline antineoplastic agent used to treat acute myeloid leukemia (AML) in adults. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Idelalisib interact?

•Drug A: Abatacept •Drug B: Idelalisib •Severity: MAJOR •Description: The metabolism of Idelalisib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Idelalisib is indicated in the treatment of chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), and relapsed small lymphocytic lymphoma (SLL). For the treatment of relapsed CLL, it is currently indicated as a second-line agent in combination with rituximab in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities, while in the treatment of FL and SLL it is intended to be used in patients who have received at least two prior systemic therapies. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Idelalisib specifically inhibits P110δ, the delta isoform of the enzyme phosphatidylinositol-4,5-bisphosphate 3-kinase, also known as PI-3K. The PI-3Ks are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In contrast to the other class IA PI3Ks p110α and p110β, p110δ is principally expressed in leukocytes (white blood cells) and is important for the function of T cells, B cell, mast cells and neutrophils. By inhibiting this enzyme, idelalisib induces apoptosis of malignant cells and inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and C-X-C chemokine receptors type 5 and type 4 signalling, which are involved in trafficking and homing of B-cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib has been shown to result in inhibition of chemotaxis and adhesion, and reduced cell viability. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following oral administration, the median Tmax was observed at 1.5 hours. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 23 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Idelalisib is greater than 84% bound to human plasma proteins with no concentration dependence. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Idelalisib is metabolized by aldehyde oxidase and CYP3A to its major metabolite GS-563117, which is inactive against P110δ. Idelalisib is also metabolized to a minor extent by UGT1A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single dose of 150 mg of [14C] idelalisib, 78% and 14% of the radioactivity was excreted in feces and urine, respectively. GS-563117, idelalisib's major metabolite, accounted for 49% of the radioactivity in the urine and 44% in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half-life is 8.2 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 14.9 L/hr •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Zydelig •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Idelalisib •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Idelalisib is an antineoplastic kinase inhibitor used to treat chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), and relapsed small lymphocytic lymphoma (SLL).

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Idelalisib interact? Information: •Drug A: Abatacept •Drug B: Idelalisib •Severity: MAJOR •Description: The metabolism of Idelalisib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Idelalisib is indicated in the treatment of chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), and relapsed small lymphocytic lymphoma (SLL). For the treatment of relapsed CLL, it is currently indicated as a second-line agent in combination with rituximab in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities, while in the treatment of FL and SLL it is intended to be used in patients who have received at least two prior systemic therapies. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Idelalisib specifically inhibits P110δ, the delta isoform of the enzyme phosphatidylinositol-4,5-bisphosphate 3-kinase, also known as PI-3K. The PI-3Ks are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In contrast to the other class IA PI3Ks p110α and p110β, p110δ is principally expressed in leukocytes (white blood cells) and is important for the function of T cells, B cell, mast cells and neutrophils. By inhibiting this enzyme, idelalisib induces apoptosis of malignant cells and inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and C-X-C chemokine receptors type 5 and type 4 signalling, which are involved in trafficking and homing of B-cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib has been shown to result in inhibition of chemotaxis and adhesion, and reduced cell viability. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following oral administration, the median Tmax was observed at 1.5 hours. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 23 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Idelalisib is greater than 84% bound to human plasma proteins with no concentration dependence. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Idelalisib is metabolized by aldehyde oxidase and CYP3A to its major metabolite GS-563117, which is inactive against P110δ. Idelalisib is also metabolized to a minor extent by UGT1A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single dose of 150 mg of [14C] idelalisib, 78% and 14% of the radioactivity was excreted in feces and urine, respectively. GS-563117, idelalisib's major metabolite, accounted for 49% of the radioactivity in the urine and 44% in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half-life is 8.2 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 14.9 L/hr •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Zydelig •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Idelalisib •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Idelalisib is an antineoplastic kinase inhibitor used to treat chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), and relapsed small lymphocytic lymphoma (SLL). Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Ifosfamide interact?

•Drug A: Abatacept •Drug B: Ifosfamide •Severity: MAJOR •Description: The metabolism of Ifosfamide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used as a component of various chemotherapeutic regimens as third-line therapy for recurrent or refractory germ cell testicular cancer. Also used as a component of various chemotherapeutic regimens for the treatment of cervical cancer, as well as in conjunction with surgery and/or radiation therapy in the treatment of various soft tissue sarcomas. Other indications include treatment of osteosarcoma, bladder cancer, ovarian cancer. small cell lung cancer, and non-Hodgkin's lymphoma. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ifosfamide requires activation by microsomal liver enzymes to active metabolites in order to exert its cytotoxic effects. Activation occurs by hydroxylation at the ring carbon atom 4 to form the unstable intermediate 4-hydroxyifosfamide. This metabolite than rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. The stable urinary metabolite, 4-carboxyifosfamide, is formed upon opening of the ring. These urinary metabolites have not been found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoric acid diamide (ifosphoramide) and acrolein are also found. The major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide, are formed upon enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation. It is the alkylated metabolites of ifosfamide that have been shown to interact with DNA. Ifosfamide is cycle-phase nonspecific. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The exact mechanism of ifosfamide has not been determined, but appears to be similar to other alkylating agents. Ifosfamide requires biotransformation in the liver by mixed-function oxidases (cytochrome P450 system) before it becomes active. After metabolic activation, active metabolites of ifosfamide alkylate or bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily through the alkylation of DNA, done by attaching the N-7 position of guanine to its reactive electrophilic groups. The formation of inter and intra strand cross-links in the DNA results in cell death. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Ifosfamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 1 and 0.72 L/kg on Day 5. When given to pediatric patients, the volume of distribution was 21±1.6 L/m^2. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Ifosfamide shows little plasma protein binding. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic. Ifosfamide is metabolized through two metabolic pathways: ring oxidation ("activation") to form the active metabolite, 4-hydroxy-ifosfamide and side-chain oxidation to form the inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide with liberation of the toxic metabolite, chloroacetaldehyde. Small quantities (nmol/mL) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma. Metabolism of ifosfamide is required for the generation of the biologically active species and while metabolism is extensive, it is also quite variable among patients. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Ifosfamide is extensively metabolized in humans and the metabolic pathways appear to be saturated at high doses. After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in the urine, with about 61% of the dose excreted as parent compound. At doses of 1.6–2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 7-15 hours. The elimination half-life increase appeared to be related to the increase in ifosfamide volume of distribution with age. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 2.4±0.33 L/h/m^2 [pediatric patients] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 (mouse) = 390-1005 mg/kg, LD 50 (rat) = 150-190 mg/kg. Side effects include nausea, vomiting and myelosuppression. Toxic effects include central nervous system toxicity (confusion, hallucinations) and urotoxic effects (cystitis, blood in urine). •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ifex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ifosfamida Ifosfamide Ifosfamidum Iphosphamide Isofosfamide Isophosphamide Isosfamide •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ifosfamide is an alkylating and immunosuppressive agent used in chemotherapy for the treatment of cancers, including testicular cancer, ovarian cancer, cervical cancer, osteocarcinoma, bladder cancer, small cell lung cancer, and non-Hodgkin's lymphoma.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Ifosfamide interact? Information: •Drug A: Abatacept •Drug B: Ifosfamide •Severity: MAJOR •Description: The metabolism of Ifosfamide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used as a component of various chemotherapeutic regimens as third-line therapy for recurrent or refractory germ cell testicular cancer. Also used as a component of various chemotherapeutic regimens for the treatment of cervical cancer, as well as in conjunction with surgery and/or radiation therapy in the treatment of various soft tissue sarcomas. Other indications include treatment of osteosarcoma, bladder cancer, ovarian cancer. small cell lung cancer, and non-Hodgkin's lymphoma. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ifosfamide requires activation by microsomal liver enzymes to active metabolites in order to exert its cytotoxic effects. Activation occurs by hydroxylation at the ring carbon atom 4 to form the unstable intermediate 4-hydroxyifosfamide. This metabolite than rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. The stable urinary metabolite, 4-carboxyifosfamide, is formed upon opening of the ring. These urinary metabolites have not been found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoric acid diamide (ifosphoramide) and acrolein are also found. The major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide, are formed upon enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation. It is the alkylated metabolites of ifosfamide that have been shown to interact with DNA. Ifosfamide is cycle-phase nonspecific. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The exact mechanism of ifosfamide has not been determined, but appears to be similar to other alkylating agents. Ifosfamide requires biotransformation in the liver by mixed-function oxidases (cytochrome P450 system) before it becomes active. After metabolic activation, active metabolites of ifosfamide alkylate or bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily through the alkylation of DNA, done by attaching the N-7 position of guanine to its reactive electrophilic groups. The formation of inter and intra strand cross-links in the DNA results in cell death. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Ifosfamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 1 and 0.72 L/kg on Day 5. When given to pediatric patients, the volume of distribution was 21±1.6 L/m^2. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Ifosfamide shows little plasma protein binding. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic. Ifosfamide is metabolized through two metabolic pathways: ring oxidation ("activation") to form the active metabolite, 4-hydroxy-ifosfamide and side-chain oxidation to form the inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide with liberation of the toxic metabolite, chloroacetaldehyde. Small quantities (nmol/mL) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma. Metabolism of ifosfamide is required for the generation of the biologically active species and while metabolism is extensive, it is also quite variable among patients. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Ifosfamide is extensively metabolized in humans and the metabolic pathways appear to be saturated at high doses. After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in the urine, with about 61% of the dose excreted as parent compound. At doses of 1.6–2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 7-15 hours. The elimination half-life increase appeared to be related to the increase in ifosfamide volume of distribution with age. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 2.4±0.33 L/h/m^2 [pediatric patients] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 (mouse) = 390-1005 mg/kg, LD 50 (rat) = 150-190 mg/kg. Side effects include nausea, vomiting and myelosuppression. Toxic effects include central nervous system toxicity (confusion, hallucinations) and urotoxic effects (cystitis, blood in urine). •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ifex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ifosfamida Ifosfamide Ifosfamidum Iphosphamide Isofosfamide Isophosphamide Isosfamide •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ifosfamide is an alkylating and immunosuppressive agent used in chemotherapy for the treatment of cancers, including testicular cancer, ovarian cancer, cervical cancer, osteocarcinoma, bladder cancer, small cell lung cancer, and non-Hodgkin's lymphoma. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Iloperidone interact?

•Drug A: Abatacept •Drug B: Iloperidone •Severity: MODERATE •Description: The metabolism of Iloperidone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Treatment of acute schizophrenia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Iloperidone shows high affinity and maximal receptor occupancy for dopamine D2 receptors in the caudate nucleus and putamen of the brains of schizophrenic patients. The improvement in cognition is attributed to iloperidone's high affinity for α adrenergic receptors. Iloperidone also binds with high affinity to serotonin 5-HT2a and dopamine 3 receptors. Iloperidone binds with moderate affinity to dopamine D4, serotonin 5-HT6 and 5-HT7, and norepinephrine NEα1 receptors. Furthermore, iloperidone binds with weak affinity to serotonin 5-HT1A, dopamine D1, and histamine H1 receptors. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Iloperidone is a dopamine D2 and 5-HT2A receptor antagonist and acts as a neuroleptic agent. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Well absorbed from the GI tract and Cmax is reached within 2-4 hours. Steady-state concentration is achieved in 3-4 days post-administration of iloperidone. Relative bioavailability of the tablet formulation compared to oral solution is 96%. Accumulation occurs in a predictable fashion. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Apparent Vd = 1340-2800 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95% of iloperidone is bound to protein. Percent bound is not altered by renal or hepatic impairment or combination therapy with ketoconazole. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Iloperidone is hepatically metabolized by cytochrome enzymes which mediates O-dealkylation (CYP3A4), hydroxylation (CYP2D6), and decarboxylation/reduction processes. Metabolites formed are P89, P95, and P88. The minor metabolite is P89, whereas P95 and P88 are the major ones. The affinity of the iloperidone metabolite P88 is generally equal or less than that of the parent compound. In contrast, the metabolite P95 only shows affinity for 5-HT2A (Ki value of 3.91) and the NEα1A, NEα1B, NEα1D, and NEα2C receptors (Ki values of 4.7, 2.7, 8.8 and 4.7 nM respectively). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Renal (in which <1% of iloperidone is excreted unchanged). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The observed mean elimination half-lives for iloperidone, P88 and P95 in CYP2D6 extensive metabolizers (EM) are 18, 26 and 23 hours, respectively, and in poor metabolizers (PM) are 33, 37 and 31 hours, respectively. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Apparent clearance (clearance/bioavilability) = 47-102 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Commonly observed adverse reactions (incidence ≥5% and two-fold greater than placebo) were: dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increased. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Fanapt •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Iloperidona Iloperidone Ilopéridone Iloperidonum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Iloperidone is an atypical antipsychotic agent used for the acute treatment of schizophrenia in adults.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Iloperidone interact? Information: •Drug A: Abatacept •Drug B: Iloperidone •Severity: MODERATE •Description: The metabolism of Iloperidone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Treatment of acute schizophrenia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Iloperidone shows high affinity and maximal receptor occupancy for dopamine D2 receptors in the caudate nucleus and putamen of the brains of schizophrenic patients. The improvement in cognition is attributed to iloperidone's high affinity for α adrenergic receptors. Iloperidone also binds with high affinity to serotonin 5-HT2a and dopamine 3 receptors. Iloperidone binds with moderate affinity to dopamine D4, serotonin 5-HT6 and 5-HT7, and norepinephrine NEα1 receptors. Furthermore, iloperidone binds with weak affinity to serotonin 5-HT1A, dopamine D1, and histamine H1 receptors. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Iloperidone is a dopamine D2 and 5-HT2A receptor antagonist and acts as a neuroleptic agent. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Well absorbed from the GI tract and Cmax is reached within 2-4 hours. Steady-state concentration is achieved in 3-4 days post-administration of iloperidone. Relative bioavailability of the tablet formulation compared to oral solution is 96%. Accumulation occurs in a predictable fashion. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Apparent Vd = 1340-2800 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95% of iloperidone is bound to protein. Percent bound is not altered by renal or hepatic impairment or combination therapy with ketoconazole. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Iloperidone is hepatically metabolized by cytochrome enzymes which mediates O-dealkylation (CYP3A4), hydroxylation (CYP2D6), and decarboxylation/reduction processes. Metabolites formed are P89, P95, and P88. The minor metabolite is P89, whereas P95 and P88 are the major ones. The affinity of the iloperidone metabolite P88 is generally equal or less than that of the parent compound. In contrast, the metabolite P95 only shows affinity for 5-HT2A (Ki value of 3.91) and the NEα1A, NEα1B, NEα1D, and NEα2C receptors (Ki values of 4.7, 2.7, 8.8 and 4.7 nM respectively). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Renal (in which <1% of iloperidone is excreted unchanged). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The observed mean elimination half-lives for iloperidone, P88 and P95 in CYP2D6 extensive metabolizers (EM) are 18, 26 and 23 hours, respectively, and in poor metabolizers (PM) are 33, 37 and 31 hours, respectively. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Apparent clearance (clearance/bioavilability) = 47-102 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Commonly observed adverse reactions (incidence ≥5% and two-fold greater than placebo) were: dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increased. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Fanapt •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Iloperidona Iloperidone Ilopéridone Iloperidonum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Iloperidone is an atypical antipsychotic agent used for the acute treatment of schizophrenia in adults. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Imatinib interact?

•Drug A: Abatacept •Drug B: Imatinib •Severity: MODERATE •Description: The metabolism of Imatinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Imatinib is indicated for the treatment of adult and pediatric chronic myeloid leukemia with Philadelphia chromosome mutation (Ph+) in blast crisis, accelerated phase, or chronic phase after IFN-alpha therapy failure. Additionally, imatinib is also indicated to treat adult and pediatric Ph+ acute lymphoblastic leukemia, adult myelodysplastic/myeloproliferative diseases, adult aggressive systemic mastocytosis, adult hypereosinophilic syndrome and/or chronic eosinophilic leukemia (CEL), adult dermatofibrosarcoma protuberans, and malignant gastrointestinal stromal tumors (GIST). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Imatinib is a 2-phenylaminopyrimidine derivative neoplastic agent that belongs to the class of tyrosine kinase inhibitors. Although imatinib inhibits a number of tyrosine kinases, it is quite selective toward the BCR-ABL fusion protein that is present in various cancers. BCR-ABL pathway controls many downstream pathways that are heavily implicated in neoplastic growth such as the Ras/MapK pathway (cellular proliferation), Src/Pax/Fak/Rac pathway (cellular motility), and PI/PI3K/AKT/BCL-2 pathway (apoptosis pathway). Therefore, the BCR-ABL pathway is an attractive target for cancer treatment. Although normal cells also depend on these pathways for growth, these cells tend to have redundant tyrosine kinases to continually function in spite of ABL inhibition from imatinib. Cancer cells, on the other hand, can have a dependence on BCR-ABL, thus more heavily impacted by imatinib. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutively active tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Although the function of normal BCR is still unclear, ABL activation is overexpressed in various tumors and is heavily implicated in cancer cells growth and survival. Imatinib inhibits the BCR-ABL protein by binding to the ATP pocket in the active site, thus preventing downstream phosphorylation of target protein. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Imatinib is well absorbed after oral administration with Cmax achieved within 2-4 hours post-dose. Mean absolute bioavailability is 98%. Mean imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5- to 2.5-fold at a steady state when Gleevec is dosed once daily. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Population pharmacokinetics in adult CML patients estimated the steady-state volume of distribution of imatinib to be 295.0 ± 62.5 L. At a dose of 340 mg/m, the volume of distribution of imatinib in pediatric patients was calculated to be 167 ± 84 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and α1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): CYP3A4 is the major enzyme responsible for the metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-desmethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicities. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The most frequently reported adverse reactions (>30%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain. In the 2-year rat carcinogenicity study administration of imatinib at 15, 30, and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at greater than or equal to 30 mg/kg/day. Target organs for neoplastic changes were the kidneys (renal tubule and renal pelvis), urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands, and non-glandular stomach. Neoplastic lesions were not seen at 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands, and non-glandular stomach, and 15 mg/kg/day for the preputial and clitoral gland. The papilloma/carcinoma of the preputial/clitoral gland was noted at 30 and 60 mg/kg/day, representing approximately 0.5 to 4 or 0.3 to 2.4 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 to 3.0 times the daily exposure in children (based on AUC) at 340 mg/m2. The renal tubule adenoma/carcinoma, renal pelvis transitional cell neoplasms, the urinary bladder and urethra transitional cell papillomas, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumors of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day. The relevance of these findings in the rat carcinogenicity study for humans is not known. Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus assay. In a study of fertility, male rats were dosed for 70 days prior to mating and female rats were dosed 14 days prior to mating and through to gestational Day 6. Testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately three-fourths the maximum clinical dose of 800 mg/day based on BSA. This was not seen at doses less than or equal to 20 mg/kg (one-fourth of the maximum human dose of 800 mg). The fertility of male and female rats was not affected. Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights, as well as a reduced number of motile sperm, were observed in the high-dose male rats. In the preclinical pre-and postnatal study in rats, fertility in the first generation offspring was also not affected by imatinib mesylate. It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney, and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in the worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died in the study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females), and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study that were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs, and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Gleevec, Glivec •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Imatinib Imatinibum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Imatinib is a tyrosine kinase inhibitor used to treat a number of leukemias, myelodysplastic/myeloproliferative disease, systemic mastocytosis, hypereosinophilic syndrome, dermatofibrosarcoma protuberans, and gastrointestinal stromal tumors.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Imatinib interact? Information: •Drug A: Abatacept •Drug B: Imatinib •Severity: MODERATE •Description: The metabolism of Imatinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Imatinib is indicated for the treatment of adult and pediatric chronic myeloid leukemia with Philadelphia chromosome mutation (Ph+) in blast crisis, accelerated phase, or chronic phase after IFN-alpha therapy failure. Additionally, imatinib is also indicated to treat adult and pediatric Ph+ acute lymphoblastic leukemia, adult myelodysplastic/myeloproliferative diseases, adult aggressive systemic mastocytosis, adult hypereosinophilic syndrome and/or chronic eosinophilic leukemia (CEL), adult dermatofibrosarcoma protuberans, and malignant gastrointestinal stromal tumors (GIST). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Imatinib is a 2-phenylaminopyrimidine derivative neoplastic agent that belongs to the class of tyrosine kinase inhibitors. Although imatinib inhibits a number of tyrosine kinases, it is quite selective toward the BCR-ABL fusion protein that is present in various cancers. BCR-ABL pathway controls many downstream pathways that are heavily implicated in neoplastic growth such as the Ras/MapK pathway (cellular proliferation), Src/Pax/Fak/Rac pathway (cellular motility), and PI/PI3K/AKT/BCL-2 pathway (apoptosis pathway). Therefore, the BCR-ABL pathway is an attractive target for cancer treatment. Although normal cells also depend on these pathways for growth, these cells tend to have redundant tyrosine kinases to continually function in spite of ABL inhibition from imatinib. Cancer cells, on the other hand, can have a dependence on BCR-ABL, thus more heavily impacted by imatinib. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutively active tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Although the function of normal BCR is still unclear, ABL activation is overexpressed in various tumors and is heavily implicated in cancer cells growth and survival. Imatinib inhibits the BCR-ABL protein by binding to the ATP pocket in the active site, thus preventing downstream phosphorylation of target protein. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Imatinib is well absorbed after oral administration with Cmax achieved within 2-4 hours post-dose. Mean absolute bioavailability is 98%. Mean imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5- to 2.5-fold at a steady state when Gleevec is dosed once daily. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Population pharmacokinetics in adult CML patients estimated the steady-state volume of distribution of imatinib to be 295.0 ± 62.5 L. At a dose of 340 mg/m, the volume of distribution of imatinib in pediatric patients was calculated to be 167 ± 84 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and α1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): CYP3A4 is the major enzyme responsible for the metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-desmethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicities. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The most frequently reported adverse reactions (>30%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain. In the 2-year rat carcinogenicity study administration of imatinib at 15, 30, and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at greater than or equal to 30 mg/kg/day. Target organs for neoplastic changes were the kidneys (renal tubule and renal pelvis), urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands, and non-glandular stomach. Neoplastic lesions were not seen at 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands, and non-glandular stomach, and 15 mg/kg/day for the preputial and clitoral gland. The papilloma/carcinoma of the preputial/clitoral gland was noted at 30 and 60 mg/kg/day, representing approximately 0.5 to 4 or 0.3 to 2.4 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 to 3.0 times the daily exposure in children (based on AUC) at 340 mg/m2. The renal tubule adenoma/carcinoma, renal pelvis transitional cell neoplasms, the urinary bladder and urethra transitional cell papillomas, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumors of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day. The relevance of these findings in the rat carcinogenicity study for humans is not known. Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus assay. In a study of fertility, male rats were dosed for 70 days prior to mating and female rats were dosed 14 days prior to mating and through to gestational Day 6. Testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately three-fourths the maximum clinical dose of 800 mg/day based on BSA. This was not seen at doses less than or equal to 20 mg/kg (one-fourth of the maximum human dose of 800 mg). The fertility of male and female rats was not affected. Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights, as well as a reduced number of motile sperm, were observed in the high-dose male rats. In the preclinical pre-and postnatal study in rats, fertility in the first generation offspring was also not affected by imatinib mesylate. It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney, and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in the worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died in the study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females), and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study that were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs, and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Gleevec, Glivec •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Imatinib Imatinibum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Imatinib is a tyrosine kinase inhibitor used to treat a number of leukemias, myelodysplastic/myeloproliferative disease, systemic mastocytosis, hypereosinophilic syndrome, dermatofibrosarcoma protuberans, and gastrointestinal stromal tumors. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Imipramine interact?

•Drug A: Abatacept •Drug B: Imipramine •Severity: MAJOR •Description: The metabolism of Imipramine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the relief of symptoms of depression and as temporary adjunctive therapy in reducing enuresis in children aged 6 years and older. May also be used off-label to manage panic disorders with or without agoraphobia, as a second line agent for ADHD in children and adolescents, to manage bulimia nervosa, for short-term management of acute depressive episodes in bipolar disorder and schizophrenia, for the treatment of acute stress disorder and posttraumatic stress disorder, and for symptomatic treatment of postherpetic neuralgia and painful diabetic neuropathy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Imipramine is a tricyclic antidepressant with general pharmacological properties similar to those of structurally related tricyclic antidepressant drugs such as amitriptyline and doxepin. While it acts to block both, imipramine displays a much higher affinity for the serotonin reuptake transporter than for the norepinephrine reuptake transporter. Imipramine produces effects similar to other monoamine targeting antidepressants, increasing serotonin- and norepinephrine-based neurotransmission. This modulation of neurotransmission produces a complex range of changes in brain structure and function along with an improvement in depressive symptoms. The changes include increases in hippocampal neurogenesis and reduced downregulation of this neurogenesis in response to stress. These implicate brain derived neurotrophic factor signalling as a necessary contributor to antidepressant effect although the link to the direct increase in monoamine neurotransmission is unclear. Serotonin reuptake targeting agents may also produce a down-regulation in β-adrenergic receptors in the brain. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Imipramine works by inhibiting the neuronal reuptake of the neurotransmitters norepinephrine and serotonin. It binds the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter reducing the reuptake of norepinephrine and serotonin by neurons. Depression has been linked to a lack of stimulation of the post-synaptic neuron by norepinephrine and serotonin. Slowing the reuptake of these neurotransmitters increases their concentration in the synaptic cleft, producing knock-on effects in protein kinase signalling which is thought to contribute to changes in neurotransmission and brain physiology which relieves symptoms of depression. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly and well absorbed (>95%) after oral administration. The primary site of absorption is the small intestine as the basic amine groups are ionized in the acidic environment of the stomach, preventing movement across tissues. Bioavailability ranges from 29-77% due to high inter-individual variability. Peak plasma concentration is usually attained 2-6 hours following oral administration. Absorption is unaffected by food. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Imipramine has a high apparent volume of distribution of 10-20 L/kg. The drug is known to accumulate in the brain at concentrations 30-40 times that in systemic circulation. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Imipramine is 60-96% bound to plasma proteins in circulation. It is known to bind albumin, α1-acid glycoprotein, and lipoproteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Imipramine is nearly exclusively metabolized by the liver. Imipramine is converted to desipramine by CYP1A2, CYP3A4, CYP2C19. Both imipramine and desipramine are hydroxylated by CYP2D6. Desipramine is an active metabolite. Minor metabolic pathways include dealkylation to form an imidodibenzyl product as well as demethylation of desipramine to didemethylimipramine and subsequent hydroxylation. Less than 5% of orally administered imipramine is excreted unchanged. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Imipramine is primarily excreted in the urine with less than 5% present as the parent compound •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Imipramine has a mean half life of 12 h. Its active metabolite, desipramine has a mean half life of 22.5 h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Imipramine has a mean clearance of 1 L/h/kg. Its active metabolite, desipramine has a mean clearance of 1.8 L/h/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The anticholinergic actvity of imipramine can produce dry mucous membranes, blurred vision, increased intraocular pressure, hyperthermia, constipation, adynamic ileus, urinary retention, delayed micturition, and dilation of the urinary tract. Central nervous system and neuromuscular effects include drowsiness, lethargy, fatigue, agitation, excitement, nightmares, restlessness, insomnia, confusion, disturbed concentration, disorientation, delusions, and hallucinations. Effects on the GI tract include anorexia, nausea and vomiting, diarrhea, abdominal cramps, increases in pancreatic enzymes, epigastric distress, stomatitis, peculiar taste, and black tongue. Rarely agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, and purpura have occured. Infants whose mothers were receiving tricyclic antidepressants prior to delivery have experienced cardiac problems, irritability, respiratory distress, muscle spasms, seizures, and urinary retention. Serotonin syndrome can occur when used in conjunction with other pro-serotonergic drugs. LD 50 Values Rat - Oral 250 mg/kg - Intraperitoneal 79mg/kg - Subcutaneous 250 mg/kg - Intravenous 15.9 mg/kg Mouse - Oral 188 mg/kg - Intraperitoneal 51.6 mg/kg - Subcutaneous 195 μg/kg - Intravenous 21 mg/kg Human range of toxicity is considered to include single dosages greater than 5 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tofranil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Imipramin Imipramina Imipramine Imipraminum Imizine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Imipramine is a tricyclic antidepressant indicated for the treatment of depression and to reduce childhood enuresis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Imipramine interact? Information: •Drug A: Abatacept •Drug B: Imipramine •Severity: MAJOR •Description: The metabolism of Imipramine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the relief of symptoms of depression and as temporary adjunctive therapy in reducing enuresis in children aged 6 years and older. May also be used off-label to manage panic disorders with or without agoraphobia, as a second line agent for ADHD in children and adolescents, to manage bulimia nervosa, for short-term management of acute depressive episodes in bipolar disorder and schizophrenia, for the treatment of acute stress disorder and posttraumatic stress disorder, and for symptomatic treatment of postherpetic neuralgia and painful diabetic neuropathy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Imipramine is a tricyclic antidepressant with general pharmacological properties similar to those of structurally related tricyclic antidepressant drugs such as amitriptyline and doxepin. While it acts to block both, imipramine displays a much higher affinity for the serotonin reuptake transporter than for the norepinephrine reuptake transporter. Imipramine produces effects similar to other monoamine targeting antidepressants, increasing serotonin- and norepinephrine-based neurotransmission. This modulation of neurotransmission produces a complex range of changes in brain structure and function along with an improvement in depressive symptoms. The changes include increases in hippocampal neurogenesis and reduced downregulation of this neurogenesis in response to stress. These implicate brain derived neurotrophic factor signalling as a necessary contributor to antidepressant effect although the link to the direct increase in monoamine neurotransmission is unclear. Serotonin reuptake targeting agents may also produce a down-regulation in β-adrenergic receptors in the brain. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Imipramine works by inhibiting the neuronal reuptake of the neurotransmitters norepinephrine and serotonin. It binds the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter reducing the reuptake of norepinephrine and serotonin by neurons. Depression has been linked to a lack of stimulation of the post-synaptic neuron by norepinephrine and serotonin. Slowing the reuptake of these neurotransmitters increases their concentration in the synaptic cleft, producing knock-on effects in protein kinase signalling which is thought to contribute to changes in neurotransmission and brain physiology which relieves symptoms of depression. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly and well absorbed (>95%) after oral administration. The primary site of absorption is the small intestine as the basic amine groups are ionized in the acidic environment of the stomach, preventing movement across tissues. Bioavailability ranges from 29-77% due to high inter-individual variability. Peak plasma concentration is usually attained 2-6 hours following oral administration. Absorption is unaffected by food. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Imipramine has a high apparent volume of distribution of 10-20 L/kg. The drug is known to accumulate in the brain at concentrations 30-40 times that in systemic circulation. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Imipramine is 60-96% bound to plasma proteins in circulation. It is known to bind albumin, α1-acid glycoprotein, and lipoproteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Imipramine is nearly exclusively metabolized by the liver. Imipramine is converted to desipramine by CYP1A2, CYP3A4, CYP2C19. Both imipramine and desipramine are hydroxylated by CYP2D6. Desipramine is an active metabolite. Minor metabolic pathways include dealkylation to form an imidodibenzyl product as well as demethylation of desipramine to didemethylimipramine and subsequent hydroxylation. Less than 5% of orally administered imipramine is excreted unchanged. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Imipramine is primarily excreted in the urine with less than 5% present as the parent compound •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Imipramine has a mean half life of 12 h. Its active metabolite, desipramine has a mean half life of 22.5 h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Imipramine has a mean clearance of 1 L/h/kg. Its active metabolite, desipramine has a mean clearance of 1.8 L/h/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The anticholinergic actvity of imipramine can produce dry mucous membranes, blurred vision, increased intraocular pressure, hyperthermia, constipation, adynamic ileus, urinary retention, delayed micturition, and dilation of the urinary tract. Central nervous system and neuromuscular effects include drowsiness, lethargy, fatigue, agitation, excitement, nightmares, restlessness, insomnia, confusion, disturbed concentration, disorientation, delusions, and hallucinations. Effects on the GI tract include anorexia, nausea and vomiting, diarrhea, abdominal cramps, increases in pancreatic enzymes, epigastric distress, stomatitis, peculiar taste, and black tongue. Rarely agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, and purpura have occured. Infants whose mothers were receiving tricyclic antidepressants prior to delivery have experienced cardiac problems, irritability, respiratory distress, muscle spasms, seizures, and urinary retention. Serotonin syndrome can occur when used in conjunction with other pro-serotonergic drugs. LD 50 Values Rat - Oral 250 mg/kg - Intraperitoneal 79mg/kg - Subcutaneous 250 mg/kg - Intravenous 15.9 mg/kg Mouse - Oral 188 mg/kg - Intraperitoneal 51.6 mg/kg - Subcutaneous 195 μg/kg - Intravenous 21 mg/kg Human range of toxicity is considered to include single dosages greater than 5 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tofranil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Imipramin Imipramina Imipramine Imipraminum Imizine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Imipramine is a tricyclic antidepressant indicated for the treatment of depression and to reduce childhood enuresis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Indinavir interact?

•Drug A: Abatacept •Drug B: Indinavir •Severity: MODERATE •Description: The metabolism of Indinavir can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indinavir is an antiretroviral drug for the treatment of HIV infection. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Indinavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Indinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Indinavir inhibits the HIV viral protease enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly absorbed •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 60% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Seven metabolites have been identified, one glucuronide conjugate and six oxidative metabolites. In vitro studies indicate that cytochrome P-450 3A4 (CYP3A4) is the major enzyme responsible for formation of the oxidative metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Less than 20% of indinavir is excreted unchanged in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 1.8 (± 0.4) hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose include myocardial infarction and angina pectoris. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Crixivan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Indinavir •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Indinavir is a protease inhibitor used to treat HIV infection.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Indinavir interact? Information: •Drug A: Abatacept •Drug B: Indinavir •Severity: MODERATE •Description: The metabolism of Indinavir can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indinavir is an antiretroviral drug for the treatment of HIV infection. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Indinavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Indinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Indinavir inhibits the HIV viral protease enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Rapidly absorbed •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 60% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Seven metabolites have been identified, one glucuronide conjugate and six oxidative metabolites. In vitro studies indicate that cytochrome P-450 3A4 (CYP3A4) is the major enzyme responsible for formation of the oxidative metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Less than 20% of indinavir is excreted unchanged in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 1.8 (± 0.4) hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose include myocardial infarction and angina pectoris. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Crixivan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Indinavir •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Indinavir is a protease inhibitor used to treat HIV infection. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Indomethacin interact?

•Drug A: Abatacept •Drug B: Indomethacin •Severity: MODERATE •Description: The metabolism of Indomethacin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Oral indometacin is indicated for symptomatic management of moderate to severe rheumatoid arthritis including acute flares of chronic disease, moderate to severe ankylosing spondylitis, moderate to severe osteoarthritis, acute painful shoulder (bursitis and/or tendinitis) and acute gouty arthritis. Intravenous indometacin is indicated to induce closure of a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1750 g when after 48 hours usual medical management (e.g., fluid restriction, diuretics, digitalis, respiratory support, etc.) is ineffective. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Indometacin is an NSAID with analgesic and antipyretic properties that exerts its pharmacological effects by inhibiting the synthesis of factors involved in pain, fever, and inflammation. Its therapeutic action does not involve pituitary-adrenal stimulation. Indometacin primarily works by suppressing inflammation in rheumatoid arthritis by providing relief of pain as well as reducing fever, swelling, and tenderness. This effectiveness has been demonstrated by a reduction in the extent of joint swelling, the average number of joints displaying symptoms of inflammation, and the severity of morning stiffness. Increased mobility was demonstrated by a decrease in total walking time and by improved functional capability seen as an increase in grip strength. In clinical trials, indometacin was shown to be effective in relieving the pain, reducing the fever, swelling, redness, and tenderness of acute gouty arthritis. Due to its pharmacological actions, the use of indometacin is associated with the risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, as well as gastrointestinal effects such as bleeding, ulceration, and perforation of the stomach or intestines. In a study of healthy individuals, acute oral and intravenous indometacin therapy resulted in a transiently diminished basal and CO2 stimulated cerebral blood flow; this effect disappeared in one study after one week of oral treatment. The clinical significance of this effect has not been established. Compared to other NSAIDs, it is suggested that indometacin is a more potent vasoconstrictor that is more consistent in decreasing cerebral blood flow and inhibiting CO2 reactivity. There have been studies that show indometacin directly inhibiting neuronal activity to some extent in the trigeminocervical complex after either superior salivatory nucleus or dural stimulation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Indometacin is a nonspecific and reversible inhibitor of the cyclo-oxygenase (COX) enzyme or prostaglandin G/H synthase. There are two identified isoforms of COX: COX-1 is universally present in most body tissues and is involved in the synthesis of the prostaglandins and thromboxane A2, while COX-2 is expressed in response to injury or inflammation. Constitutively expressed, the COX-1 enzyme is involved in gastric mucosal protection, platelet, and kidney function by catalyzing the conversion of arachidonic acid to prostaglandin (PG) G2 and PGG2 to PGH2. COX-2 is constitutively expressed and highly inducible by inflammatory stimuli. It is found in the central nervous system, kidneys, uterus, and other organs. COX-2 also catalyzes the conversion of arachidonic acid to PGG2 and PGG2 to PGH2. In the COX-2-mediated pathway, PGH2 is further converted to PGE2 and PGI2 (also known as prostacyclin). PGE2 is involved in mediating inflammation, pain, and fever. Decreasing levels of PGE2 leads to reduced inflammatory reactions. Indometacin is known to inhibit both isoforms of COX, however, with greater selectivity for COX-1, which accounts for its increased adverse gastric effects relative to other NSAIDs. It binds to the enzyme's active site and prevents the interaction between the enzyme and its substrate, arachidonic acid. Indometacin, unlike other NSAIDs, also inhibits phospholipase A2, the enzyme responsible for releasing arachidonic acid from phospholipids. The analgesic, antipyretic and anti-inflammatory effects of indomethacin as well as adverse reactions associated with the drug occur as a result of decreased prostaglandin synthesis. Its antipyretic effects may be due to action on the hypothalamus, resulting in increased peripheral blood flow, vasodilation, and subsequent heat dissipation. The exact mechanism of action of indometacin in inducing closure of a patent ductus arteriosus is not fully understood; however, it is thought to be through inhibition of prostaglandin synthesis. At birth, the ductus arteriosus is normally closed as the tension of the oxygen increases significantly after birth. Patent ductus arteriosus in premature infants is associated with congenital heart malformations where PGE1 mediates an opposite effect to that of oxygen. PGE1 dilates the ductus arteriosus through smooth muscle relaxation and prevents the closure of the ductus arteriosus. By inhibiting the synthesis of prostaglandins, indometacin promotes the closure of ductus arteriosus. Indometacin has been described as possessing anticancer and antiviral properties through activation of protein kinase R (PKR) and downstream phosphorylation of eIF2α, inhibiting protein synthesis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Indometacin displays a linear pharmacokinetics profile where the plasma concentrations and area under the curve (AUC) are dose-proportional, whereas half-life (T1/2) and plasma and renal clearance are dose-dependent. Indometacin is readily and rapidly absorbed from the gastrointestinal tract. The bioavailability is virtually 100% following oral administration and about 90% of the dose is absorbed within 4 hours. The bioavailability is about 80-90% following rectal administration. The peak plasma concentrations following a single oral dose were achieved between 0.9 ± 0.4 and 1.5 ± 0.8 hours in a fasting state. Despite large intersubject variation as well using the same preparation, peak plasma concentrations are dose-proportional and averaged 1.54 ± 0.76 μg/mL, 2.65 ± 1.03 μg/mL, and 4.92 ± 1.88 μg/mL following 25 mg, 50 mg, and 75 mg single doses in fasting subjects, respectively. With a typical therapeutic regimen of 25 or 50 mg t.i.d., the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution ranged from 0.34 to 1.57 L/kg following oral, intravenous, or rectal administration of single and multiple doses of indometacin in healthy individuals. Indometacin is distributed into the synovial fluid and is extensively bound to tissues. It has been detected in human breast milk and placenta. Although indometacin has been shown to cross the blood-brain barrier (BBB), its extensive plasma protein binding allows only the small fraction of free or unbound indometacin to diffuse across the BBB. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Indometacin is a weak organic acid that is 90-99% bound to protein in plasma over the expected range of therapeutic plasma concentrations. Like other NSAIDs, indometacin is bound to plasma albumin but it does not bind to red blood cells. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Indometacin undergoes hepatic metabolism involving glucuronidation, O-desmethylation, and N-deacylation. O-desmethyl-indomethacin, N-deschlorobenzoyl-indomethacin, and O-desmethyl-N-deschlorobenzoyl-indomethacin metabolites and their glucuronides are primarily inactive and have no pharmacological activity. Unconjugated metabolites are also detected in the plasma. Its high bioavailability indicates that indometacin is unlikely to be subject to the first-pass metabolism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Indometacin is eliminated via renal excretion, metabolism, and biliary excretion. It is also subject to enter the enterohepatic circulation through excretion of its glucuronide metabolites into bile followed by resorption of indometacin after hydrolysis. The extent of involvement in the enterohepatic circulation ranges from 27 to 115%. About 60 percent of an oral dosage is recovered in urine as drug and metabolites (26 percent as indomethacin and its glucuronide), and 33 percent in the feces (1.5 percent as indomethacin). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Indometacin disposition from the plasma is reported to be biphasic, with a half-life of 1 hour during the initial phase and 2.6–11.2 hours during the second phase. Interindividual and intraindividual variations are possible due to the extensive and sporadic nature of the enterohepatic recycling and biliary discharge of the drug. The mean half-life of oral indomethacin is estimated to be about 4.5 hours. The disposition of intravenous indometacin in preterm neonates was shown to vary across premature infants. In neonates older than 7 days, the mean plasma half-life of intravenous indometacin was approximately 20 hours, ranging from 15 hours in infants weighing more than 1000 g and 21 hours in infants weighing less than 1000 g. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In a clinical pharmacokinetic study, the plasma clearance of indometacin was reported to range from 1 to 2.5 mL/kg/min following oral administration. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Acute oral LD50 is 2.42 mg/kg in rats and 13 mg/kg in mice. The oral LD50 of indomethacin in mice and rats (based on 14-day mortality response) was 50 and 12 mg/kg, respectively. Symptoms of overdose may be characterized by nausea, vomiting, intense headache, dizziness, mental confusion, disorientation, or lethargy. In addition, there have been reports of paresthesias, numbness, and convulsions. In case of an overdose, the patient should receive symptomatic and supportive treatment with stomach emptying through induced vomiting or gastric lavage. The patient should then be closely monitored for any signs of gastrointestinal ulceration and hemorrhage. Antacids may be useful. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Indocin, Tivorbex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Indometacin Indometacina Indometacine Indometacinum Indomethacin •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Indomethacin is a nonsteroidal anti-inflammatory (NSAID) used for symptomatic management of chronic musculoskeletal pain conditions and to induce closure of a hemodynamically significant patent ductus arteriosus in premature infants.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Indomethacin interact? Information: •Drug A: Abatacept •Drug B: Indomethacin •Severity: MODERATE •Description: The metabolism of Indomethacin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Oral indometacin is indicated for symptomatic management of moderate to severe rheumatoid arthritis including acute flares of chronic disease, moderate to severe ankylosing spondylitis, moderate to severe osteoarthritis, acute painful shoulder (bursitis and/or tendinitis) and acute gouty arthritis. Intravenous indometacin is indicated to induce closure of a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1750 g when after 48 hours usual medical management (e.g., fluid restriction, diuretics, digitalis, respiratory support, etc.) is ineffective. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Indometacin is an NSAID with analgesic and antipyretic properties that exerts its pharmacological effects by inhibiting the synthesis of factors involved in pain, fever, and inflammation. Its therapeutic action does not involve pituitary-adrenal stimulation. Indometacin primarily works by suppressing inflammation in rheumatoid arthritis by providing relief of pain as well as reducing fever, swelling, and tenderness. This effectiveness has been demonstrated by a reduction in the extent of joint swelling, the average number of joints displaying symptoms of inflammation, and the severity of morning stiffness. Increased mobility was demonstrated by a decrease in total walking time and by improved functional capability seen as an increase in grip strength. In clinical trials, indometacin was shown to be effective in relieving the pain, reducing the fever, swelling, redness, and tenderness of acute gouty arthritis. Due to its pharmacological actions, the use of indometacin is associated with the risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, as well as gastrointestinal effects such as bleeding, ulceration, and perforation of the stomach or intestines. In a study of healthy individuals, acute oral and intravenous indometacin therapy resulted in a transiently diminished basal and CO2 stimulated cerebral blood flow; this effect disappeared in one study after one week of oral treatment. The clinical significance of this effect has not been established. Compared to other NSAIDs, it is suggested that indometacin is a more potent vasoconstrictor that is more consistent in decreasing cerebral blood flow and inhibiting CO2 reactivity. There have been studies that show indometacin directly inhibiting neuronal activity to some extent in the trigeminocervical complex after either superior salivatory nucleus or dural stimulation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Indometacin is a nonspecific and reversible inhibitor of the cyclo-oxygenase (COX) enzyme or prostaglandin G/H synthase. There are two identified isoforms of COX: COX-1 is universally present in most body tissues and is involved in the synthesis of the prostaglandins and thromboxane A2, while COX-2 is expressed in response to injury or inflammation. Constitutively expressed, the COX-1 enzyme is involved in gastric mucosal protection, platelet, and kidney function by catalyzing the conversion of arachidonic acid to prostaglandin (PG) G2 and PGG2 to PGH2. COX-2 is constitutively expressed and highly inducible by inflammatory stimuli. It is found in the central nervous system, kidneys, uterus, and other organs. COX-2 also catalyzes the conversion of arachidonic acid to PGG2 and PGG2 to PGH2. In the COX-2-mediated pathway, PGH2 is further converted to PGE2 and PGI2 (also known as prostacyclin). PGE2 is involved in mediating inflammation, pain, and fever. Decreasing levels of PGE2 leads to reduced inflammatory reactions. Indometacin is known to inhibit both isoforms of COX, however, with greater selectivity for COX-1, which accounts for its increased adverse gastric effects relative to other NSAIDs. It binds to the enzyme's active site and prevents the interaction between the enzyme and its substrate, arachidonic acid. Indometacin, unlike other NSAIDs, also inhibits phospholipase A2, the enzyme responsible for releasing arachidonic acid from phospholipids. The analgesic, antipyretic and anti-inflammatory effects of indomethacin as well as adverse reactions associated with the drug occur as a result of decreased prostaglandin synthesis. Its antipyretic effects may be due to action on the hypothalamus, resulting in increased peripheral blood flow, vasodilation, and subsequent heat dissipation. The exact mechanism of action of indometacin in inducing closure of a patent ductus arteriosus is not fully understood; however, it is thought to be through inhibition of prostaglandin synthesis. At birth, the ductus arteriosus is normally closed as the tension of the oxygen increases significantly after birth. Patent ductus arteriosus in premature infants is associated with congenital heart malformations where PGE1 mediates an opposite effect to that of oxygen. PGE1 dilates the ductus arteriosus through smooth muscle relaxation and prevents the closure of the ductus arteriosus. By inhibiting the synthesis of prostaglandins, indometacin promotes the closure of ductus arteriosus. Indometacin has been described as possessing anticancer and antiviral properties through activation of protein kinase R (PKR) and downstream phosphorylation of eIF2α, inhibiting protein synthesis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Indometacin displays a linear pharmacokinetics profile where the plasma concentrations and area under the curve (AUC) are dose-proportional, whereas half-life (T1/2) and plasma and renal clearance are dose-dependent. Indometacin is readily and rapidly absorbed from the gastrointestinal tract. The bioavailability is virtually 100% following oral administration and about 90% of the dose is absorbed within 4 hours. The bioavailability is about 80-90% following rectal administration. The peak plasma concentrations following a single oral dose were achieved between 0.9 ± 0.4 and 1.5 ± 0.8 hours in a fasting state. Despite large intersubject variation as well using the same preparation, peak plasma concentrations are dose-proportional and averaged 1.54 ± 0.76 μg/mL, 2.65 ± 1.03 μg/mL, and 4.92 ± 1.88 μg/mL following 25 mg, 50 mg, and 75 mg single doses in fasting subjects, respectively. With a typical therapeutic regimen of 25 or 50 mg t.i.d., the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution ranged from 0.34 to 1.57 L/kg following oral, intravenous, or rectal administration of single and multiple doses of indometacin in healthy individuals. Indometacin is distributed into the synovial fluid and is extensively bound to tissues. It has been detected in human breast milk and placenta. Although indometacin has been shown to cross the blood-brain barrier (BBB), its extensive plasma protein binding allows only the small fraction of free or unbound indometacin to diffuse across the BBB. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Indometacin is a weak organic acid that is 90-99% bound to protein in plasma over the expected range of therapeutic plasma concentrations. Like other NSAIDs, indometacin is bound to plasma albumin but it does not bind to red blood cells. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Indometacin undergoes hepatic metabolism involving glucuronidation, O-desmethylation, and N-deacylation. O-desmethyl-indomethacin, N-deschlorobenzoyl-indomethacin, and O-desmethyl-N-deschlorobenzoyl-indomethacin metabolites and their glucuronides are primarily inactive and have no pharmacological activity. Unconjugated metabolites are also detected in the plasma. Its high bioavailability indicates that indometacin is unlikely to be subject to the first-pass metabolism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Indometacin is eliminated via renal excretion, metabolism, and biliary excretion. It is also subject to enter the enterohepatic circulation through excretion of its glucuronide metabolites into bile followed by resorption of indometacin after hydrolysis. The extent of involvement in the enterohepatic circulation ranges from 27 to 115%. About 60 percent of an oral dosage is recovered in urine as drug and metabolites (26 percent as indomethacin and its glucuronide), and 33 percent in the feces (1.5 percent as indomethacin). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Indometacin disposition from the plasma is reported to be biphasic, with a half-life of 1 hour during the initial phase and 2.6–11.2 hours during the second phase. Interindividual and intraindividual variations are possible due to the extensive and sporadic nature of the enterohepatic recycling and biliary discharge of the drug. The mean half-life of oral indomethacin is estimated to be about 4.5 hours. The disposition of intravenous indometacin in preterm neonates was shown to vary across premature infants. In neonates older than 7 days, the mean plasma half-life of intravenous indometacin was approximately 20 hours, ranging from 15 hours in infants weighing more than 1000 g and 21 hours in infants weighing less than 1000 g. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In a clinical pharmacokinetic study, the plasma clearance of indometacin was reported to range from 1 to 2.5 mL/kg/min following oral administration. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Acute oral LD50 is 2.42 mg/kg in rats and 13 mg/kg in mice. The oral LD50 of indomethacin in mice and rats (based on 14-day mortality response) was 50 and 12 mg/kg, respectively. Symptoms of overdose may be characterized by nausea, vomiting, intense headache, dizziness, mental confusion, disorientation, or lethargy. In addition, there have been reports of paresthesias, numbness, and convulsions. In case of an overdose, the patient should receive symptomatic and supportive treatment with stomach emptying through induced vomiting or gastric lavage. The patient should then be closely monitored for any signs of gastrointestinal ulceration and hemorrhage. Antacids may be useful. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Indocin, Tivorbex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Indometacin Indometacina Indometacine Indometacinum Indomethacin •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Indomethacin is a nonsteroidal anti-inflammatory (NSAID) used for symptomatic management of chronic musculoskeletal pain conditions and to induce closure of a hemodynamically significant patent ductus arteriosus in premature infants. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Inebilizumab interact?

•Drug A: Abatacept •Drug B: Inebilizumab •Severity: MINOR •Description: The risk or severity of infection can be increased when Abatacept is combined with Inebilizumab. •Extended Description: Inebilizumab has immunosuppressive properties. The combination of inebilizumab with other immunosuppressants may increase the risk of infection. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Inebilizumab is indicated for the treatment of aquaporin-4 (AQP4) immunoglobulin-positive (AQP4-IgG) neuromyelitis optica spectrum disorder (NMOSD) in adult patients. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Inebilizumab is a CD19-directed monoclonal antibody that results in immunosuppression through B-cell depletion with sufficient efficacy to allow a six-month dosing schedule. Due to this mechanism of action, patients undergoing inebilizumab treatment may be at higher risk of infections and should be monitored for active infections and immunoglobulin levels while undergoing treatment; vaccination is not recommended during inebilizumab treatment. Also, there is a risk of severe infusion reactions. Animal data suggests the possibility of fetal harm with inebilizumab and therefore, effective contraception during and for six months following inebilizumab treatment is recommended. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Neuromyelitis optica spectrum disorder (NMOSD), formerly referred to as Devic's disease, is an antibody-mediated autoimmune condition resulting in astroglial cell death, demyelination, and central nervous system (CNS) inflammation. The presence of anti-aquaporin 4 immunoglobulin (AQP4-IgG) is the most frequent biomarker, although AQP4-IgG negative, anti-myelin oligodendrocyte glycoprotein (anti-MOG) positive, variants with similar presentation also exist. The theoretical origin of symptoms is through AQP4-IgG-mediated astrocyte cytotoxicity and subsequent infiltration of neutrophils, eosinophils, and macrophages, leading to inflammatory-mediated oligodendrocyte damage and myelin sheath loss. In general, this manifests as optic neuritis and transverse myelitis with occasional involvement of the diencephalic, brainstem, and cerebral hemisphere. CD19 is a B-cell surface antigen expressed on most B-cells, including the expanded population of CD27 CD38 CD180 CD19 plasmablasts that are the origin of astrocytic AQP4-IgG in most NMOSD patients. Inebilizumab binds to CD19 and, through one of several potential mechanisms, results in cell death. Destruction of the specific AQP4-IgG-producing plasmablasts results in lower amounts of AQP4-IgG in the CNS and therefore slows neuronal damage and improves patient outcomes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Inebilizumab is given intravenously and hence is immediately exposed to the systemic circulation. The mean reported C max following second dose 300 mg administration was 108 μg/mL, and the cumulative AUC following 26 weeks of treatment with two IV administrations was 2980 μg*d/mL. In a clinical trial investigating the use of inebilizumab in relapsing multiple sclerosis, the mean C max corresponding to 30, 100, and 600 mg of inebilizumab was 17.9, 43.1, and 248.0 μg/mL and the AUC 0-∞ was 440, 1150, and 6950 μg*d/mL. In another trial for patients with systemic sclerosis, the mean C max varied between 2.7 and 227.0 μg/mL and the AUC 0-∞ varied between 16.1 and 2890.0 μg*d/mL for doses between 0.1 and 10.0 mg/kg. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Inebilizumab has an estimated central volume of distribution of 2.95L and a peripheral volume of distribution of 2.57L. The steady-state volume of distribution in patients administered with a range of doses between 0.1 and 10.0 mg/kg ranged from 53.7 to 71.7 mL/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Inebilizumab is a monoclonal antibody and is hence likely degraded through proteolysis. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Inebilizumab exhibits biphasic pharmacokinetics with a mean terminal half-life of 18 days. The terminal half-life reported in phase I studies varied by dose but was typically close to 18 days, with a range of 6.8 to 18.7 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Inebilizumab has an estimated systemic clearance of 0.19 L/day. In phase I studies, the reported clearance varied between 139-180 mL/day in one study, and 3.5-6.2 mL/kg/day in another, depending on the dose. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Toxicity information regarding inebilizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as severe infusion reactions, infections, and arthralgia. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Uplizna 3 Vial Kit •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Inebilizumab is a humanized anti-CD19 cytolytic monoclonal antibody for B-cell depletion in autoimmune conditions. Currently approved only for neuromyelitis optica spectrum disorder (NMOSD).

Inebilizumab has immunosuppressive properties. The combination of inebilizumab with other immunosuppressants may increase the risk of infection. The severity of the interaction is minor.

Question: Does Abatacept and Inebilizumab interact? Information: •Drug A: Abatacept •Drug B: Inebilizumab •Severity: MINOR •Description: The risk or severity of infection can be increased when Abatacept is combined with Inebilizumab. •Extended Description: Inebilizumab has immunosuppressive properties. The combination of inebilizumab with other immunosuppressants may increase the risk of infection. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Inebilizumab is indicated for the treatment of aquaporin-4 (AQP4) immunoglobulin-positive (AQP4-IgG) neuromyelitis optica spectrum disorder (NMOSD) in adult patients. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Inebilizumab is a CD19-directed monoclonal antibody that results in immunosuppression through B-cell depletion with sufficient efficacy to allow a six-month dosing schedule. Due to this mechanism of action, patients undergoing inebilizumab treatment may be at higher risk of infections and should be monitored for active infections and immunoglobulin levels while undergoing treatment; vaccination is not recommended during inebilizumab treatment. Also, there is a risk of severe infusion reactions. Animal data suggests the possibility of fetal harm with inebilizumab and therefore, effective contraception during and for six months following inebilizumab treatment is recommended. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Neuromyelitis optica spectrum disorder (NMOSD), formerly referred to as Devic's disease, is an antibody-mediated autoimmune condition resulting in astroglial cell death, demyelination, and central nervous system (CNS) inflammation. The presence of anti-aquaporin 4 immunoglobulin (AQP4-IgG) is the most frequent biomarker, although AQP4-IgG negative, anti-myelin oligodendrocyte glycoprotein (anti-MOG) positive, variants with similar presentation also exist. The theoretical origin of symptoms is through AQP4-IgG-mediated astrocyte cytotoxicity and subsequent infiltration of neutrophils, eosinophils, and macrophages, leading to inflammatory-mediated oligodendrocyte damage and myelin sheath loss. In general, this manifests as optic neuritis and transverse myelitis with occasional involvement of the diencephalic, brainstem, and cerebral hemisphere. CD19 is a B-cell surface antigen expressed on most B-cells, including the expanded population of CD27 CD38 CD180 CD19 plasmablasts that are the origin of astrocytic AQP4-IgG in most NMOSD patients. Inebilizumab binds to CD19 and, through one of several potential mechanisms, results in cell death. Destruction of the specific AQP4-IgG-producing plasmablasts results in lower amounts of AQP4-IgG in the CNS and therefore slows neuronal damage and improves patient outcomes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Inebilizumab is given intravenously and hence is immediately exposed to the systemic circulation. The mean reported C max following second dose 300 mg administration was 108 μg/mL, and the cumulative AUC following 26 weeks of treatment with two IV administrations was 2980 μg*d/mL. In a clinical trial investigating the use of inebilizumab in relapsing multiple sclerosis, the mean C max corresponding to 30, 100, and 600 mg of inebilizumab was 17.9, 43.1, and 248.0 μg/mL and the AUC 0-∞ was 440, 1150, and 6950 μg*d/mL. In another trial for patients with systemic sclerosis, the mean C max varied between 2.7 and 227.0 μg/mL and the AUC 0-∞ varied between 16.1 and 2890.0 μg*d/mL for doses between 0.1 and 10.0 mg/kg. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Inebilizumab has an estimated central volume of distribution of 2.95L and a peripheral volume of distribution of 2.57L. The steady-state volume of distribution in patients administered with a range of doses between 0.1 and 10.0 mg/kg ranged from 53.7 to 71.7 mL/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Inebilizumab is a monoclonal antibody and is hence likely degraded through proteolysis. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Inebilizumab exhibits biphasic pharmacokinetics with a mean terminal half-life of 18 days. The terminal half-life reported in phase I studies varied by dose but was typically close to 18 days, with a range of 6.8 to 18.7 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Inebilizumab has an estimated systemic clearance of 0.19 L/day. In phase I studies, the reported clearance varied between 139-180 mL/day in one study, and 3.5-6.2 mL/kg/day in another, depending on the dose. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Toxicity information regarding inebilizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as severe infusion reactions, infections, and arthralgia. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Uplizna 3 Vial Kit •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Inebilizumab is a humanized anti-CD19 cytolytic monoclonal antibody for B-cell depletion in autoimmune conditions. Currently approved only for neuromyelitis optica spectrum disorder (NMOSD). Output: Inebilizumab has immunosuppressive properties. The combination of inebilizumab with other immunosuppressants may increase the risk of infection. The severity of the interaction is minor.

Does Abatacept and Infigratinib interact?

•Drug A: Abatacept •Drug B: Infigratinib •Severity: MODERATE •Description: The metabolism of Infigratinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Infigratinib is indicated for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) fusion or another rearrangement as detected by an FDA-approved test. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Infigratinib is an anti-tumour agent that works to suppress tumour growth in cholangiocarcinoma. It exhibits anti-tumour activity in mouse and rat xenograft models of human tumours with activating FGFR2 or FGFR3 alterations, such as FGFR2-TTC28 or FGFR2-TRA2B fusions. In clinical trials, patients with cholangiocarcinoma who were treated with infigratinib had an overall response rate of 23% - where one patient had a complete response - and a duration of response of 5.5 months, with a range between 0.03 and 28.3 months. Some patients with cancers with FGFR mutations display intrinsic resistance to infigratinib, leading to negligible therapeutic efficacy: investigations are ongoing to target molecular pathways to combat drug resistance. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors that play a role in cell proliferation, differentiation, migration, survival, and angiogenesis. Upon binding of extracellular signals, primarily fibroblast growth factors, FGFR dimerizes to promote phosphorylation of downstream molecules and activation of the Ras-mitogen-activated protein kinase (MAPK) pathway. In some cancers, the FGFR signalling pathway is aberrant and disrupted, leading to unregulated cell proliferation and growth, including malignant cells. Alterations in the FGFR receptors, including mutations, amplifications, and fusions, are associated with a wide array of neoplasms, including prostate, urothelial, ovarian, breast, and liver cancer. In particular, FGFR2 fusion is closely related to intrahepatic cholangiocarcinoma: recent studies show that up to 45% of patients with intrahepatic cholangiocarcinoma exhibited gene rearrangements resulting in FGFR2 fusion proteins. Alterations in FGFR in tumours can lead to constitutive FGFR signalling, supporting the proliferation and survival of malignant cells. Infigratinib is a reversible, non-competitive inhibitor of all four FGFR subtypes - FGFR1, FGFR2, FGFR3, and FGFR4 - that blocks FGFR signalling and inhibits cell proliferation in cancer cell lines with activating FGFR amplification, mutations, or fusions. Out of the four FGFR subtypes, infigratinib has the highest affinity for FGFR1, FGFR2, and FGFR3. Infigratinib binds to the allosteric site between the two kinase lobes of the FGFR - or more specifically, to the ATP-binding cleft. Binding to this cleft prevents autophosphorylation of the receptor and blocks downstream signalling cascades that would otherwise activate MAPK. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Mean (%CV) C max is 282.5 ng/mL (54%) and AUC 0-24h is 3780 ngxh/mL (59%) for infigratinib. Infigratinib C max and AUC increase more than proportionally across the dose range of 5 to 150 mg and steady state is achieved within 15 days. At steady state, median time to achieve peak infigratinib plasma concentration (T max ) is six hours, with a range between two and seven hours. Mean (%CV) C max is 42.1 ng/mL (65%) for BHS697 and 15.7 ng/mL (92%) for CQM157. Mean (%CV) AUC 0-24h is 717 ngxh/mL (55%) for BHS697 and 428 ngxh/mL (72%) for CQM157. In healthy subjects, a high-fat and high-calorie meal increased AUCinf of infigratinib by 80%-120% and C max by 60%-80%. The median T max also shifted from four hours to six hours. A low-fat low-calorie meal increased the mean AUC inf of infigratinib by 70% and C max by 90%/ •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): At steady state, the geometric mean (CV%) apparent volume of distribution of infigratinib was 1600 L (33%). In rats receiving a single oral dose, infigratinib had brain-to-plasma concentration ratios (based on AUC 0-inf ) of 0.682. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Infigratinib is about 96.8% bound to plasma proteins, primarily to lipoprotein. Protein binding is concentration-dependent. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): According to in vitro findings, about 94% of infigratinib is metabolized by CYP3A4 and about 6% of the drug is metabolized by flavin-containing monooxygenase 3 (FMO3). About 38% of the dose is circulating parent drug in the plasma and BHS697 and CQM157 are two major metabolites of infigratinib that are each found at >10% of the dose. They are pharmacologically active, with BHS697 representing about 16% to 33% of the overall pharmacological activity of infigratinib and CQM157 contributing to about 9% to 12%. BHS697 undergoes further metabolism mediated by CYP3A4 and CQM157 is metabolized through both Phase I and Phase II biotransformation pathways. The exact metabolic pathways and the structure of BHS697 and CQM157 are not fully characterized. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following administration of a single oral dose of radiolabeled infigratinib in healthy subjects, approximately 77% of the dose was recovered in feces, where 3.4% of the dose was in the unchanged parent form. About 7.2% was recovered in urine with 1.9% of the dose was unchanged. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The geometric mean (CV%) terminal half-life of infigratinib was 33.5 h (39%) at steady state. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The geometric mean (CV%) total apparent clearance (CL/F) of infigratinib was 33.1 L/h (59%) at steady state. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There is limited information on lethal doses and overdose of infigratinib. In clinical trials, infigratinib was associated with ocular toxicity (retinal pigment epithelial detachment), hyperphosphatemia leading to soft tissue mineralization, and embryo-fetal toxicity. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Truseltiq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Infigratinib is an FGFR inhibitor used to treat locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) rearrangement.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Infigratinib interact? Information: •Drug A: Abatacept •Drug B: Infigratinib •Severity: MODERATE •Description: The metabolism of Infigratinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Infigratinib is indicated for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) fusion or another rearrangement as detected by an FDA-approved test. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Infigratinib is an anti-tumour agent that works to suppress tumour growth in cholangiocarcinoma. It exhibits anti-tumour activity in mouse and rat xenograft models of human tumours with activating FGFR2 or FGFR3 alterations, such as FGFR2-TTC28 or FGFR2-TRA2B fusions. In clinical trials, patients with cholangiocarcinoma who were treated with infigratinib had an overall response rate of 23% - where one patient had a complete response - and a duration of response of 5.5 months, with a range between 0.03 and 28.3 months. Some patients with cancers with FGFR mutations display intrinsic resistance to infigratinib, leading to negligible therapeutic efficacy: investigations are ongoing to target molecular pathways to combat drug resistance. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors that play a role in cell proliferation, differentiation, migration, survival, and angiogenesis. Upon binding of extracellular signals, primarily fibroblast growth factors, FGFR dimerizes to promote phosphorylation of downstream molecules and activation of the Ras-mitogen-activated protein kinase (MAPK) pathway. In some cancers, the FGFR signalling pathway is aberrant and disrupted, leading to unregulated cell proliferation and growth, including malignant cells. Alterations in the FGFR receptors, including mutations, amplifications, and fusions, are associated with a wide array of neoplasms, including prostate, urothelial, ovarian, breast, and liver cancer. In particular, FGFR2 fusion is closely related to intrahepatic cholangiocarcinoma: recent studies show that up to 45% of patients with intrahepatic cholangiocarcinoma exhibited gene rearrangements resulting in FGFR2 fusion proteins. Alterations in FGFR in tumours can lead to constitutive FGFR signalling, supporting the proliferation and survival of malignant cells. Infigratinib is a reversible, non-competitive inhibitor of all four FGFR subtypes - FGFR1, FGFR2, FGFR3, and FGFR4 - that blocks FGFR signalling and inhibits cell proliferation in cancer cell lines with activating FGFR amplification, mutations, or fusions. Out of the four FGFR subtypes, infigratinib has the highest affinity for FGFR1, FGFR2, and FGFR3. Infigratinib binds to the allosteric site between the two kinase lobes of the FGFR - or more specifically, to the ATP-binding cleft. Binding to this cleft prevents autophosphorylation of the receptor and blocks downstream signalling cascades that would otherwise activate MAPK. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Mean (%CV) C max is 282.5 ng/mL (54%) and AUC 0-24h is 3780 ngxh/mL (59%) for infigratinib. Infigratinib C max and AUC increase more than proportionally across the dose range of 5 to 150 mg and steady state is achieved within 15 days. At steady state, median time to achieve peak infigratinib plasma concentration (T max ) is six hours, with a range between two and seven hours. Mean (%CV) C max is 42.1 ng/mL (65%) for BHS697 and 15.7 ng/mL (92%) for CQM157. Mean (%CV) AUC 0-24h is 717 ngxh/mL (55%) for BHS697 and 428 ngxh/mL (72%) for CQM157. In healthy subjects, a high-fat and high-calorie meal increased AUCinf of infigratinib by 80%-120% and C max by 60%-80%. The median T max also shifted from four hours to six hours. A low-fat low-calorie meal increased the mean AUC inf of infigratinib by 70% and C max by 90%/ •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): At steady state, the geometric mean (CV%) apparent volume of distribution of infigratinib was 1600 L (33%). In rats receiving a single oral dose, infigratinib had brain-to-plasma concentration ratios (based on AUC 0-inf ) of 0.682. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Infigratinib is about 96.8% bound to plasma proteins, primarily to lipoprotein. Protein binding is concentration-dependent. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): According to in vitro findings, about 94% of infigratinib is metabolized by CYP3A4 and about 6% of the drug is metabolized by flavin-containing monooxygenase 3 (FMO3). About 38% of the dose is circulating parent drug in the plasma and BHS697 and CQM157 are two major metabolites of infigratinib that are each found at >10% of the dose. They are pharmacologically active, with BHS697 representing about 16% to 33% of the overall pharmacological activity of infigratinib and CQM157 contributing to about 9% to 12%. BHS697 undergoes further metabolism mediated by CYP3A4 and CQM157 is metabolized through both Phase I and Phase II biotransformation pathways. The exact metabolic pathways and the structure of BHS697 and CQM157 are not fully characterized. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following administration of a single oral dose of radiolabeled infigratinib in healthy subjects, approximately 77% of the dose was recovered in feces, where 3.4% of the dose was in the unchanged parent form. About 7.2% was recovered in urine with 1.9% of the dose was unchanged. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The geometric mean (CV%) terminal half-life of infigratinib was 33.5 h (39%) at steady state. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The geometric mean (CV%) total apparent clearance (CL/F) of infigratinib was 33.1 L/h (59%) at steady state. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There is limited information on lethal doses and overdose of infigratinib. In clinical trials, infigratinib was associated with ocular toxicity (retinal pigment epithelial detachment), hyperphosphatemia leading to soft tissue mineralization, and embryo-fetal toxicity. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Truseltiq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Infigratinib is an FGFR inhibitor used to treat locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) rearrangement. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Does Abatacept and Infliximab interact?

•Drug A: Abatacept •Drug B: Infliximab •Severity: MAJOR •Description: The risk or severity of infection can be increased when Infliximab is combined with Abatacept. •Extended Description: Concomitant use of abatacept and TNF-α inhibitors, which are both immunosuppressive agents, increases the risk of serious infection with no therapeutic benefit. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult or pediatric (≥ 6 years of age) patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy Indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease. Indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult or pediatric (≥ 6 years of age) patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy. Indicated for, in combination with methotrexate, reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. Indicated for reducing signs and symptoms in patients with active ankylosing spondylitis. Indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis. Indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Infliximab disrupts the activation of pro-inflammaory cascade signalling. Infliximab has shown to reduce infiltration of inflammatory cells into sites of inflammation. It also attenautes the expression of molecules mediating cellular adhesion {including E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)}, chemoattraction {[IL-8 and monocyte chemotactic protein (MCP-1)} and tissue degradation {matrix metalloproteinase (MMP) 1 and 3}. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Infliximab is a IgG1κ monoclonal antibody that binds to soluble and transmembrane forms of TNF-α with high affinity to disrupt the pro-inflammatory cascade signalling. Binding of the antibody to TNF-α prevents TNF-α from interacting with its receptors. Infliximab does not neutralize TNF-β (lymphotoxin-α), a related cytokine that utilizes the same receptors as TNF-α. Blocked actions of TNF-α further leads to downregulation of local and systemic pro-inflammatory cytokines (i.e. IL-1, IL-6), reduction of lymphocyte and leukocyte migration to sites of inflammation, induction of apoptosis of TNF-producing cells (i.e. activated monocytes and T lymphocytes), increased levels of nuclear factor-κB inhibitor, and reduction of reduction of endothelial adhesion molecules and acute phase proteins. Its inhibitory actions on TNF-α was demonstrated in human fibroblasts, endothelial cells, neutrophils, B and Tlymphocytes and epithelial cells. Infliximab also atteunates the production of tissue degrading enzymes synthesized by synoviocytes and/or chondrocytes. According to a transgenic mice study that developed polyarthritis due to consitutive levels of human TNF-α, infliximab decreased synovitis and joint erosions in collagen-induced arthritis and allows eroded joints to heal. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following a single intravenous infusion, infliximab absorption displays a linear relationship between the dose administered and the maximum serum concentration. In patients with Crohn's disease, the maximum plasma concentration (Cmax) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 75 µg/mL and 181 µg/mL, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in Cmax of 120 µg/mL and 189 µg/mL, respectively. In patients with rheumatoid arthritis, the Cmax of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 192±51 µg/mL, 427±106 µg/mL, and 907±183 µg/mL, respectively. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Based on a pharmacokinetic study of adult patients, the distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment. In patients with Crohn's disease, the apparent volume of distribution at steady state (Vss) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 80 mL/kg and 65 mL/kg, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in Vss of 70 mL/kg and 81 mL/kg, respectively. In patients with rheumatoid arthritis, the Vss of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 4.3±2.5 L, 3.2±0.7 L, and 3.1±0.6 L, respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Therapeutic monoclonal antibodies including infliximab are predicted to be nonspecifically metabolized to peptides and amino acids that can be re-used in the body for de novo synthesis of proteins or arc excreted by the kidney. The reticuloendothelial system (RES) are phagocytic cells of the immune system such as macrophages and monocytes that play a role in the elimination of endogenous IgG antibodies. Although administered infliximab accounts for a small fraction of total endogenous IgG and this route is not likely saturated by therapeutic mAbs, infliximab may be removed by opsonization via RES following binding of the Fc part of the antibody to Fcy-receptors expressed on the RES. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The median terminal half-life of infliximab is 7.7 to 9.5 days. The data is based on a pharmacokinetic study in patients with Crohn's disease, plaque psoriasis and rheumatoid arthritis receiving a single dose of infliximab. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In patients with Crohn's disease, the total body clearance (CL) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 18.4 mL/h and 14.3 mL/h, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in CL of 15.2 mL/h and 15.2 mL/h, respectively. In patients with rheumatoid arthritis, the CL of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 11±7.5 mL/h, 11.4±5 mL/h, and 11±8.9 mL/h, respectively. Development of antibodies to infliximab increased infliximab clearance. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In an acute toxicity animal study, the NOAEL of intravenous infliximab in rats was 50 mg/kg. In a repeated dose animal study, the NOAEL values of intravenous infliximab was 50 mg/kg in rats at 2 weeks following 3 doses and 40 mg/kg/day in mice at 6 months. The toxicological potential of infliximab in humans has not yet been fully established. According to an analogous antibody study, infliximab is not predicted to induce tumorigenic, clastogenic or mutagenic effects. No impairment of fertility was observed in a fertility and general reproduction toxicity study with the analogous mouse antibody used in the 6-month chronic toxicity study. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Avsola, Flixabi, Inflectra, Remicade, Renflexis, Zymfentra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Infliximab is a monoclonal anti tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis.

Concomitant use of abatacept and TNF-α inhibitors, which are both immunosuppressive agents, increases the risk of serious infection with no therapeutic benefit. The severity of the interaction is major.

Question: Does Abatacept and Infliximab interact? Information: •Drug A: Abatacept •Drug B: Infliximab •Severity: MAJOR •Description: The risk or severity of infection can be increased when Infliximab is combined with Abatacept. •Extended Description: Concomitant use of abatacept and TNF-α inhibitors, which are both immunosuppressive agents, increases the risk of serious infection with no therapeutic benefit. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult or pediatric (≥ 6 years of age) patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy Indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease. Indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult or pediatric (≥ 6 years of age) patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy. Indicated for, in combination with methotrexate, reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. Indicated for reducing signs and symptoms in patients with active ankylosing spondylitis. Indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis. Indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Infliximab disrupts the activation of pro-inflammaory cascade signalling. Infliximab has shown to reduce infiltration of inflammatory cells into sites of inflammation. It also attenautes the expression of molecules mediating cellular adhesion {including E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)}, chemoattraction {[IL-8 and monocyte chemotactic protein (MCP-1)} and tissue degradation {matrix metalloproteinase (MMP) 1 and 3}. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Infliximab is a IgG1κ monoclonal antibody that binds to soluble and transmembrane forms of TNF-α with high affinity to disrupt the pro-inflammatory cascade signalling. Binding of the antibody to TNF-α prevents TNF-α from interacting with its receptors. Infliximab does not neutralize TNF-β (lymphotoxin-α), a related cytokine that utilizes the same receptors as TNF-α. Blocked actions of TNF-α further leads to downregulation of local and systemic pro-inflammatory cytokines (i.e. IL-1, IL-6), reduction of lymphocyte and leukocyte migration to sites of inflammation, induction of apoptosis of TNF-producing cells (i.e. activated monocytes and T lymphocytes), increased levels of nuclear factor-κB inhibitor, and reduction of reduction of endothelial adhesion molecules and acute phase proteins. Its inhibitory actions on TNF-α was demonstrated in human fibroblasts, endothelial cells, neutrophils, B and Tlymphocytes and epithelial cells. Infliximab also atteunates the production of tissue degrading enzymes synthesized by synoviocytes and/or chondrocytes. According to a transgenic mice study that developed polyarthritis due to consitutive levels of human TNF-α, infliximab decreased synovitis and joint erosions in collagen-induced arthritis and allows eroded joints to heal. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following a single intravenous infusion, infliximab absorption displays a linear relationship between the dose administered and the maximum serum concentration. In patients with Crohn's disease, the maximum plasma concentration (Cmax) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 75 µg/mL and 181 µg/mL, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in Cmax of 120 µg/mL and 189 µg/mL, respectively. In patients with rheumatoid arthritis, the Cmax of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 192±51 µg/mL, 427±106 µg/mL, and 907±183 µg/mL, respectively. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Based on a pharmacokinetic study of adult patients, the distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment. In patients with Crohn's disease, the apparent volume of distribution at steady state (Vss) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 80 mL/kg and 65 mL/kg, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in Vss of 70 mL/kg and 81 mL/kg, respectively. In patients with rheumatoid arthritis, the Vss of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 4.3±2.5 L, 3.2±0.7 L, and 3.1±0.6 L, respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Therapeutic monoclonal antibodies including infliximab are predicted to be nonspecifically metabolized to peptides and amino acids that can be re-used in the body for de novo synthesis of proteins or arc excreted by the kidney. The reticuloendothelial system (RES) are phagocytic cells of the immune system such as macrophages and monocytes that play a role in the elimination of endogenous IgG antibodies. Although administered infliximab accounts for a small fraction of total endogenous IgG and this route is not likely saturated by therapeutic mAbs, infliximab may be removed by opsonization via RES following binding of the Fc part of the antibody to Fcy-receptors expressed on the RES. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The median terminal half-life of infliximab is 7.7 to 9.5 days. The data is based on a pharmacokinetic study in patients with Crohn's disease, plaque psoriasis and rheumatoid arthritis receiving a single dose of infliximab. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In patients with Crohn's disease, the total body clearance (CL) of infliximab following single doses of 5 mg/kg and 10 mg/kg was 18.4 mL/h and 14.3 mL/h, respectively. In a maintenance therapy study, multiple infusions of infliximab (at week 0, 2 and 6) at the same dose of 5 mg/kg and 10 mg/kg resulted in CL of 15.2 mL/h and 15.2 mL/h, respectively. In patients with rheumatoid arthritis, the CL of infliximab following a single dose infusion of 5 mg/kg, 10 mg/kg and 20 mg/kg were 11±7.5 mL/h, 11.4±5 mL/h, and 11±8.9 mL/h, respectively. Development of antibodies to infliximab increased infliximab clearance. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In an acute toxicity animal study, the NOAEL of intravenous infliximab in rats was 50 mg/kg. In a repeated dose animal study, the NOAEL values of intravenous infliximab was 50 mg/kg in rats at 2 weeks following 3 doses and 40 mg/kg/day in mice at 6 months. The toxicological potential of infliximab in humans has not yet been fully established. According to an analogous antibody study, infliximab is not predicted to induce tumorigenic, clastogenic or mutagenic effects. No impairment of fertility was observed in a fertility and general reproduction toxicity study with the analogous mouse antibody used in the 6-month chronic toxicity study. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Avsola, Flixabi, Inflectra, Remicade, Renflexis, Zymfentra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Infliximab is a monoclonal anti tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. Output: Concomitant use of abatacept and TNF-α inhibitors, which are both immunosuppressive agents, increases the risk of serious infection with no therapeutic benefit. The severity of the interaction is major.

Does Abatacept and Interferon alfa-2a interact?

•Drug A: Abatacept •Drug B: Interferon alfa-2a •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Interferon alfa-2a is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of chronic hepatitis C, hairy cell leukemia, AIDS-related Kaposi's sarcoma, and chronic myelogenous leukemia. Also for the treatment of oral warts arising from HIV infection. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Upregulates the expression of MHC I proteins, allowing for increased presentation of peptides derived from viral antigens. This enhances the activation of CD8+ T cells that are the precursors for cytotoxic T lymphocytes (CTLs) and makes the macrophage a better target for CTL-mediated killing. Interferon alpha also induce the synthesis of several key antiviral mediators, including 2'-5' oligoadenylate synthetase (2'-5' A synthetase) and protein kinase R. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Interferon alpha binds to type I interferon receptors (IFNAR1 and IFNAR2c) which, upon dimerization, activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2). These transphosphorylate themselves and phosphorylate the receptors. The phosphorylated INFAR receptors then bind to Stat1 and Stat2 (signal transducers and activators of transcription)which dimerize and activate multiple (~100) immunomodulatory and antiviral proteins. Interferon alpha binds less stably to type I interferon receptors than interferon beta. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption is high (greater than 80%) when administered intramuscularly or subcutaneously. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 0.223 to 0.748 L/kg [healthy people] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Alpha-interferons are totally filtered through the glomeruli and undergo rapid proteolytic degradation during tubular reabsorption, rendering a negligible reappearance of intact alfa interferon in the systemic circulation. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The IM half-life of interferon alfa-2a is 6 hours to 8 hours; the half-life for IV infusion is 3.7 hours to 8.5 hours (mean 5.1 hours). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 2.14 - 3.62 mL/min/kg [healthy] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Interferon alfa-2 may cause serious adverse effects such as anemia; autoimmune diseases, including vasculitis, arthritis, hemolytic anemia, and erythematosus syndrome; cardiotoxicity; hepatotoxicity; hyperthyroidism or hypothyroidism; transient ischemic attacks; leukopenia; neurotoxicity; peripheral neuropathy; and thrombocytopenia. Some lesser side effects that may not need medical attention include blurred vision, change in taste or metallic taste, cold sores or stomatitis, diarrhea, dizziness, dry mouth, dry skin or itching, flu-like syndrome, increased sweating, leg cramps, loss of appetite, nausea or vomiting, skin rash, unusual tiredness, weight loss, and partial loss of hair. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Interferon alfa-2a Interferon alfa-2a (genetical recombination) Interferon alfa-2a (recombinant) Interferon alfa-2a, recombinant Interferon alfa-2a,recombinant Interferon alpha-2a Interferon-alfa-2a Recombinant human interferon alfa-2a Recombinant human interferon-alfa-2a •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Interferon alfa-2a is a form of recombinant human interferon used to stimulate the innate antiviral response in the treatment of hepatitis B and C viruses.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Interferon alfa-2a interact? Information: •Drug A: Abatacept •Drug B: Interferon alfa-2a •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Interferon alfa-2a is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of chronic hepatitis C, hairy cell leukemia, AIDS-related Kaposi's sarcoma, and chronic myelogenous leukemia. Also for the treatment of oral warts arising from HIV infection. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Upregulates the expression of MHC I proteins, allowing for increased presentation of peptides derived from viral antigens. This enhances the activation of CD8+ T cells that are the precursors for cytotoxic T lymphocytes (CTLs) and makes the macrophage a better target for CTL-mediated killing. Interferon alpha also induce the synthesis of several key antiviral mediators, including 2'-5' oligoadenylate synthetase (2'-5' A synthetase) and protein kinase R. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Interferon alpha binds to type I interferon receptors (IFNAR1 and IFNAR2c) which, upon dimerization, activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2). These transphosphorylate themselves and phosphorylate the receptors. The phosphorylated INFAR receptors then bind to Stat1 and Stat2 (signal transducers and activators of transcription)which dimerize and activate multiple (~100) immunomodulatory and antiviral proteins. Interferon alpha binds less stably to type I interferon receptors than interferon beta. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption is high (greater than 80%) when administered intramuscularly or subcutaneously. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 0.223 to 0.748 L/kg [healthy people] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Alpha-interferons are totally filtered through the glomeruli and undergo rapid proteolytic degradation during tubular reabsorption, rendering a negligible reappearance of intact alfa interferon in the systemic circulation. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The IM half-life of interferon alfa-2a is 6 hours to 8 hours; the half-life for IV infusion is 3.7 hours to 8.5 hours (mean 5.1 hours). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 2.14 - 3.62 mL/min/kg [healthy] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Interferon alfa-2 may cause serious adverse effects such as anemia; autoimmune diseases, including vasculitis, arthritis, hemolytic anemia, and erythematosus syndrome; cardiotoxicity; hepatotoxicity; hyperthyroidism or hypothyroidism; transient ischemic attacks; leukopenia; neurotoxicity; peripheral neuropathy; and thrombocytopenia. Some lesser side effects that may not need medical attention include blurred vision, change in taste or metallic taste, cold sores or stomatitis, diarrhea, dizziness, dry mouth, dry skin or itching, flu-like syndrome, increased sweating, leg cramps, loss of appetite, nausea or vomiting, skin rash, unusual tiredness, weight loss, and partial loss of hair. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Interferon alfa-2a Interferon alfa-2a (genetical recombination) Interferon alfa-2a (recombinant) Interferon alfa-2a, recombinant Interferon alfa-2a,recombinant Interferon alpha-2a Interferon-alfa-2a Recombinant human interferon alfa-2a Recombinant human interferon-alfa-2a •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Interferon alfa-2a is a form of recombinant human interferon used to stimulate the innate antiviral response in the treatment of hepatitis B and C viruses. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Interferon alfa-2b interact?

•Drug A: Abatacept •Drug B: Interferon alfa-2b •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Interferon alfa-2b is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of hairy cell leukemia, malignant melanoma, and AIDS-related Kaposi's sarcoma. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Upregulates the expression of MHC I proteins, allowing for increased presentation of peptides derived from viral antigens. This enhances the activation of CD8+ T cells that are the precursors for cytotoxic T lymphocytes (CTLs) and makes the macrophage a better target for CTL-mediated killing. Interferon alpha also induce the synthesis of several key antiviral mediators, including 2'-5' oligoadenylate synthetase (2'-5' A synthetase) and protein kinase R. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Interferon alpha binds to type I interferon receptors (IFNAR1 and IFNAR2c) which upon dimerization activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2). These transphosphorylate themselves and phosphorylate the receptors. The phosphorylated INFAR receptors then bind to Stat1 and Stat2 (signal transducers and activators of transcription)which dimerize and activate multiple (~100) immunomodulatory and antiviral proteins. Interferon alpha binds less stably to type I interferon receptors than interferon beta. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption is high (greater than 80%) when administered intramuscularly or subcutaneously. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life following both intramuscular and subcutaneous injections was approximately 2 to 3 hours. The elimination half-life was approximately 2 hours following intravenous injection. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There is limited experience with overdosage. Postmarketing surveillance includes reports of patients receiving a single dose as great as 10 times the recommended dose. In general, the primary effects of an overdose are consistent with the effects seen with therapeutic doses of interferon alfa-2b. Hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction have been reported with single administration overdoses and/or with longer durations of treatment than prescribed. Toxic effects after ingestion of interferon alfa-2b are not expected because interferons are poorly absorbed orally. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Intron A •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Interferon alfa-2b is a form of recombinant human interferon used to treat hepatitis B and C infection, genital warts, hairy cell leukemia, follicular lymphoma, malignant melanoma, and AIDs-related Kaposi's sarcoma.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Interferon alfa-2b interact? Information: •Drug A: Abatacept •Drug B: Interferon alfa-2b •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Interferon alfa-2b is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of hairy cell leukemia, malignant melanoma, and AIDS-related Kaposi's sarcoma. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Upregulates the expression of MHC I proteins, allowing for increased presentation of peptides derived from viral antigens. This enhances the activation of CD8+ T cells that are the precursors for cytotoxic T lymphocytes (CTLs) and makes the macrophage a better target for CTL-mediated killing. Interferon alpha also induce the synthesis of several key antiviral mediators, including 2'-5' oligoadenylate synthetase (2'-5' A synthetase) and protein kinase R. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Interferon alpha binds to type I interferon receptors (IFNAR1 and IFNAR2c) which upon dimerization activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2). These transphosphorylate themselves and phosphorylate the receptors. The phosphorylated INFAR receptors then bind to Stat1 and Stat2 (signal transducers and activators of transcription)which dimerize and activate multiple (~100) immunomodulatory and antiviral proteins. Interferon alpha binds less stably to type I interferon receptors than interferon beta. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption is high (greater than 80%) when administered intramuscularly or subcutaneously. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life following both intramuscular and subcutaneous injections was approximately 2 to 3 hours. The elimination half-life was approximately 2 hours following intravenous injection. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There is limited experience with overdosage. Postmarketing surveillance includes reports of patients receiving a single dose as great as 10 times the recommended dose. In general, the primary effects of an overdose are consistent with the effects seen with therapeutic doses of interferon alfa-2b. Hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction have been reported with single administration overdoses and/or with longer durations of treatment than prescribed. Toxic effects after ingestion of interferon alfa-2b are not expected because interferons are poorly absorbed orally. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Intron A •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Interferon alfa-2b is a form of recombinant human interferon used to treat hepatitis B and C infection, genital warts, hairy cell leukemia, follicular lymphoma, malignant melanoma, and AIDs-related Kaposi's sarcoma. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Interferon alfa-n3 interact?

•Drug A: Abatacept •Drug B: Interferon alfa-n3 •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Interferon alfa-n3 is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the intralesional treatment of refractory or recurring external condylomata acuminata. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Interferon alfa-n3 upregulates the expression of MHC I proteins, allowing for increased presentation of peptides derived from viral antigens. This enhances the activation of CD8+ T cells that are the precursors for cytotoxic T lymphocytes (CTLs) and makes the macrophage a better target for CTL-mediated killing. Interferon alpha also induce the synthesis of several key antiviral mediators, including 2'-5' oligoadenylate synthetase (2'-5' A synthetase), beta-2 microglobulin, neopterin and protein kinase R. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Interferon alpha binds to type I interferon receptors (IFNAR1 and IFNAR2c) which, upon dimerization, activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2). These transphosphorylate themselves and phosphorylate the receptors. The phosphorylated INFAR receptors then bind to Stat1 and Stat2 (signal transducers and activators of transcription) which dimerize and activate multiple (~100) immunomodulatory and antiviral proteins. Interferon alpha binds less stably to type I interferon receptors than interferon beta. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alferon N •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Interferon alfa-n3 is a purified form of human interferon used to stimulate the innate antiviral response in the treatment of genital warts due to human papilloma virus.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Interferon alfa-n3 interact? Information: •Drug A: Abatacept •Drug B: Interferon alfa-n3 •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Interferon alfa-n3 is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the intralesional treatment of refractory or recurring external condylomata acuminata. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Interferon alfa-n3 upregulates the expression of MHC I proteins, allowing for increased presentation of peptides derived from viral antigens. This enhances the activation of CD8+ T cells that are the precursors for cytotoxic T lymphocytes (CTLs) and makes the macrophage a better target for CTL-mediated killing. Interferon alpha also induce the synthesis of several key antiviral mediators, including 2'-5' oligoadenylate synthetase (2'-5' A synthetase), beta-2 microglobulin, neopterin and protein kinase R. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Interferon alpha binds to type I interferon receptors (IFNAR1 and IFNAR2c) which, upon dimerization, activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2). These transphosphorylate themselves and phosphorylate the receptors. The phosphorylated INFAR receptors then bind to Stat1 and Stat2 (signal transducers and activators of transcription) which dimerize and activate multiple (~100) immunomodulatory and antiviral proteins. Interferon alpha binds less stably to type I interferon receptors than interferon beta. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alferon N •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Interferon alfa-n3 is a purified form of human interferon used to stimulate the innate antiviral response in the treatment of genital warts due to human papilloma virus. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Interferon beta-1b interact?

•Drug A: Abatacept •Drug B: Interferon beta-1b •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Interferon beta-1b is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Interferon beta-1b is a drug used for the treatment of relapsing/remitting multiple sclerosis. It has been shown to slow the advance of the disease as well as to decrease the frequency of attacks. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Interferon beta upregulates the expression of MHC I proteins, allowing for increased presentation of peptides derived from viral antigens. This enhances the activation of CD8+ T cells that are the precursors for cytotoxic T lymphocytes (CTLs) and makes the macrophage a better target for CTL-mediated killing. Type I interferons also induce the synthesis of several key antiviral mediators including 2'-5' oligoadenylate synthetase (2'-5' A synthetase), beta-2 microglobulin, neopterin and protein kinase R. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Interferon beta binds to type I interferon receptors (IFNAR1 and IFNAR2c) which activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2). These transphosphorylate themselves and phosphorylate the receptors. The phosphorylated INFAR receptors then bind to Stat1 and Stat2 (signal transducers and activators of transcription)which dimerize and activate multiple (~100) immunomodulatory and antiviral proteins. Interferon beta binds more stably to type I interferon receptors than interferon alpha. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 0.25 to 2,88 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 9.4 – 28.9 mL/min•kg-1 [patients with diseases other than MS receiving single intravenous doses up to 2.0 mg] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Betaferon, Betaseron, Extavia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Interferon beta-1b is a form of recombinant human interferon used to slow the progression of relapsing multiple sclerosis and to reduce the frequency of clinical symptoms.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Interferon beta-1b interact? Information: •Drug A: Abatacept •Drug B: Interferon beta-1b •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Interferon beta-1b is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Interferon beta-1b is a drug used for the treatment of relapsing/remitting multiple sclerosis. It has been shown to slow the advance of the disease as well as to decrease the frequency of attacks. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Interferon beta upregulates the expression of MHC I proteins, allowing for increased presentation of peptides derived from viral antigens. This enhances the activation of CD8+ T cells that are the precursors for cytotoxic T lymphocytes (CTLs) and makes the macrophage a better target for CTL-mediated killing. Type I interferons also induce the synthesis of several key antiviral mediators including 2'-5' oligoadenylate synthetase (2'-5' A synthetase), beta-2 microglobulin, neopterin and protein kinase R. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Interferon beta binds to type I interferon receptors (IFNAR1 and IFNAR2c) which activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2). These transphosphorylate themselves and phosphorylate the receptors. The phosphorylated INFAR receptors then bind to Stat1 and Stat2 (signal transducers and activators of transcription)which dimerize and activate multiple (~100) immunomodulatory and antiviral proteins. Interferon beta binds more stably to type I interferon receptors than interferon alpha. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 0.25 to 2,88 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 9.4 – 28.9 mL/min•kg-1 [patients with diseases other than MS receiving single intravenous doses up to 2.0 mg] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Betaferon, Betaseron, Extavia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Interferon beta-1b is a form of recombinant human interferon used to slow the progression of relapsing multiple sclerosis and to reduce the frequency of clinical symptoms. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Interferon gamma-1b interact?

•Drug A: Abatacept •Drug B: Interferon gamma-1b •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Interferon gamma-1b is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Interferon gamma-1b is used for the treatment of Chronic granulomatous disease and Osteopetrosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): IFN gamma stimulates expression of the immunoglobulin heavy chain C gamma 3 and C gamma 2a germline transcripts in B cells. Many components of the antigen presentation pathways are also up-regulated by interferon gamma. It is also a potent activator of macrophages, it has antiproliferative effects on transformed cells and it can potentiate the antiviral and antitumor effects of type I interferons. Interferon gamma may also help the body regulate the activity of fibroblasts. By directly blocking the multiplication of fibroblasts and inhibiting the production and action of TGF-b, a potent scar-inducing molecule, Interferon gamma-1b may prevent excessive scarring. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Binds directly to the type II interferon gamma receptor IFNGR1, leading to a complex of IFNGR1 and IFNGR2. This activates JAK1 and JAK2 kinases which form a STAT1 docking site. This leads to STAT1 phosphorylation, nuclear translocation and initiation of gene transcription of multiple immune-related genes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Actimmune •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Interferon gamma-1b is a form of recombinant human interferon used to treat infections associated with chronic granulomatous disease and to slow the progression of severe malignant osteopetrosis.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Interferon gamma-1b interact? Information: •Drug A: Abatacept •Drug B: Interferon gamma-1b •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Interferon gamma-1b is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Interferon gamma-1b is used for the treatment of Chronic granulomatous disease and Osteopetrosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): IFN gamma stimulates expression of the immunoglobulin heavy chain C gamma 3 and C gamma 2a germline transcripts in B cells. Many components of the antigen presentation pathways are also up-regulated by interferon gamma. It is also a potent activator of macrophages, it has antiproliferative effects on transformed cells and it can potentiate the antiviral and antitumor effects of type I interferons. Interferon gamma may also help the body regulate the activity of fibroblasts. By directly blocking the multiplication of fibroblasts and inhibiting the production and action of TGF-b, a potent scar-inducing molecule, Interferon gamma-1b may prevent excessive scarring. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Binds directly to the type II interferon gamma receptor IFNGR1, leading to a complex of IFNGR1 and IFNGR2. This activates JAK1 and JAK2 kinases which form a STAT1 docking site. This leads to STAT1 phosphorylation, nuclear translocation and initiation of gene transcription of multiple immune-related genes. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Actimmune •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Interferon gamma-1b is a form of recombinant human interferon used to treat infections associated with chronic granulomatous disease and to slow the progression of severe malignant osteopetrosis. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Iptacopan interact?

•Drug A: Abatacept •Drug B: Iptacopan •Severity: MODERATE •Description: The metabolism of Iptacopan can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Iptacopan is indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Inhibition of the alternative complement pathway biomarkers, in vitro alternative pathway assay, and plasma Bb (fragment Bb of Factor B), started approximately 2 hours after a single iptacopan dose in healthy volunteers. In paroxysmal nocturnal hemoglobinuria (PNH) patients receiving concomitant anti-C5 treatment and iptacopan 200 mg twice daily, the in vitro alternative pathway assay and plasma Bb decreased from baseline by 54.1% and 56.1%, respectively, on the first observation on Day 8. In treatment-naive PNH patients, these same biomarkers decreased from baseline by 78.4% and 58.9%, respectively, on the first observation after 4 weeks of treatment with iptacopan 200 mg twice daily. In PNH patients on concomitant anti-C5 treatment and FABHALTA 200 mg twice daily, the mean PNH red blood cell (RBC) clone size was 54.8% at baseline and increased to 89.2% after 13 weeks; the proportion of PNH Type II + III RBCs with C3 deposition was 12.4% at baseline and decreased to 0.2% after 13 weeks. In treatment-naive PNH patients, the mean PNH RBC clone size was 49.1% at baseline and increased to 91.1% after 12 weeks; there were negligible PNH Type II + III RBCs with C3 deposition in this population due to the predominance of IVH. Iptacopan reduces serum LDH levels. In PNH patients previously treated with eculizumab, all patients treated with FABHALTA 200 mg twice daily achieved a reduction of LDH levels to < 1.5 times the upper limit of normal (ULN) at 13 weeks. In treatment-naive PNH patients, iptacopan 200 mg twice daily reduced LDH by > 60% compared to baseline after 12 weeks and maintained the effect through the end of the study at 2 years. In a QTc clinical study in healthy volunteers, single supra-therapeutic iptacopan doses up to 1,200 mg (which provided greater than 4-fold peak concentration of the MRHD) showed no effect on cardiac repolarization or QT interval. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Iptacopan binds to Factor B of the alternative complement pathway and regulates the cleavage of C3, the generation of downstream effectors, and the amplification of the terminal pathway. In paroxysmal nocturnal hemoglobinuria, intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC), while extravascular hemolysis (EVH) is facilitated by C3b opsonization. Iptacopan acts proximally in the alternative pathway of the complement cascade to control both C3b-mediated EVH and terminal complement-mediated IVH. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following oral administration, iptacopan reached peak plasma concentrations approximately 2 hours post-dose. At the recommended dosing regimen of 200 mg twice daily, a steady state is achieved in approximately 5 days with minor accumulation (1.4-fold). Based on a food-effect study in healthy volunteers, a high-fat meal did not affect the exposure of iptacopan to a clinically meaningful degree. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): After administration of iptacopan 200 mg twice daily, the apparent volume of distribution at steady state was approximately 288 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Iptacopan showed concentration-dependent plasma protein binding due to binding to the target Factor B in the systemic circulation. Iptacopan was 75% to 93% protein-bound in vitro at the relevant clinical plasma concentrations. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism is a predominant elimination pathway for iptacopan with approximately 50% of the dose attributed to oxidative pathways. Metabolism of iptacopan includes N-dealkylation, O-deethylation, oxidation, and dehydrogenation, mostly driven by CYP2C8 (98%) with a small contribution from CYP2D6 (2%). Iptacopan undergoes Phase 2 metabolism through glucuronidation by UGT1A1, UGT1A3, and UGT1A8. In plasma, iptacopan was the major component, accounting for 83% of the drug-related species. Two acyl glucuronides were the only metabolites detected in plasma and were minor, accounting for 8% and 5% of the drug-related species. Iptacopan metabolites are not pharmacologically active. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In a human study, following a single 100 mg oral dose of [ C]-iptacopan, the mean total excretion of radioactivity (iptacopan and metabolites) was 71.5% in the feces and 24.8% in the urine, for a total mean excretion of >96% of the dose. Specifically, 17.9% of the dose was excreted as parent iptacopan in the urine, and 16.8% of the dose was excreted as parent iptacopan in feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life (t 1/2 ) of iptacopan at steady state is approximately 25 hours after administration of 200 mg twice daily. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance of iptacopan at steady state is 7.96 L/h after administration of 200 mg twice daily. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Available data from clinical trials with iptacopan use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) in pregnancy. The use of iptacopan in pregnant women or women planning to become pregnant may be considered following an assessment of the risks and benefits. PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombosis, infections, bleeding, miscarriages, increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. In animal reproduction studies, oral administration of iptacopan to pregnant rats and rabbits during organogenesis at exposures 4 to 6 times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 200 mg twice daily did not induce embryo or fetal toxicity. Iptacopan was not genotoxic or mutagenic in a battery of in vitro and in vivo assays. Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential. The highest exposure to iptacopan in rats corresponds to ~9 times the MRHD based on AUC. In a fertility study in male rats, iptacopan did not adversely impact fertility up to the highest tested dose of 750 mg/kg/day, which corresponds to 4 times the MRHD based on AUC. Reversible effects on the male reproductive system (testicular tubular degeneration and cellular debris in epididymis) were observed in repeatdose toxicity studies with oral administration in dogs at doses ≥ 2 times the MRHD based on AUC, with no clear effects on sperm numbers, morphology, or motility. In a fertility and early embryonic developmental study in female rats, oral administration of iptacopan caused increased pre-and post-implantation losses when given at the highest dose of 1,000 mg/kg/day orally, which corresponds to ~11 times the MRHD based on AUC. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Fabhalta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Iptacopan is a factor B inhibitor used to treat paroxysmal nocturnal hemoglobinuria.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Iptacopan interact? Information: •Drug A: Abatacept •Drug B: Iptacopan •Severity: MODERATE •Description: The metabolism of Iptacopan can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Iptacopan is indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Inhibition of the alternative complement pathway biomarkers, in vitro alternative pathway assay, and plasma Bb (fragment Bb of Factor B), started approximately 2 hours after a single iptacopan dose in healthy volunteers. In paroxysmal nocturnal hemoglobinuria (PNH) patients receiving concomitant anti-C5 treatment and iptacopan 200 mg twice daily, the in vitro alternative pathway assay and plasma Bb decreased from baseline by 54.1% and 56.1%, respectively, on the first observation on Day 8. In treatment-naive PNH patients, these same biomarkers decreased from baseline by 78.4% and 58.9%, respectively, on the first observation after 4 weeks of treatment with iptacopan 200 mg twice daily. In PNH patients on concomitant anti-C5 treatment and FABHALTA 200 mg twice daily, the mean PNH red blood cell (RBC) clone size was 54.8% at baseline and increased to 89.2% after 13 weeks; the proportion of PNH Type II + III RBCs with C3 deposition was 12.4% at baseline and decreased to 0.2% after 13 weeks. In treatment-naive PNH patients, the mean PNH RBC clone size was 49.1% at baseline and increased to 91.1% after 12 weeks; there were negligible PNH Type II + III RBCs with C3 deposition in this population due to the predominance of IVH. Iptacopan reduces serum LDH levels. In PNH patients previously treated with eculizumab, all patients treated with FABHALTA 200 mg twice daily achieved a reduction of LDH levels to < 1.5 times the upper limit of normal (ULN) at 13 weeks. In treatment-naive PNH patients, iptacopan 200 mg twice daily reduced LDH by > 60% compared to baseline after 12 weeks and maintained the effect through the end of the study at 2 years. In a QTc clinical study in healthy volunteers, single supra-therapeutic iptacopan doses up to 1,200 mg (which provided greater than 4-fold peak concentration of the MRHD) showed no effect on cardiac repolarization or QT interval. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Iptacopan binds to Factor B of the alternative complement pathway and regulates the cleavage of C3, the generation of downstream effectors, and the amplification of the terminal pathway. In paroxysmal nocturnal hemoglobinuria, intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC), while extravascular hemolysis (EVH) is facilitated by C3b opsonization. Iptacopan acts proximally in the alternative pathway of the complement cascade to control both C3b-mediated EVH and terminal complement-mediated IVH. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following oral administration, iptacopan reached peak plasma concentrations approximately 2 hours post-dose. At the recommended dosing regimen of 200 mg twice daily, a steady state is achieved in approximately 5 days with minor accumulation (1.4-fold). Based on a food-effect study in healthy volunteers, a high-fat meal did not affect the exposure of iptacopan to a clinically meaningful degree. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): After administration of iptacopan 200 mg twice daily, the apparent volume of distribution at steady state was approximately 288 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Iptacopan showed concentration-dependent plasma protein binding due to binding to the target Factor B in the systemic circulation. Iptacopan was 75% to 93% protein-bound in vitro at the relevant clinical plasma concentrations. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism is a predominant elimination pathway for iptacopan with approximately 50% of the dose attributed to oxidative pathways. Metabolism of iptacopan includes N-dealkylation, O-deethylation, oxidation, and dehydrogenation, mostly driven by CYP2C8 (98%) with a small contribution from CYP2D6 (2%). Iptacopan undergoes Phase 2 metabolism through glucuronidation by UGT1A1, UGT1A3, and UGT1A8. In plasma, iptacopan was the major component, accounting for 83% of the drug-related species. Two acyl glucuronides were the only metabolites detected in plasma and were minor, accounting for 8% and 5% of the drug-related species. Iptacopan metabolites are not pharmacologically active. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): In a human study, following a single 100 mg oral dose of [ C]-iptacopan, the mean total excretion of radioactivity (iptacopan and metabolites) was 71.5% in the feces and 24.8% in the urine, for a total mean excretion of >96% of the dose. Specifically, 17.9% of the dose was excreted as parent iptacopan in the urine, and 16.8% of the dose was excreted as parent iptacopan in feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life (t 1/2 ) of iptacopan at steady state is approximately 25 hours after administration of 200 mg twice daily. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance of iptacopan at steady state is 7.96 L/h after administration of 200 mg twice daily. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Available data from clinical trials with iptacopan use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) in pregnancy. The use of iptacopan in pregnant women or women planning to become pregnant may be considered following an assessment of the risks and benefits. PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombosis, infections, bleeding, miscarriages, increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. In animal reproduction studies, oral administration of iptacopan to pregnant rats and rabbits during organogenesis at exposures 4 to 6 times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 200 mg twice daily did not induce embryo or fetal toxicity. Iptacopan was not genotoxic or mutagenic in a battery of in vitro and in vivo assays. Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential. The highest exposure to iptacopan in rats corresponds to ~9 times the MRHD based on AUC. In a fertility study in male rats, iptacopan did not adversely impact fertility up to the highest tested dose of 750 mg/kg/day, which corresponds to 4 times the MRHD based on AUC. Reversible effects on the male reproductive system (testicular tubular degeneration and cellular debris in epididymis) were observed in repeatdose toxicity studies with oral administration in dogs at doses ≥ 2 times the MRHD based on AUC, with no clear effects on sperm numbers, morphology, or motility. In a fertility and early embryonic developmental study in female rats, oral administration of iptacopan caused increased pre-and post-implantation losses when given at the highest dose of 1,000 mg/kg/day orally, which corresponds to ~11 times the MRHD based on AUC. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Fabhalta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Iptacopan is a factor B inhibitor used to treat paroxysmal nocturnal hemoglobinuria. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Irbesartan interact?

•Drug A: Abatacept •Drug B: Irbesartan •Severity: MODERATE •Description: The metabolism of Irbesartan can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Irbesartan is indicated to treat hypertension and diabetic nephropathy in hypertensive patients with type 2 diabetes, elevated serum creatinine, and proteinuria. A combination product with hydrochlorothiazide is indicated for hypertension in patients with uncontrolled hypertension with monotherapy or first line in patients not expected to be well controlled with monotherapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Irbesartan is an angiotensin receptor blocker used to treat hypertension and diabetic nephropathy. It has a long duration of action as it is usually taken once daily and a wide therapeutic index as doses may be as low as 150mg daily but doses of 900mg/day were well tolerated in healthy human subjects. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Irbesartan prevents angiotensin II binding to the AT 1 receptor in tissues like vascular smooth muscle and the adrenal gland. Irbesartan and its active metabolite bind the AT 1 receptor with 8500 times more affinity than they bind to the AT 2 receptor. Irbesartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation and prevents the secretion of aldosterone, lowering blood pressure. Angiotensin II would otherwise bind to the AT 1 receptor, inducing vasoconstriction and aldosterone secretion, raising blood pressure. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Irbesartan is 60-80% bioavailable with a T max of 1.5-2hours. Taking irbesartan with food does not affect the bioavailability. In one study, healthy subjects were given single or multiple oral doses of 150mg, 300mg, 600mg, and 900mg of irbesartan. A single 150mg dose resulted in an AUC of 9.7±3.0µg\•hr/mL, a T max of 1.5 hours, a half life of 16±7 hours, and a C max of 1.9±0.4µg/mL. A single 300mg dose resulted in an AUC of 20.0±5.2µg\•hr/mL, a T max of 1.5 hours, a half life of 14±7 hours, and a C max of 2.9±0.9µg/mL. A single 600mg dose resulted in an AUC of 32.6±11.9µg\•hr/mL, a T max of 1.5 hours, a half life of 14±8 hours, and a C max of 4.9±1.2µg/mL. A single 900mg dose resulted in an AUC of 44.8±20.0µg\•hr/mL, a T max of 1.5 hours, a half life of 17±7 hours, and a C max of 5.3±1.9µg/mL. Multiple 150mg doses resulted in an AUC of 9.3±3.0µg\•hr/mL, a T max of 1.5 hours, a half life of 11±4 hours, and a C max of 2.04±0.4µg/mL. Multiple 300mg doses resulted in an AUC of 19.8±5.8µg\•hr/mL, a T max of 2.0 hours, a half life of 11±5 hours, and a C max of 3.3±0.8µg/mL. Multiple 600mg doses resulted in an AUC of 31.9±9.7µg\•hr/mL, a T max of 1.5 hours, a half life of 15±7 hours, and a C max of 4.4±0.7µg/mL. Multiple 900mg doses resulted in an AUC of 34.2±9.3µg\•hr/mL, a T max of 1.8 hours, a half life of 14±6 hours, and a C max of 5.6±2.1µg/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of irbesartan is 53-93L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Irbesartan is 90% protein bound in plasma, mainly to albumin and α 1 -acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Irbesaran is largely metabolized by glucuronidation and oxidation in the liver. The majority of metabolism occurs through the action of CYP2C9 with a negligible contribution from CYP3A4. Some hydroxylation also occurs in irbesartan metabolism. Irbesartan can be glucuronidated by UGT1A3 to the M8 metabolite, oxidized to the M3 metabolite, or hydroxylated by CYP2C9 to one of the M4, M5, or M7 metabolites. The M4, M5, and M7 metabolites are all hydroxylated to become the M1 metabolite, which is then oxidized to the M2 metabolite. The M4 metabolite can also be oxidized to the M6 metabolite before hydroxylation to the M2 metabolite. Finally, the minor metabolite SR 49498 is generated from irbesartan by an unknown mechanism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 20% of a radiolabelled oral dose of irbesartan is recovered in urine, and the rest is recovered in the feces. <2% of the dose is recovered in urine as the unchanged drug. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half life of irbesartan is 11-15 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Total plasma clearance of irbesartan is 157-176mL/min while renal clearance is 3.0-3.5mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral TDLO in humans is 30mg/kg/6W. Symptoms of overdose include hypotension and tachycardia or bradycardia. Terlipressin may be given to treat hypotension and tachycardia if conventional vasopressors fail to control blood pressure. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Avalide, Avapro, Ifirmacombi, Karvea, Karvezide •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Irbesartan •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Irbesartan is an angiotensin receptor blocker used to treat hypertension, delay progression of diabetic nephropathy, and treat congestive heart failure.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Irbesartan interact? Information: •Drug A: Abatacept •Drug B: Irbesartan •Severity: MODERATE •Description: The metabolism of Irbesartan can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Irbesartan is indicated to treat hypertension and diabetic nephropathy in hypertensive patients with type 2 diabetes, elevated serum creatinine, and proteinuria. A combination product with hydrochlorothiazide is indicated for hypertension in patients with uncontrolled hypertension with monotherapy or first line in patients not expected to be well controlled with monotherapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Irbesartan is an angiotensin receptor blocker used to treat hypertension and diabetic nephropathy. It has a long duration of action as it is usually taken once daily and a wide therapeutic index as doses may be as low as 150mg daily but doses of 900mg/day were well tolerated in healthy human subjects. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Irbesartan prevents angiotensin II binding to the AT 1 receptor in tissues like vascular smooth muscle and the adrenal gland. Irbesartan and its active metabolite bind the AT 1 receptor with 8500 times more affinity than they bind to the AT 2 receptor. Irbesartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation and prevents the secretion of aldosterone, lowering blood pressure. Angiotensin II would otherwise bind to the AT 1 receptor, inducing vasoconstriction and aldosterone secretion, raising blood pressure. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Irbesartan is 60-80% bioavailable with a T max of 1.5-2hours. Taking irbesartan with food does not affect the bioavailability. In one study, healthy subjects were given single or multiple oral doses of 150mg, 300mg, 600mg, and 900mg of irbesartan. A single 150mg dose resulted in an AUC of 9.7±3.0µg\•hr/mL, a T max of 1.5 hours, a half life of 16±7 hours, and a C max of 1.9±0.4µg/mL. A single 300mg dose resulted in an AUC of 20.0±5.2µg\•hr/mL, a T max of 1.5 hours, a half life of 14±7 hours, and a C max of 2.9±0.9µg/mL. A single 600mg dose resulted in an AUC of 32.6±11.9µg\•hr/mL, a T max of 1.5 hours, a half life of 14±8 hours, and a C max of 4.9±1.2µg/mL. A single 900mg dose resulted in an AUC of 44.8±20.0µg\•hr/mL, a T max of 1.5 hours, a half life of 17±7 hours, and a C max of 5.3±1.9µg/mL. Multiple 150mg doses resulted in an AUC of 9.3±3.0µg\•hr/mL, a T max of 1.5 hours, a half life of 11±4 hours, and a C max of 2.04±0.4µg/mL. Multiple 300mg doses resulted in an AUC of 19.8±5.8µg\•hr/mL, a T max of 2.0 hours, a half life of 11±5 hours, and a C max of 3.3±0.8µg/mL. Multiple 600mg doses resulted in an AUC of 31.9±9.7µg\•hr/mL, a T max of 1.5 hours, a half life of 15±7 hours, and a C max of 4.4±0.7µg/mL. Multiple 900mg doses resulted in an AUC of 34.2±9.3µg\•hr/mL, a T max of 1.8 hours, a half life of 14±6 hours, and a C max of 5.6±2.1µg/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of irbesartan is 53-93L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Irbesartan is 90% protein bound in plasma, mainly to albumin and α 1 -acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Irbesaran is largely metabolized by glucuronidation and oxidation in the liver. The majority of metabolism occurs through the action of CYP2C9 with a negligible contribution from CYP3A4. Some hydroxylation also occurs in irbesartan metabolism. Irbesartan can be glucuronidated by UGT1A3 to the M8 metabolite, oxidized to the M3 metabolite, or hydroxylated by CYP2C9 to one of the M4, M5, or M7 metabolites. The M4, M5, and M7 metabolites are all hydroxylated to become the M1 metabolite, which is then oxidized to the M2 metabolite. The M4 metabolite can also be oxidized to the M6 metabolite before hydroxylation to the M2 metabolite. Finally, the minor metabolite SR 49498 is generated from irbesartan by an unknown mechanism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 20% of a radiolabelled oral dose of irbesartan is recovered in urine, and the rest is recovered in the feces. <2% of the dose is recovered in urine as the unchanged drug. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half life of irbesartan is 11-15 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Total plasma clearance of irbesartan is 157-176mL/min while renal clearance is 3.0-3.5mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral TDLO in humans is 30mg/kg/6W. Symptoms of overdose include hypotension and tachycardia or bradycardia. Terlipressin may be given to treat hypotension and tachycardia if conventional vasopressors fail to control blood pressure. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Avalide, Avapro, Ifirmacombi, Karvea, Karvezide •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Irbesartan •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Irbesartan is an angiotensin receptor blocker used to treat hypertension, delay progression of diabetic nephropathy, and treat congestive heart failure. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Irinotecan interact?

•Drug A: Abatacept •Drug B: Irinotecan •Severity: MAJOR •Description: The metabolism of Irinotecan can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Irinotecan is indicated for the treatment of: - Metastatic carcinoma of the colon or rectum as first-line treatment in combination with fluorouracil and leucovorin. - Metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy, as monotherapy or in combination with fluorouracil and leucovorin. Irinotecan liposome injection is used in adults for the treatment of: - Metastatic pancreatic adenocarcinoma in combination with oxaliplatin, fluorouracil, and leucovorin as first-line treatment. - Metastatic pancreatic adenocarcinoma in combination with fluorouracil and leucovorin after disease progression following gemcitabine-based therapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Irinotecan is an antineoplastic agent. The administration of irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): DNA topoisomerase I is a nuclear enzyme that ensures proper DNA topology during replication and transcription. It relieves torsional strain in the DNA double helix during replication and transcription by creating reversible single-strand breaks. Upon administration, irinotecan is converted into its active metabolite, SN-38, by carboxylesterase in the liver and gastrointestinal tract. Irinotecan and SN-38 both inhibit DNA topoisomerase I, acting on the S and G2 phases of the cell cycle. Irinotecan and SN-38 bind to the topoisomerase I-DNA complex and prevent the religation of single-strand breaks. The ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38 interferes with the moving replication fork, inducing replication arrest and lethal double-stranded breaks in DNA. Because double-stranded breaks cannot be efficiently repaired by mammalian cells, apoptosis of cancer cells occurs. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Over the recommended dose range of 50 to 350 mg/m, the AUC of irinotecan increases linearly with dose; the AUC of SN-38 increases less than proportionally with dose. Maximum concentrations of the active metabolite SN-38 are generally seen within 1 hour following the end of a 90-minute infusion of irinotecan. The plasma levels of SN-38 are much lower than that of irinotecan. Following intravenous infusion in patients with solid tumours, the mean (± standard deviation) C max was 1,660 ± 797 ng/mL at a dose of 125 mg/m and 3,392 ± 874 ng/mL at a dose of 340 mg/m. The AUC 0–24 was 10,200 ± 3,270 ng x h/mL at a dose of 125 mg/m and 20,604 ± 6,027 ng x h/mL at a dose of 340 mg/m. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Following intravenous infusion in patients with solid tumours, the mean (± standard deviation) volume of distribution of terminal elimination phase was 110 ± 48.5 L/m at a dose of 125 mg/m and 234 ± 69.6 L/m at a dose of 340 mg/m. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Irinotecan is about 30% to 68% bound to plasma proteins. SN-38 is approximately 95% bound to plasma proteins. Irinotecan and SN-38 are mainly bound to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Upon administration, irinotecan is converted primarily in the liver into its active metabolite, SN-38, by carboxylesterase. SN-38 is formed by cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. While in vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies, SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I. SN-38 can further be glucuronidated by UGT1A1 to form SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidation to form NPC and APC. While some sources state that NPC and APC are weak inhibitors of topoisomerase I, they are unlikely to contribute to the pharmacological activity of irinotecan. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The disposition of irinotecan has not been fully elucidated in humans. The urinary excretion of irinotecan, SN-38, and SN-38 glucuronide are 11% to 20%, <1%, and 3%, respectively. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours in two patients ranged from approximately 25% (100 mg/m ) to 50% (300 mg/m ). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): After intravenous infusion of irinotecan in humans, the mean terminal elimination half-life of irinotecan is about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean (± standard deviation) total systemic clearance of irinotecan in patients with solid tumours was 13.3 ± 6.01 L/h/m at a dose of 125 mg/m and 13.9 ± 4.0 L/h/m at a dose of 340 mg/m. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 is 1045 mg/kg in mice and 867 mg/kg in rats. In clinical trials involving patients with various cancers, single doses of up to 750 mg/m of irinotecan were associated with similar adverse events reported with the recommended dosage and regimen. There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhea. Because there is no known antidote for overdosage of irinotecan, maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Camptosar, Onivyde •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(2-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-1H-indol-1-yl)ethyl)piperidine-1-carboxylate Irinotecan Irinotecan lactone Irinotecan liposome injection Irinotecanum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Irinotecan is a topoisomerase inhibitor used to treat metastatic carcinoma of the colon or rectum and pancreatic adenocarcinoma.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Irinotecan interact? Information: •Drug A: Abatacept •Drug B: Irinotecan •Severity: MAJOR •Description: The metabolism of Irinotecan can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Irinotecan is indicated for the treatment of: - Metastatic carcinoma of the colon or rectum as first-line treatment in combination with fluorouracil and leucovorin. - Metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy, as monotherapy or in combination with fluorouracil and leucovorin. Irinotecan liposome injection is used in adults for the treatment of: - Metastatic pancreatic adenocarcinoma in combination with oxaliplatin, fluorouracil, and leucovorin as first-line treatment. - Metastatic pancreatic adenocarcinoma in combination with fluorouracil and leucovorin after disease progression following gemcitabine-based therapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Irinotecan is an antineoplastic agent. The administration of irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): DNA topoisomerase I is a nuclear enzyme that ensures proper DNA topology during replication and transcription. It relieves torsional strain in the DNA double helix during replication and transcription by creating reversible single-strand breaks. Upon administration, irinotecan is converted into its active metabolite, SN-38, by carboxylesterase in the liver and gastrointestinal tract. Irinotecan and SN-38 both inhibit DNA topoisomerase I, acting on the S and G2 phases of the cell cycle. Irinotecan and SN-38 bind to the topoisomerase I-DNA complex and prevent the religation of single-strand breaks. The ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38 interferes with the moving replication fork, inducing replication arrest and lethal double-stranded breaks in DNA. Because double-stranded breaks cannot be efficiently repaired by mammalian cells, apoptosis of cancer cells occurs. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Over the recommended dose range of 50 to 350 mg/m, the AUC of irinotecan increases linearly with dose; the AUC of SN-38 increases less than proportionally with dose. Maximum concentrations of the active metabolite SN-38 are generally seen within 1 hour following the end of a 90-minute infusion of irinotecan. The plasma levels of SN-38 are much lower than that of irinotecan. Following intravenous infusion in patients with solid tumours, the mean (± standard deviation) C max was 1,660 ± 797 ng/mL at a dose of 125 mg/m and 3,392 ± 874 ng/mL at a dose of 340 mg/m. The AUC 0–24 was 10,200 ± 3,270 ng x h/mL at a dose of 125 mg/m and 20,604 ± 6,027 ng x h/mL at a dose of 340 mg/m. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Following intravenous infusion in patients with solid tumours, the mean (± standard deviation) volume of distribution of terminal elimination phase was 110 ± 48.5 L/m at a dose of 125 mg/m and 234 ± 69.6 L/m at a dose of 340 mg/m. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Irinotecan is about 30% to 68% bound to plasma proteins. SN-38 is approximately 95% bound to plasma proteins. Irinotecan and SN-38 are mainly bound to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Upon administration, irinotecan is converted primarily in the liver into its active metabolite, SN-38, by carboxylesterase. SN-38 is formed by cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. While in vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies, SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I. SN-38 can further be glucuronidated by UGT1A1 to form SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidation to form NPC and APC. While some sources state that NPC and APC are weak inhibitors of topoisomerase I, they are unlikely to contribute to the pharmacological activity of irinotecan. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The disposition of irinotecan has not been fully elucidated in humans. The urinary excretion of irinotecan, SN-38, and SN-38 glucuronide are 11% to 20%, <1%, and 3%, respectively. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours in two patients ranged from approximately 25% (100 mg/m ) to 50% (300 mg/m ). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): After intravenous infusion of irinotecan in humans, the mean terminal elimination half-life of irinotecan is about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean (± standard deviation) total systemic clearance of irinotecan in patients with solid tumours was 13.3 ± 6.01 L/h/m at a dose of 125 mg/m and 13.9 ± 4.0 L/h/m at a dose of 340 mg/m. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 is 1045 mg/kg in mice and 867 mg/kg in rats. In clinical trials involving patients with various cancers, single doses of up to 750 mg/m of irinotecan were associated with similar adverse events reported with the recommended dosage and regimen. There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhea. Because there is no known antidote for overdosage of irinotecan, maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Camptosar, Onivyde •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(2-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-1H-indol-1-yl)ethyl)piperidine-1-carboxylate Irinotecan Irinotecan lactone Irinotecan liposome injection Irinotecanum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Irinotecan is a topoisomerase inhibitor used to treat metastatic carcinoma of the colon or rectum and pancreatic adenocarcinoma. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Isavuconazole interact?

•Drug A: Abatacept •Drug B: Isavuconazole •Severity: MODERATE •Description: The metabolism of Isavuconazole can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for patients 18 years of age and older for the treatment of invasive aspergillosis. Indicated for patients 18 years of age and older for the treatment of invasive mucormycosis, including patients where treatment amphotericin B is inappropriate. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Isavucoanzole exhibits antifungal activity against most strains of Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, and Mucorales such as Rhizopus oryzae and Mucormycetes species in vivo and in vitro. In a cardiac electrophysiology study involving healthy subjects, isavuconazole induced dose-related shortening of the QTc interval but the additive effect of isavuconazole with other QTc-prolonging drug is unknown. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Isavuconazole displays fungicidal actions by disrupting the biosynthesis of ergosterol, which is a key component of fungal cell membrane. It inhibits cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase that mediates the conversion of lanosterol to ergosterol. The side arm of of the active isavuconazole molecule allows for greater affinity for the binding pocket in the fungal CYP51 protein by orienting the triazole ring of the molecule to engage with the heme moiety at the bottom of the binding pocket. This explains the wide antifungal spectrum of isavuconazole and possible cross-resistance to other triazoles. As a result of lanosterol 14-alpha-demethylase inhibition, toxic methylated sterol precursors such as 14-α-methylated lanosterol, 4,14-dimethylzymosterol, and 24-methylenedihydrolanosterol alter the function of fungal membrane and accumulate within the fungal cytoplasm. Depletion of ergosterol within the fungal cell membrane leads to decreased structural integrity and function of the cell membrane, inhibited fungal cell growth and replication, and ultimately cell death. Mammalian cell demethylation is less sensitive to isavuconazole inhibition. Mechanism of resistance and reduced susceptibility to isavuconazole arises from mutations in the fungal cyp51A and cyp51B genes coding for the target protein lanosterol 14-alpha-demethylase. Other multiple mechanisms leading to resistance, including changes in sterol profile and elevated efflux pump activity of fungal species, cannot be excluded. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following oral administration of 200 mg isavuconazole, the mean peak plasma concentration (Cmax) at steady state was 7499 ng/mL. Cmax following oral administration of 600 mg isavuconazole was 20028 ng/mL. It is proposed that the Cmax at steady state is reached approximately 2–3 hours after single and multiple dosing of isavuconazole. Administration of 400 mg of oral and intravenous isavuconazole resulted in mean AUC of 189462.8 h ng/mL and 193906.8 h ng/mL, respectively. While isavuconazole can be administered with or without food, concurrent consumption of a high-fat meal reduced oral isavuconazole Cmax by 9% and increased AUC by 9%. The absolute bioavailability of isavuconazole following oral administration of a single dose of isavuconazole is 98%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean steady state volume of distribution (Vss) was approximately 450 L following intravenous administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Following rapid conversion of the prodrug isavuconazonium to isavuconazole via esterase-mediated hydrolysis, a number of minor metabolites were identified in addition to the active moiety itself and the inactive cleavage product of isavuconazonium. However, no individual metabolite was observed with an AUC greater than 10% of total radio-labeled material. The main enzymes involved in the metabolism of isavuconazole are CYP3A4, CYP3A5, and subsequently uridine diphosphate- glucuronosyltransferases (UGT) according to the findings of in vivo and in vitro studies. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration, 46.1% of total radiolabelled isavuconzaole was detected in the feces, and about 45.5% was recovered in urine. Unchanged isavuconazole in the urine was less than 1% of the total dose administered. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours. The mean half life following oral and intravenous administration of 400 mg isavuconazole was 110 and 115 hours, respectively. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance (CL) rate was 2.5 ± 1.6 L/h in patients receiving 200 mg isavuconazole orally or intravenously. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): At three times the recommended maintenance dose of isavuconazole, treatment-emergent adverse reactions included headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. As there is no specific antidote or effective method of hemodialysis for isavuconazole, supportive treatment with appropriate monitoring is recommended in case of overdose. No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats. However, isavuconazole was weakly clastogenic at cytotoxic concentrations in the L5178Y tk+/- mouse lymphoma chromosome aberration assay without any significant evidence of increased frequency of micronuclei in an in vivo rat micronucleus test. While carcinogenicity studies isavuconazole have not been performed, other drugs in the azole class at near human recommended doses were associated with the development of hepatocellular adenomas and carcinomas in mice and rat carcinogenicity studies. At doses up to 90 mg/kg/day, oral isavuconazole did not affect the fertility in male or female rats. Isavuconazole at systemic exposures of subtherapeutic levels was associated with dose-related increases in the incidence of skeletal anomalies in rat and rabbit offsprings. In rats, a dose-related increase in the incidence of zygomatic arch fusion was also noted in offspring. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cresemba •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): No summary available

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Isavuconazole interact? Information: •Drug A: Abatacept •Drug B: Isavuconazole •Severity: MODERATE •Description: The metabolism of Isavuconazole can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for patients 18 years of age and older for the treatment of invasive aspergillosis. Indicated for patients 18 years of age and older for the treatment of invasive mucormycosis, including patients where treatment amphotericin B is inappropriate. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Isavucoanzole exhibits antifungal activity against most strains of Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, and Mucorales such as Rhizopus oryzae and Mucormycetes species in vivo and in vitro. In a cardiac electrophysiology study involving healthy subjects, isavuconazole induced dose-related shortening of the QTc interval but the additive effect of isavuconazole with other QTc-prolonging drug is unknown. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Isavuconazole displays fungicidal actions by disrupting the biosynthesis of ergosterol, which is a key component of fungal cell membrane. It inhibits cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase that mediates the conversion of lanosterol to ergosterol. The side arm of of the active isavuconazole molecule allows for greater affinity for the binding pocket in the fungal CYP51 protein by orienting the triazole ring of the molecule to engage with the heme moiety at the bottom of the binding pocket. This explains the wide antifungal spectrum of isavuconazole and possible cross-resistance to other triazoles. As a result of lanosterol 14-alpha-demethylase inhibition, toxic methylated sterol precursors such as 14-α-methylated lanosterol, 4,14-dimethylzymosterol, and 24-methylenedihydrolanosterol alter the function of fungal membrane and accumulate within the fungal cytoplasm. Depletion of ergosterol within the fungal cell membrane leads to decreased structural integrity and function of the cell membrane, inhibited fungal cell growth and replication, and ultimately cell death. Mammalian cell demethylation is less sensitive to isavuconazole inhibition. Mechanism of resistance and reduced susceptibility to isavuconazole arises from mutations in the fungal cyp51A and cyp51B genes coding for the target protein lanosterol 14-alpha-demethylase. Other multiple mechanisms leading to resistance, including changes in sterol profile and elevated efflux pump activity of fungal species, cannot be excluded. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following oral administration of 200 mg isavuconazole, the mean peak plasma concentration (Cmax) at steady state was 7499 ng/mL. Cmax following oral administration of 600 mg isavuconazole was 20028 ng/mL. It is proposed that the Cmax at steady state is reached approximately 2–3 hours after single and multiple dosing of isavuconazole. Administration of 400 mg of oral and intravenous isavuconazole resulted in mean AUC of 189462.8 h ng/mL and 193906.8 h ng/mL, respectively. While isavuconazole can be administered with or without food, concurrent consumption of a high-fat meal reduced oral isavuconazole Cmax by 9% and increased AUC by 9%. The absolute bioavailability of isavuconazole following oral administration of a single dose of isavuconazole is 98%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean steady state volume of distribution (Vss) was approximately 450 L following intravenous administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Following rapid conversion of the prodrug isavuconazonium to isavuconazole via esterase-mediated hydrolysis, a number of minor metabolites were identified in addition to the active moiety itself and the inactive cleavage product of isavuconazonium. However, no individual metabolite was observed with an AUC greater than 10% of total radio-labeled material. The main enzymes involved in the metabolism of isavuconazole are CYP3A4, CYP3A5, and subsequently uridine diphosphate- glucuronosyltransferases (UGT) according to the findings of in vivo and in vitro studies. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration, 46.1% of total radiolabelled isavuconzaole was detected in the feces, and about 45.5% was recovered in urine. Unchanged isavuconazole in the urine was less than 1% of the total dose administered. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours. The mean half life following oral and intravenous administration of 400 mg isavuconazole was 110 and 115 hours, respectively. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance (CL) rate was 2.5 ± 1.6 L/h in patients receiving 200 mg isavuconazole orally or intravenously. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): At three times the recommended maintenance dose of isavuconazole, treatment-emergent adverse reactions included headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. As there is no specific antidote or effective method of hemodialysis for isavuconazole, supportive treatment with appropriate monitoring is recommended in case of overdose. No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats. However, isavuconazole was weakly clastogenic at cytotoxic concentrations in the L5178Y tk+/- mouse lymphoma chromosome aberration assay without any significant evidence of increased frequency of micronuclei in an in vivo rat micronucleus test. While carcinogenicity studies isavuconazole have not been performed, other drugs in the azole class at near human recommended doses were associated with the development of hepatocellular adenomas and carcinomas in mice and rat carcinogenicity studies. At doses up to 90 mg/kg/day, oral isavuconazole did not affect the fertility in male or female rats. Isavuconazole at systemic exposures of subtherapeutic levels was associated with dose-related increases in the incidence of skeletal anomalies in rat and rabbit offsprings. In rats, a dose-related increase in the incidence of zygomatic arch fusion was also noted in offspring. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cresemba •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): No summary available Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Does Abatacept and Isavuconazonium interact?

•Drug A: Abatacept •Drug B: Isavuconazonium •Severity: MODERATE •Description: The metabolism of Isavuconazonium can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Isavuconazonium is indicated for the treatment of invasive aspergillosis and mucormycosis in adults and pediatric patients 1 year of age and older in capsule form and adults and pediatric patients 6 years of age and older who weigh 16 kilograms (kg) and greater in injection form. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In patients treated with isavuconazonium for invasive aspergillosis in a controlled trial, there was no significant association between plasma AUC or plasma isavuconazole concentration and efficacy. The effect on QTc interval of multiple doses of isavuconazonium capsules was evaluated. Isavuconazonium was administered as 2 capsules (equivalent to 200 mg isavuconazole) three times daily on days 1 and 2 followed by either 2 capsules or 6 capsules (equivalent to 600 mg isavuconazole) once daily for 13 days in a randomized, placebo- and active-controlled (moxifloxacin 400 mg single-dose), four-treatment-arms, parallel study in 160 healthy subjects. Isavuconazole resulted in dose-related shortening of the QTc interval. For the 2-capsule dosing regimen, the least squares mean (LSM) difference from placebo was -13.1 msec at 2 hours postdose [90% CI: -17.1, -9.1 msec]. Increasing the dose to 6 capsules resulted in an LSM difference from the placebo of -24.6 msec at 2 hours postdose [90% CI: -28.7, -20.4]. Isavuconazonium was not evaluated in combination with other drugs that reduce the QTc interval, so the additive effects are not known. The mechanism of resistance to isavuconazole, like other azole antifungals, is likely due to multiple mechanisms that include substitutions in the target gene CYP51. Changes in sterol profile and elevated efflux pump activity were observed; however, the clinical relevance of these findings is unclear. In vitro and animal studies suggest cross-resistance between isavuconazole and other azoles. The relevance of cross-resistance to clinical outcomes has not been fully characterized; however, patients failing prior azole therapy may require alternative antifungal therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Isavuconazonium sulfate is the prodrug of isavuconazole, an azole antifungal. Isavuconazole inhibits the synthesis of ergosterol, a key component of the fungal cell membrane, by inhibiting cytochrome P-450-dependent enzyme lanosterol 14-alpha-demethylase (Erg11p). This enzyme is responsible for the conversion of lanosterol to ergosterol. An accumulation of methylated sterol precursors and a depletion of ergosterol within the fungal cell membrane weaken the membrane structure and function. Mammalian cell demethylation is less sensitive to isavuconazole inhibition. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In healthy subjects, the pharmacokinetics of isavuconazole following oral administration of isavuconazonium capsules at isavuconazole equivalent doses up to 600 mg per day (6 capsules) are dose-proportional. Following oral administration of isavuconazonium capsules at an isavuconazole equivalent dose of 200 mg in 66 fasted healthy male subjects, a single dose administration of two 186 mg isavuconazonium capsules and five 74.5 mg isavuconazonium capsules exhibited a mean (SD) C max and AUC of 3.3 (0.6) mg/L and 112.2 (30.3) mg·hr/L, respectively, and 3.3 (0.6) mg/L and 118.0 (33.1) mg·hr/L, respectively. After oral administration of isavuconazonium in healthy volunteers, the active moiety, isavuconazole, generally reaches maximum plasma concentrations (C max ) 2 hours to 3 hours after single and multiple dosing. The absolute bioavailability of isavuconazole following oral administration of isavuconazonium is 98%. No significant concentrations of the prodrug or inactive cleavage product were seen in plasma after oral administration. Following intravenous administration of isavuconazonium, maximal plasma concentrations of the prodrug and inactive cleavage product were detectable during infusion and declined rapidly following the end of administration. The prodrug was below the level of detection by 1.25 hours after the start of a one-hour infusion. The total exposure of the prodrug based on AUC was less than 1% that of isavuconazole. The inactive cleavage product was quantifiable in some subjects up to 8 hours after the start of infusion. The total exposure of inactive cleavage product based on AUC was approximately 1.3% that of isavuconazole. Isavuconazonium given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule. Coadministration of isavuconazonium equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C max by 9% and increased AUC by 9%. isavuconazonium can be taken with or without food. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Isavuconazole is extensively distributed with a mean steady-state volume of distribution (Vss) of approximately 450 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In in vitro studies, isavuconazonium sulfate is rapidly hydrolyzed in blood to isavuconazole by esterases, predominantly by butylcholinesterase. Isavuconazole is a substrate of cytochrome P450 enzymes 3A4 and 3A5. Following single doses of [cyano 14C] isavuconazonium and [pyridinylmethyl 14C] isavuconazonium in humans, in addition to the active moiety (isavuconazole) and the inactive cleavage product, several minor metabolites were identified. Except for the active moiety isavuconazole, no individual metabolite was observed with an AUC greater than 10% of drug-related material. In vivo studies indicate that CYP3A4, CYP3A5, and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration of radio-labeled isavuconazonium sulfate to healthy volunteers, a mean of 46.1% of the total radioactive dose was recovered in the feces and 45.5% was recovered in the urine. Renal excretion of isavuconazole itself was less than 1% of the dose administered. The inactive cleavage product is primarily eliminated by metabolism and subsequent renal excretion of the metabolites. Renal elimination of intact cleavage product was less than 1% of the total dose administered. Following intravenous administration of radio-labeled cleavage product, 95% of the total radioactive dose was excreted in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In healthy subjects, the clearance of isavuconazole was estimated to be from 2.4 to 4.1 L/h. Chinese subjects were found to have on average a 40% lower clearance compared to Western subjects (1.6 L/hr for Chinese subjects as compared to 2.6 L/hr for Western subjects). •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on findings from animal studies, isavuconazonium may cause fetal harm when administered to a pregnant woman. There are no available human data on the use of isavuconazonium in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, perinatal mortality was increased in the offspring of pregnant rats dosed orally with isavuconazonium sulfate at approximately 0.5 times the clinical exposure during pregnancy through the weaning period. In animal studies when isavuconazonium chloride was administered by oral gavage to pregnant rats and rabbits during organogenesis at exposures corresponding to less than the human maintenance dose increases in the incidences of multiple skeletal abnormalities, including rudimentary cervical ribs and fused zygomatic arches were observed. During clinical studies, total daily isavuconazonium doses higher than the recommended dose regimen were associated with an increased rate of adverse reactions. At supratherapeutic doses (three times the recommended maintenance dose) evaluated in a thorough QT study, there were proportionally more treatment-emergent adverse reactions than in the therapeutic dose group (maintenance dose) for the following: headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. Adverse reactions leading to discontinuation of the study drug occurred in 7 of 39 (17.9%) subjects in the supratherapeutic dose group. Isavuconazole is not removed by hemodialysis. There is no specific antidote for isavuconazole. Treatment should be supportive with appropriate monitoring. In a 2-year rat carcinogenicity study and a 2-year mouse carcinogenicity study, dose-related increases in hepatocellular adenomas and/or carcinomas were observed in male and female B6C3F1/Crl mice and male, but not female Han Wistar rats at doses as low as 0.1 times the exposure seen in humans administered the maintenance dose. Hepatic hemangiomas were increased in female mice at 300 mg/kg, at an exposure similar to the maintenance dose. Hepatoblastoma was increased in male mice at 100 mg/kg, about 0.4 times the systemic exposures based on AUC comparisons. Thyroid follicular cell adenomas were observed in male and female rats at doses as low as 60 mg/kg in male rats (about 0.2 times the human clinical maintenance dose). The relevance of rat thyroid tumors to human carcinogenic risk remains unclear. A significant increase in the incidence of skin fibromas was seen in male rats at 300 mg/kg, exposures 0.8 times the human exposure at the human clinical maintenance dose. Uterine adenocarcinomas were observed in female rats at 200 mg/kg, at systemic exposures similar to the human exposure at the human clinical maintenance dose. No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats. Oral administration of isavuconazonium sulfate did not affect fertility in male or female rats treated at doses up to 90 mg/kg/day (approximately 0.3 times the systemic exposure at the human clinical maintenance dose). •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cresemba •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Isavuconazonium is a triazole antifungal used for the treatment of invasive aspergillosis and mucormycosis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Isavuconazonium interact? Information: •Drug A: Abatacept •Drug B: Isavuconazonium •Severity: MODERATE •Description: The metabolism of Isavuconazonium can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Isavuconazonium is indicated for the treatment of invasive aspergillosis and mucormycosis in adults and pediatric patients 1 year of age and older in capsule form and adults and pediatric patients 6 years of age and older who weigh 16 kilograms (kg) and greater in injection form. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In patients treated with isavuconazonium for invasive aspergillosis in a controlled trial, there was no significant association between plasma AUC or plasma isavuconazole concentration and efficacy. The effect on QTc interval of multiple doses of isavuconazonium capsules was evaluated. Isavuconazonium was administered as 2 capsules (equivalent to 200 mg isavuconazole) three times daily on days 1 and 2 followed by either 2 capsules or 6 capsules (equivalent to 600 mg isavuconazole) once daily for 13 days in a randomized, placebo- and active-controlled (moxifloxacin 400 mg single-dose), four-treatment-arms, parallel study in 160 healthy subjects. Isavuconazole resulted in dose-related shortening of the QTc interval. For the 2-capsule dosing regimen, the least squares mean (LSM) difference from placebo was -13.1 msec at 2 hours postdose [90% CI: -17.1, -9.1 msec]. Increasing the dose to 6 capsules resulted in an LSM difference from the placebo of -24.6 msec at 2 hours postdose [90% CI: -28.7, -20.4]. Isavuconazonium was not evaluated in combination with other drugs that reduce the QTc interval, so the additive effects are not known. The mechanism of resistance to isavuconazole, like other azole antifungals, is likely due to multiple mechanisms that include substitutions in the target gene CYP51. Changes in sterol profile and elevated efflux pump activity were observed; however, the clinical relevance of these findings is unclear. In vitro and animal studies suggest cross-resistance between isavuconazole and other azoles. The relevance of cross-resistance to clinical outcomes has not been fully characterized; however, patients failing prior azole therapy may require alternative antifungal therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Isavuconazonium sulfate is the prodrug of isavuconazole, an azole antifungal. Isavuconazole inhibits the synthesis of ergosterol, a key component of the fungal cell membrane, by inhibiting cytochrome P-450-dependent enzyme lanosterol 14-alpha-demethylase (Erg11p). This enzyme is responsible for the conversion of lanosterol to ergosterol. An accumulation of methylated sterol precursors and a depletion of ergosterol within the fungal cell membrane weaken the membrane structure and function. Mammalian cell demethylation is less sensitive to isavuconazole inhibition. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In healthy subjects, the pharmacokinetics of isavuconazole following oral administration of isavuconazonium capsules at isavuconazole equivalent doses up to 600 mg per day (6 capsules) are dose-proportional. Following oral administration of isavuconazonium capsules at an isavuconazole equivalent dose of 200 mg in 66 fasted healthy male subjects, a single dose administration of two 186 mg isavuconazonium capsules and five 74.5 mg isavuconazonium capsules exhibited a mean (SD) C max and AUC of 3.3 (0.6) mg/L and 112.2 (30.3) mg·hr/L, respectively, and 3.3 (0.6) mg/L and 118.0 (33.1) mg·hr/L, respectively. After oral administration of isavuconazonium in healthy volunteers, the active moiety, isavuconazole, generally reaches maximum plasma concentrations (C max ) 2 hours to 3 hours after single and multiple dosing. The absolute bioavailability of isavuconazole following oral administration of isavuconazonium is 98%. No significant concentrations of the prodrug or inactive cleavage product were seen in plasma after oral administration. Following intravenous administration of isavuconazonium, maximal plasma concentrations of the prodrug and inactive cleavage product were detectable during infusion and declined rapidly following the end of administration. The prodrug was below the level of detection by 1.25 hours after the start of a one-hour infusion. The total exposure of the prodrug based on AUC was less than 1% that of isavuconazole. The inactive cleavage product was quantifiable in some subjects up to 8 hours after the start of infusion. The total exposure of inactive cleavage product based on AUC was approximately 1.3% that of isavuconazole. Isavuconazonium given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule. Coadministration of isavuconazonium equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C max by 9% and increased AUC by 9%. isavuconazonium can be taken with or without food. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Isavuconazole is extensively distributed with a mean steady-state volume of distribution (Vss) of approximately 450 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In in vitro studies, isavuconazonium sulfate is rapidly hydrolyzed in blood to isavuconazole by esterases, predominantly by butylcholinesterase. Isavuconazole is a substrate of cytochrome P450 enzymes 3A4 and 3A5. Following single doses of [cyano 14C] isavuconazonium and [pyridinylmethyl 14C] isavuconazonium in humans, in addition to the active moiety (isavuconazole) and the inactive cleavage product, several minor metabolites were identified. Except for the active moiety isavuconazole, no individual metabolite was observed with an AUC greater than 10% of drug-related material. In vivo studies indicate that CYP3A4, CYP3A5, and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration of radio-labeled isavuconazonium sulfate to healthy volunteers, a mean of 46.1% of the total radioactive dose was recovered in the feces and 45.5% was recovered in the urine. Renal excretion of isavuconazole itself was less than 1% of the dose administered. The inactive cleavage product is primarily eliminated by metabolism and subsequent renal excretion of the metabolites. Renal elimination of intact cleavage product was less than 1% of the total dose administered. Following intravenous administration of radio-labeled cleavage product, 95% of the total radioactive dose was excreted in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): In healthy subjects, the clearance of isavuconazole was estimated to be from 2.4 to 4.1 L/h. Chinese subjects were found to have on average a 40% lower clearance compared to Western subjects (1.6 L/hr for Chinese subjects as compared to 2.6 L/hr for Western subjects). •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Based on findings from animal studies, isavuconazonium may cause fetal harm when administered to a pregnant woman. There are no available human data on the use of isavuconazonium in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, perinatal mortality was increased in the offspring of pregnant rats dosed orally with isavuconazonium sulfate at approximately 0.5 times the clinical exposure during pregnancy through the weaning period. In animal studies when isavuconazonium chloride was administered by oral gavage to pregnant rats and rabbits during organogenesis at exposures corresponding to less than the human maintenance dose increases in the incidences of multiple skeletal abnormalities, including rudimentary cervical ribs and fused zygomatic arches were observed. During clinical studies, total daily isavuconazonium doses higher than the recommended dose regimen were associated with an increased rate of adverse reactions. At supratherapeutic doses (three times the recommended maintenance dose) evaluated in a thorough QT study, there were proportionally more treatment-emergent adverse reactions than in the therapeutic dose group (maintenance dose) for the following: headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. Adverse reactions leading to discontinuation of the study drug occurred in 7 of 39 (17.9%) subjects in the supratherapeutic dose group. Isavuconazole is not removed by hemodialysis. There is no specific antidote for isavuconazole. Treatment should be supportive with appropriate monitoring. In a 2-year rat carcinogenicity study and a 2-year mouse carcinogenicity study, dose-related increases in hepatocellular adenomas and/or carcinomas were observed in male and female B6C3F1/Crl mice and male, but not female Han Wistar rats at doses as low as 0.1 times the exposure seen in humans administered the maintenance dose. Hepatic hemangiomas were increased in female mice at 300 mg/kg, at an exposure similar to the maintenance dose. Hepatoblastoma was increased in male mice at 100 mg/kg, about 0.4 times the systemic exposures based on AUC comparisons. Thyroid follicular cell adenomas were observed in male and female rats at doses as low as 60 mg/kg in male rats (about 0.2 times the human clinical maintenance dose). The relevance of rat thyroid tumors to human carcinogenic risk remains unclear. A significant increase in the incidence of skin fibromas was seen in male rats at 300 mg/kg, exposures 0.8 times the human exposure at the human clinical maintenance dose. Uterine adenocarcinomas were observed in female rats at 200 mg/kg, at systemic exposures similar to the human exposure at the human clinical maintenance dose. No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats. Oral administration of isavuconazonium sulfate did not affect fertility in male or female rats treated at doses up to 90 mg/kg/day (approximately 0.3 times the systemic exposure at the human clinical maintenance dose). •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cresemba •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Isavuconazonium is a triazole antifungal used for the treatment of invasive aspergillosis and mucormycosis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Isoflurane interact?

•Drug A: Abatacept •Drug B: Isoflurane •Severity: MODERATE •Description: The metabolism of Isoflurane can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For induction and maintenance of general anesthesia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Isoflurane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Isoflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Isoflurane also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane. Also appears to bind the D subunit of ATP synthase and NADH dehydogenase. Isoflurane also binds to the GABA receptor, the large conductance Ca activated potassium channel, the glutamate receptor and the glycine receptor. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Minimal •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LC50=15300 ppm/3 hrs (inhalation by rat) •Brand Names (Drug A): Orencia •Brand Names (Drug B): Forane, Terrell •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Isoflurane Isoflurano Isofluranum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Isoflurane is an inhaled general anesthetic used in surgery.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Isoflurane interact? Information: •Drug A: Abatacept •Drug B: Isoflurane •Severity: MODERATE •Description: The metabolism of Isoflurane can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For induction and maintenance of general anesthesia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Isoflurane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Isoflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Isoflurane also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane. Also appears to bind the D subunit of ATP synthase and NADH dehydogenase. Isoflurane also binds to the GABA receptor, the large conductance Ca activated potassium channel, the glutamate receptor and the glycine receptor. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Minimal •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LC50=15300 ppm/3 hrs (inhalation by rat) •Brand Names (Drug A): Orencia •Brand Names (Drug B): Forane, Terrell •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Isoflurane Isoflurano Isofluranum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Isoflurane is an inhaled general anesthetic used in surgery. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Does Abatacept and Istradefylline interact?

•Drug A: Abatacept •Drug B: Istradefylline •Severity: MODERATE •Description: The metabolism of Istradefylline can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Istradefylline is indicated in adjunct to levodopa and carbidopa in the treatment of Parkinson's disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Istradefylline is a selective adenosine A 2A receptor inhibitor. It has a long duration of action as it is given once daily and has a half life of 64-69 hours. Patients taking this medication should be monitored for dyskinesia, hallucinations, and lack of impulse control. Consider dose reductions for these patients. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Istradefylline is a selective adenosine A 2A receptor inhibitor. These receptors are found in the basal ganglia, a region of the brain that suffers degeneration in Parkinson's disease, and is also significantly involved in motor control. A 2A receptors are also expressed on GABAergic medium spiny neurons within the indirect striato-pallidal pathway. The GABAergic action of this pathway is thereby reduced. Istradefylline has 56 times the affinity for A 2A receptors than A 1 receptors. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Istradefylline reaches a C max of 181.1ng/mL with a T max of 2.0h and an AUC of 11,100ng*h/mL. M1, the primary active metabolite, reaches a C max of 4.34ng/mL with a T max of 3.5h. The M8 metabolite reaches a C max of 12.6ng/mL with a T max of 3.0h and an AUC of 610ng*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of istradefylline is 448-557L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Istradefylline is approximately 98% protein bound in plasma, mostly to serum albumin and alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The primary metabolite found in urine is the active 4'-O-monodesmethyl istradefylline (M1). Istradefylline is metabolized mainly by CYP1A1, CYP3A4, and CYP3A5. CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP2D6 also partly contribute the the metabolism of istradefylline. Other identified metabolites are 1-β-hydroxylated-4’-O-demethyl istradefylline (M2), 3’,4’-O-didemethyl istradefylline (M3), M1 sulfate conjugate (M4), M1 glucuronide (M5), 1-β-hydroxylated istradefylline (M8) and hydrogenated M3 (M10). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): A 3mg/kg oral dose given to male rats was 17.6% elminated in the urine and 68.3% eliminated in the feces. In urine, 5.31% of the total dose was the M3 metabolite and 1.96% of the total dose was the M1 metabolite. In feces, 30.60% of the total dose was the M3 metabolite, 9.34% of the total dose was the M1 metabolite, 8.33% of the total dose was the M10 metabolite, and 1.62% of the total dose was unchanged istradefylline. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half life of istradefylline was 64-69 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent clearance of istradefylline is 4.1-6.0L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in mice is >300mg/kg. Patients experiencing an overdose may present with hallucinations, agitation, and dyskinesia. Treat patients by discontinuing istradefylline and administering supportive treatment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Nourianz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Istradefylline is a selective adenoside A2A receptor antagonist indicated in adjunct to levodopa and carbidopa for the treatment of Parkinson's Disease.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Istradefylline interact? Information: •Drug A: Abatacept •Drug B: Istradefylline •Severity: MODERATE •Description: The metabolism of Istradefylline can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Istradefylline is indicated in adjunct to levodopa and carbidopa in the treatment of Parkinson's disease. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Istradefylline is a selective adenosine A 2A receptor inhibitor. It has a long duration of action as it is given once daily and has a half life of 64-69 hours. Patients taking this medication should be monitored for dyskinesia, hallucinations, and lack of impulse control. Consider dose reductions for these patients. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Istradefylline is a selective adenosine A 2A receptor inhibitor. These receptors are found in the basal ganglia, a region of the brain that suffers degeneration in Parkinson's disease, and is also significantly involved in motor control. A 2A receptors are also expressed on GABAergic medium spiny neurons within the indirect striato-pallidal pathway. The GABAergic action of this pathway is thereby reduced. Istradefylline has 56 times the affinity for A 2A receptors than A 1 receptors. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Istradefylline reaches a C max of 181.1ng/mL with a T max of 2.0h and an AUC of 11,100ng*h/mL. M1, the primary active metabolite, reaches a C max of 4.34ng/mL with a T max of 3.5h. The M8 metabolite reaches a C max of 12.6ng/mL with a T max of 3.0h and an AUC of 610ng*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of istradefylline is 448-557L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Istradefylline is approximately 98% protein bound in plasma, mostly to serum albumin and alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The primary metabolite found in urine is the active 4'-O-monodesmethyl istradefylline (M1). Istradefylline is metabolized mainly by CYP1A1, CYP3A4, and CYP3A5. CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP2D6 also partly contribute the the metabolism of istradefylline. Other identified metabolites are 1-β-hydroxylated-4’-O-demethyl istradefylline (M2), 3’,4’-O-didemethyl istradefylline (M3), M1 sulfate conjugate (M4), M1 glucuronide (M5), 1-β-hydroxylated istradefylline (M8) and hydrogenated M3 (M10). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): A 3mg/kg oral dose given to male rats was 17.6% elminated in the urine and 68.3% eliminated in the feces. In urine, 5.31% of the total dose was the M3 metabolite and 1.96% of the total dose was the M1 metabolite. In feces, 30.60% of the total dose was the M3 metabolite, 9.34% of the total dose was the M1 metabolite, 8.33% of the total dose was the M10 metabolite, and 1.62% of the total dose was unchanged istradefylline. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half life of istradefylline was 64-69 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent clearance of istradefylline is 4.1-6.0L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in mice is >300mg/kg. Patients experiencing an overdose may present with hallucinations, agitation, and dyskinesia. Treat patients by discontinuing istradefylline and administering supportive treatment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Nourianz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Istradefylline is a selective adenoside A2A receptor antagonist indicated in adjunct to levodopa and carbidopa for the treatment of Parkinson's Disease. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Ivacaftor interact?

•Drug A: Abatacept •Drug B: Ivacaftor •Severity: MODERATE •Description: The metabolism of Ivacaftor can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): When used as monotherapy as the product Kalydeco, ivacaftor is indicated for the treatment of cystic fibrosis (CF) in patients aged one month and older who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data. When used in combination with the drug lumacaftor as the product Orkambi, ivacaftor is indicated for the management of CF in patients aged one year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. When used in combination with tezacaftor in the product Symdeko, it is used to manage CF in patients 12 years and older who have at least one mutation in the CFTR gene or patients aged 12 or older who are shown to be homozygous for the F508del mutation. When used in combination with tezacaftor and elexacaftor in the product Trikafta, it is indicated for the treatment of cystic fibrosis in patients 12 years of age and older who have at least one F508del mutation in the CFTR gene. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): The use of Ivacaftor has been shown to both improve CF symptoms and modulate underlying disease pathology. This is achieved by potentiating the channel opening probability (or gating) of CFTR protein in patients with impaired gating mechanisms. This is in contrast to Lumacaftor, another CF medication, that functions by preventing misfolding of the CFTR protein and thereby results in increased processing and trafficking of mature protein to the cell surface. Results from clinical trials indicated that treatment with ivacaftor results in improved lung function, reduced chance of experiencing a pulmonary exacerbation, reduced sweat chloride, increased weight gain, and improvements in CF symptoms and quality of life. When combined with tezacaftor, significant improvements in lung function have been observed in clinical studies. Ivacaftor was not found to increase the QTc interval in a clinically significant manner. Although ivacaftor given alone has not shown any significant improvements in patients with the delta-F508 mutation, it has shown significant improvements (>10% increase in FEV1 from baseline) in lung function for the following mutations: E56K, P67L, R74W, D110E, D110H, R117C, R117H, G178R, E193K, L206W, R347H, R352Q, A455E, S549N, S549R, G551D, G551S, D579G, S945L, S977F, F1052V, K1060T, A1067T, G1069R, R1070Q, R1070W, F1074L, D1152H, G1244E, S1251N, S1255P, D1270N, and G1349. This list was expanded by the FDA in May 2017 from 10 to 33 to accommodate more rare mutations. It is important to note that this drug may cause an increase in liver transaminases (ALT, AST). Ensure to assess liver transaminases before the initiation of treatment, every 3 months during the first year of administration, followed by every year thereafter. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): A wide variety of CFTR mutations correlate to the Cystic Fibrosis phenotype and are associated with differing levels of disease severity. The most common mutation, affecting approximately 70% of patients with CF worldwide, is known as F508del-CFTR or delta-F508 (ΔF508), in which a deletion in the amino acid phenylalanine at position 508 results in impaired production of the CFTR protein, thereby causing a significant reduction in the amount of ion transporter present on cell membranes. Ivacaftor as monotherapy has failed to show a benefit for patients with delta-F508 mutations, most likely due to an insufficient amount of protein available at the cell membrane for interaction and potentiation by the drug. The next most common mutation, G551D, affecting 4-5% of CF patients worldwide is characterized as a missense mutation, whereby there is sufficient amount of protein at the cell surface, but opening and closing mechanisms of the channel are altered. Ivacaftor is indicated for the management of CF in patients with this second type of mutation, as it binds to and potentiates the channel opening ability of CFTR proteins on the cell membrane. Ivacaftor exerts its effect by acting as a potentiator of the CFTR protein, an ion channel involved in the transport of chloride and sodium ions across cell membranes of the lungs, pancreas, and other organs. Alterations in the CFTR gene result in altered production, misfolding, or function of the protein and consequently abnormal fluid and ion transport across cell membranes. Ivacaftor improves CF symptoms and underlying disease pathology by potentiating the channel open probability (or gating) of CFTR protein in patients with impaired CFTR gating mechanisms. The overall level of ivacaftor-mediated CFTR chloride transport is dependent on the amount of CFTR protein at the cell surface and how responsive a particular mutant CFTR protein is to ivacaftor potentiation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Ivacaftor is well absorbed in the gastrointestinal tract. Following administration of ivacaftor with fat-containing foods, peak plasma concentrations were reached at 4 hours (Tmax) with a maximum concentration (Cmax) of 768 ng/mL and AUC of 10600 ng * hr/mL. It is recommended that ivacaftor is taken with fat-containing foods as they increase absorption by approximately 2.5- to 4-fold. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (±SD) for apparent volume of distribution was 353 (122) L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): About 99% of ivacaftor is bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ivacaftor is extensively metabolized in humans. In vitro and clinical studies indicate that ivacaftor is primarily metabolized by CYP3A. From this metabolism, the major formed metabolites are M1 and M6. M1 is considered pharmacologically active even though it just presents approximately one-sixth the effect of the parent compound ivacaftor. On the other hand, M6 is not considered pharmacologically active as it represents less than one-fiftieth of the effect of the parent compound. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After oral administration, ivacaftor is mainly eliminated in the feces after metabolic conversion and this elimination represents 87.8% of the dose. From the total eliminated dose, the metabolites M1 and M6 account for the majority of the eliminated dose, being 22% for M1 and 43% for M6. Ivacaftor shows negligible urinary excretion as the unchanged drug. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In a clinical study, the apparent terminal half-life was approximately 12 hours following a single dose of ivacaftor. One source mentions the half-life ranges from 12 to 14 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50 information is not readily available. There have been no reports of overdose with ivacaftor, but when given with tezacaftor, the highest clinical dose lead to diarrhea and dizziness. Provide supportive measures in cases of a suspected overdose. No antidote is available at this time. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Kalydeco, Orkambi, Symdeko, Trikafta (100 Mg / 50 Mg / 75 Mg; 150 Mg) •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ivacaftor Ivacaftorum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator used alone or in combination products to treat cystic fibrosis in patients who have specific genetic mutations that are responsive to the medication.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Ivacaftor interact? Information: •Drug A: Abatacept •Drug B: Ivacaftor •Severity: MODERATE •Description: The metabolism of Ivacaftor can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): When used as monotherapy as the product Kalydeco, ivacaftor is indicated for the treatment of cystic fibrosis (CF) in patients aged one month and older who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data. When used in combination with the drug lumacaftor as the product Orkambi, ivacaftor is indicated for the management of CF in patients aged one year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. When used in combination with tezacaftor in the product Symdeko, it is used to manage CF in patients 12 years and older who have at least one mutation in the CFTR gene or patients aged 12 or older who are shown to be homozygous for the F508del mutation. When used in combination with tezacaftor and elexacaftor in the product Trikafta, it is indicated for the treatment of cystic fibrosis in patients 12 years of age and older who have at least one F508del mutation in the CFTR gene. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): The use of Ivacaftor has been shown to both improve CF symptoms and modulate underlying disease pathology. This is achieved by potentiating the channel opening probability (or gating) of CFTR protein in patients with impaired gating mechanisms. This is in contrast to Lumacaftor, another CF medication, that functions by preventing misfolding of the CFTR protein and thereby results in increased processing and trafficking of mature protein to the cell surface. Results from clinical trials indicated that treatment with ivacaftor results in improved lung function, reduced chance of experiencing a pulmonary exacerbation, reduced sweat chloride, increased weight gain, and improvements in CF symptoms and quality of life. When combined with tezacaftor, significant improvements in lung function have been observed in clinical studies. Ivacaftor was not found to increase the QTc interval in a clinically significant manner. Although ivacaftor given alone has not shown any significant improvements in patients with the delta-F508 mutation, it has shown significant improvements (>10% increase in FEV1 from baseline) in lung function for the following mutations: E56K, P67L, R74W, D110E, D110H, R117C, R117H, G178R, E193K, L206W, R347H, R352Q, A455E, S549N, S549R, G551D, G551S, D579G, S945L, S977F, F1052V, K1060T, A1067T, G1069R, R1070Q, R1070W, F1074L, D1152H, G1244E, S1251N, S1255P, D1270N, and G1349. This list was expanded by the FDA in May 2017 from 10 to 33 to accommodate more rare mutations. It is important to note that this drug may cause an increase in liver transaminases (ALT, AST). Ensure to assess liver transaminases before the initiation of treatment, every 3 months during the first year of administration, followed by every year thereafter. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): A wide variety of CFTR mutations correlate to the Cystic Fibrosis phenotype and are associated with differing levels of disease severity. The most common mutation, affecting approximately 70% of patients with CF worldwide, is known as F508del-CFTR or delta-F508 (ΔF508), in which a deletion in the amino acid phenylalanine at position 508 results in impaired production of the CFTR protein, thereby causing a significant reduction in the amount of ion transporter present on cell membranes. Ivacaftor as monotherapy has failed to show a benefit for patients with delta-F508 mutations, most likely due to an insufficient amount of protein available at the cell membrane for interaction and potentiation by the drug. The next most common mutation, G551D, affecting 4-5% of CF patients worldwide is characterized as a missense mutation, whereby there is sufficient amount of protein at the cell surface, but opening and closing mechanisms of the channel are altered. Ivacaftor is indicated for the management of CF in patients with this second type of mutation, as it binds to and potentiates the channel opening ability of CFTR proteins on the cell membrane. Ivacaftor exerts its effect by acting as a potentiator of the CFTR protein, an ion channel involved in the transport of chloride and sodium ions across cell membranes of the lungs, pancreas, and other organs. Alterations in the CFTR gene result in altered production, misfolding, or function of the protein and consequently abnormal fluid and ion transport across cell membranes. Ivacaftor improves CF symptoms and underlying disease pathology by potentiating the channel open probability (or gating) of CFTR protein in patients with impaired CFTR gating mechanisms. The overall level of ivacaftor-mediated CFTR chloride transport is dependent on the amount of CFTR protein at the cell surface and how responsive a particular mutant CFTR protein is to ivacaftor potentiation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Ivacaftor is well absorbed in the gastrointestinal tract. Following administration of ivacaftor with fat-containing foods, peak plasma concentrations were reached at 4 hours (Tmax) with a maximum concentration (Cmax) of 768 ng/mL and AUC of 10600 ng * hr/mL. It is recommended that ivacaftor is taken with fat-containing foods as they increase absorption by approximately 2.5- to 4-fold. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (±SD) for apparent volume of distribution was 353 (122) L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): About 99% of ivacaftor is bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ivacaftor is extensively metabolized in humans. In vitro and clinical studies indicate that ivacaftor is primarily metabolized by CYP3A. From this metabolism, the major formed metabolites are M1 and M6. M1 is considered pharmacologically active even though it just presents approximately one-sixth the effect of the parent compound ivacaftor. On the other hand, M6 is not considered pharmacologically active as it represents less than one-fiftieth of the effect of the parent compound. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After oral administration, ivacaftor is mainly eliminated in the feces after metabolic conversion and this elimination represents 87.8% of the dose. From the total eliminated dose, the metabolites M1 and M6 account for the majority of the eliminated dose, being 22% for M1 and 43% for M6. Ivacaftor shows negligible urinary excretion as the unchanged drug. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In a clinical study, the apparent terminal half-life was approximately 12 hours following a single dose of ivacaftor. One source mentions the half-life ranges from 12 to 14 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50 information is not readily available. There have been no reports of overdose with ivacaftor, but when given with tezacaftor, the highest clinical dose lead to diarrhea and dizziness. Provide supportive measures in cases of a suspected overdose. No antidote is available at this time. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Kalydeco, Orkambi, Symdeko, Trikafta (100 Mg / 50 Mg / 75 Mg; 150 Mg) •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ivacaftor Ivacaftorum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator used alone or in combination products to treat cystic fibrosis in patients who have specific genetic mutations that are responsive to the medication. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Ivosidenib interact?

•Drug A: Abatacept •Drug B: Ivosidenib •Severity: MAJOR •Description: The metabolism of Ivosidenib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor approved for use in the US and Europe. It is indicated for the treatment of patients with a susceptible IDH1 mutation with: Newly Diagnosed Acute Myeloid Leukemia (AML) in combination azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults who have comorbidities that preclude the use of intensive induction chemotherapy. this indication is reserved for adults 75 years or older in the US. Relapsed or refractory AML in adults in the US. Locally Advanced or Metastatic Cholangiocarcinoma in adults who have been previously treated. Relapsed or Refractory Myelodysplastic Syndromes in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ivosidenib is an antineoplastic agent that is effective in cancers with a susceptible IDH1 mutation, which indicates increased levels of oncometabolite D-2-hydroxyglutarate (D-2HG) in cancer cells. Ivosidenib decreases D-2HG levels in a dose-dependent manner by inhibiting the IDH1 enzyme. Ivosidenib inhibits both the mutant and wild-type IDH1 but does not inhibit IDH2. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme in the cytoplasm and peroxisomes that plays a role in many cellular processes, including mitochondrial oxidative phosphorylation, glutamine metabolism, lipogenesis, glucose sensing, and regulation of cellular redox status. IDH1 converts isocitrate to α-ketoglutarate (α-KG), a normal metabolite in the carboxylic acid cycle. Multiple cancers are associated with missense mutations in IDH1, leading to the substitution of the amino acid arginine 132 in the enzyme active site, acquired gain-of-function activity, and increased enzyme activity. IDH1 mutation results in the accumulation of D-2-hydroxyglutarate (D-2HG), an oncometabolite that is structurally similar to α-KG. D-2HG inhibits α-KG-dependent dioxygenases, including histone and DNA demethylases, which play a role in histone and DNA demethylation along with other cellular processes. Inhibition of these enzymes leads to histone and DNA hypermethylation and a block in cell differentiation, including hematopoietic differentiation. With histone hypermethylation, methylation-sensitive insulators cannot regulate the activation of oncogenes. Excess D-2HG ultimately interferes with cellular metabolism and alters epigenetic regulation towards oncogenesis. Ivosidenib inhibits the mutant IDH1 at much lower concentrations than the wild-type enzyme. It targets gene mutations at position R132, with R132H and R132C being the most common mutations. In mouse xenograft models of IDH1-mutated AML, ivosidenib caused a decrease in D-2HG levels in a dose-dependent manner and induced myeloid differentiation in vitro and in vivo. Ivosidenib works to inhibit histone demethylases and restore normal methylation conditions to promote cell differentiation and oncogene regulation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following oral administration, ivosidenib is rapidly absorbed. The C max following a single oral dose is 4503 ng/mL in patients with relapsed or refractory AML, 4820 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4060 ng/mL in patients with cholangiocarcinoma. The steady-state was reached within 14 days. The steady-state C max is 6551 ng/mL in patients with relapsed or refractory AML, 6145 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4799 ng/mL in patients with cholangiocarcinoma. The T max ranges from two to three hours. A high-fat meal increases ivosidenib exposure. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution at steady state is 403 L in patients with relapsed or refractory AML, 504 L in patients with newly diagnosed AML who were also treated with azacitidine, and 706 L in patients with cholangiocarcinoma. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, ivosidenib is 92-96% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ivosidenib is predominantly metabolized by CYP3A4 via oxidation. The exact chemical structures of the metabolites formed from CYP3A4-mediated oxidation have not been fully characterized. Ivosidenib can also undergo N-dealkylation and hydrolysis as minor metabolic pathways. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration of ivosidenib, about 77% of the dose was eliminated in feces, where 67% was in the form of unchanged parent drug. About 17% of the dose was excreted in urine, where 10% was in the form of unchanged ivosidenib. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal half-life at steady state is 58 hours in patients with relapsed or refractory AML, 98 hours in patients with newly diagnosed AML who were also treated with azacitidine, and 129 hours in patients with cholangiocarcinoma. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent clearance at steady state is 5.6 L/h in patients with relapsed or refractory AML, 4.6 L/h in patients with newly diagnosed AML who were also treated with azacitidine, and 6.1 L/h in patients with cholangiocarcinoma. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There is limited information regarding the LD 50 or overdose of ivosidenib. Ivosidenib is associated with a risk of differentiation syndrome, Guillain-Barre syndrome, and embryo-fetal toxicity. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tibsovo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ivosidenib is an isocitrate dehydrogenase-1 inhibitor used to treat acute myeloid leukemia and cholangiocarcinoma in adults with a susceptible IDH1 mutation.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Ivosidenib interact? Information: •Drug A: Abatacept •Drug B: Ivosidenib •Severity: MAJOR •Description: The metabolism of Ivosidenib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor approved for use in the US and Europe. It is indicated for the treatment of patients with a susceptible IDH1 mutation with: Newly Diagnosed Acute Myeloid Leukemia (AML) in combination azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults who have comorbidities that preclude the use of intensive induction chemotherapy. this indication is reserved for adults 75 years or older in the US. Relapsed or refractory AML in adults in the US. Locally Advanced or Metastatic Cholangiocarcinoma in adults who have been previously treated. Relapsed or Refractory Myelodysplastic Syndromes in adults. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ivosidenib is an antineoplastic agent that is effective in cancers with a susceptible IDH1 mutation, which indicates increased levels of oncometabolite D-2-hydroxyglutarate (D-2HG) in cancer cells. Ivosidenib decreases D-2HG levels in a dose-dependent manner by inhibiting the IDH1 enzyme. Ivosidenib inhibits both the mutant and wild-type IDH1 but does not inhibit IDH2. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme in the cytoplasm and peroxisomes that plays a role in many cellular processes, including mitochondrial oxidative phosphorylation, glutamine metabolism, lipogenesis, glucose sensing, and regulation of cellular redox status. IDH1 converts isocitrate to α-ketoglutarate (α-KG), a normal metabolite in the carboxylic acid cycle. Multiple cancers are associated with missense mutations in IDH1, leading to the substitution of the amino acid arginine 132 in the enzyme active site, acquired gain-of-function activity, and increased enzyme activity. IDH1 mutation results in the accumulation of D-2-hydroxyglutarate (D-2HG), an oncometabolite that is structurally similar to α-KG. D-2HG inhibits α-KG-dependent dioxygenases, including histone and DNA demethylases, which play a role in histone and DNA demethylation along with other cellular processes. Inhibition of these enzymes leads to histone and DNA hypermethylation and a block in cell differentiation, including hematopoietic differentiation. With histone hypermethylation, methylation-sensitive insulators cannot regulate the activation of oncogenes. Excess D-2HG ultimately interferes with cellular metabolism and alters epigenetic regulation towards oncogenesis. Ivosidenib inhibits the mutant IDH1 at much lower concentrations than the wild-type enzyme. It targets gene mutations at position R132, with R132H and R132C being the most common mutations. In mouse xenograft models of IDH1-mutated AML, ivosidenib caused a decrease in D-2HG levels in a dose-dependent manner and induced myeloid differentiation in vitro and in vivo. Ivosidenib works to inhibit histone demethylases and restore normal methylation conditions to promote cell differentiation and oncogene regulation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following oral administration, ivosidenib is rapidly absorbed. The C max following a single oral dose is 4503 ng/mL in patients with relapsed or refractory AML, 4820 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4060 ng/mL in patients with cholangiocarcinoma. The steady-state was reached within 14 days. The steady-state C max is 6551 ng/mL in patients with relapsed or refractory AML, 6145 ng/mL in patients with newly diagnosed AML who were also treated with azacitidine, and 4799 ng/mL in patients with cholangiocarcinoma. The T max ranges from two to three hours. A high-fat meal increases ivosidenib exposure. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution at steady state is 403 L in patients with relapsed or refractory AML, 504 L in patients with newly diagnosed AML who were also treated with azacitidine, and 706 L in patients with cholangiocarcinoma. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, ivosidenib is 92-96% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ivosidenib is predominantly metabolized by CYP3A4 via oxidation. The exact chemical structures of the metabolites formed from CYP3A4-mediated oxidation have not been fully characterized. Ivosidenib can also undergo N-dealkylation and hydrolysis as minor metabolic pathways. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration of ivosidenib, about 77% of the dose was eliminated in feces, where 67% was in the form of unchanged parent drug. About 17% of the dose was excreted in urine, where 10% was in the form of unchanged ivosidenib. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal half-life at steady state is 58 hours in patients with relapsed or refractory AML, 98 hours in patients with newly diagnosed AML who were also treated with azacitidine, and 129 hours in patients with cholangiocarcinoma. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The apparent clearance at steady state is 5.6 L/h in patients with relapsed or refractory AML, 4.6 L/h in patients with newly diagnosed AML who were also treated with azacitidine, and 6.1 L/h in patients with cholangiocarcinoma. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There is limited information regarding the LD 50 or overdose of ivosidenib. Ivosidenib is associated with a risk of differentiation syndrome, Guillain-Barre syndrome, and embryo-fetal toxicity. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tibsovo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ivosidenib is an isocitrate dehydrogenase-1 inhibitor used to treat acute myeloid leukemia and cholangiocarcinoma in adults with a susceptible IDH1 mutation. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Ixabepilone interact?

•Drug A: Abatacept •Drug B: Ixabepilone •Severity: MAJOR •Description: The metabolism of Ixabepilone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Investigated for use/treatment in breast cancer, head and neck cancer, melanoma, lung cancer, lymphoma (non-hodgkin's), prostate cancer, renal cell carcinoma, and cancer/tumors (unspecified). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Binding of Ixabepilone to beta-tubulins (e.g. beta-III tubulin) stabilizes microtubules. Microtubules are essential to cell division, and epothilones therefore stop cells from properly dividing. Like taxol, Ixabepilone binds to the αβ-tubulin heterodimer subunit. Once bound, the rate of αβ-tubulin dissociation decreases, thus stabilizing the microtubules. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 67-77% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Mostly fecal and some renal. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 52 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ixempra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ixabepilone is a microtubule inhibitor administered in combination with capecitabine or alone in the treatment of metastatic or locally advanced breast cancer that has shown inadequate response to taxanes and anthracyclines.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Ixabepilone interact? Information: •Drug A: Abatacept •Drug B: Ixabepilone •Severity: MAJOR •Description: The metabolism of Ixabepilone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Investigated for use/treatment in breast cancer, head and neck cancer, melanoma, lung cancer, lymphoma (non-hodgkin's), prostate cancer, renal cell carcinoma, and cancer/tumors (unspecified). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Binding of Ixabepilone to beta-tubulins (e.g. beta-III tubulin) stabilizes microtubules. Microtubules are essential to cell division, and epothilones therefore stop cells from properly dividing. Like taxol, Ixabepilone binds to the αβ-tubulin heterodimer subunit. Once bound, the rate of αβ-tubulin dissociation decreases, thus stabilizing the microtubules. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 67-77% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Mostly fecal and some renal. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 52 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ixempra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ixabepilone is a microtubule inhibitor administered in combination with capecitabine or alone in the treatment of metastatic or locally advanced breast cancer that has shown inadequate response to taxanes and anthracyclines. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Ixazomib interact?

•Drug A: Abatacept •Drug B: Ixazomib •Severity: MAJOR •Description: The metabolism of Ixazomib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ixazomib is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In vitro studies have shown ixazomib to induce apoptosis in multiple myeloma cells sensitive or resistant to other conventional therapies. In mouse xenograft models, ixazomib induced tumor growth inhibition. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ixazomib is an N-capped dipeptidyl leucine boronic acid which reversibly inhibits the CT-L proteolytic (β5) site of the 20S proteasome. At higher concentrations, ixazomib also seems to inhibit the proteolytic β1 and β2 subunits and to induce accumulation of ubiquitinated proteins. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): After oral administration, the time to reach maximum concentration in plasma was 1 hour. The mean absolute oral bioavailability is 58%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The steady-state volume of distribution is 543 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism of ixazomib is expected to be by CYP and non-CYP pathways, with no predominant CYP isozyme contribution. At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (<1%). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 62% in urine and 22% in feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Terminal half-life is 9.5 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in <1% of patients. Ixazomib can cause fetal harm when administered to pregnant women, and therefore it should also be advised to women of reproductive age to avoid becoming pregnant on ixazomib. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ninlaro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ixazomib is a monoclonal antibody used with other medications to treat multiple myeloma in patients who have received one other therapy already.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Ixazomib interact? Information: •Drug A: Abatacept •Drug B: Ixazomib •Severity: MAJOR •Description: The metabolism of Ixazomib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ixazomib is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In vitro studies have shown ixazomib to induce apoptosis in multiple myeloma cells sensitive or resistant to other conventional therapies. In mouse xenograft models, ixazomib induced tumor growth inhibition. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ixazomib is an N-capped dipeptidyl leucine boronic acid which reversibly inhibits the CT-L proteolytic (β5) site of the 20S proteasome. At higher concentrations, ixazomib also seems to inhibit the proteolytic β1 and β2 subunits and to induce accumulation of ubiquitinated proteins. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): After oral administration, the time to reach maximum concentration in plasma was 1 hour. The mean absolute oral bioavailability is 58%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The steady-state volume of distribution is 543 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism of ixazomib is expected to be by CYP and non-CYP pathways, with no predominant CYP isozyme contribution. At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (<1%). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 62% in urine and 22% in feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Terminal half-life is 9.5 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in <1% of patients. Ixazomib can cause fetal harm when administered to pregnant women, and therefore it should also be advised to women of reproductive age to avoid becoming pregnant on ixazomib. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ninlaro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ixazomib is a monoclonal antibody used with other medications to treat multiple myeloma in patients who have received one other therapy already. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Ixekizumab interact?

•Drug A: Abatacept •Drug B: Ixekizumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Ixekizumab. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ixekizumab is indicated for the treatment of patients aged six years or older with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. It is also indicated in adult patients with active psoriatic arthritis, ankylosing spondylitis, or non-radiographic axial spondyloarthritis with objective signs of inflammation. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ixekizumab is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) against interleukin-17A (IL-17A) and prevents it from interacting with the IL-17A receptor. As IL-17A is a pro-inflammatory cytokine involved in inflammation and immune responses, blocking its effect is beneficial for use in inflammatory conditions. In particular, IL-17A has been found to be implicated in a variety of autoimmune diseases including Rheumatoid Arthritis and plaque psoriasis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following a single subcutaneous dose of 160 mg in subjects with plaque psoriasis, ixekizumab reached peak mean (±SD) serum concentrations (Cmax) of 16.2 ±6.6 mcg/mL by approximately 4 days post dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean (geometric CV%) volume of distribution at steady-state was 7.11 L (29%) in subjects with plaque psoriasis. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolic pathway of ixekizumab has not been characterized. As a humanized IgG4 monoclonal antibody ixekizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 13 days •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 0.39 L/day •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The most common adverse reactions associated with Ixekizumab treatment are injection site reactions, upper respiratory tract infections, nausea, and tinea infections. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Taltz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ixekizumab is a monoclonal antibody used to treat moderate to severe plaque psoriasis.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Ixekizumab interact? Information: •Drug A: Abatacept •Drug B: Ixekizumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Ixekizumab. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ixekizumab is indicated for the treatment of patients aged six years or older with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. It is also indicated in adult patients with active psoriatic arthritis, ankylosing spondylitis, or non-radiographic axial spondyloarthritis with objective signs of inflammation. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ixekizumab is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) against interleukin-17A (IL-17A) and prevents it from interacting with the IL-17A receptor. As IL-17A is a pro-inflammatory cytokine involved in inflammation and immune responses, blocking its effect is beneficial for use in inflammatory conditions. In particular, IL-17A has been found to be implicated in a variety of autoimmune diseases including Rheumatoid Arthritis and plaque psoriasis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following a single subcutaneous dose of 160 mg in subjects with plaque psoriasis, ixekizumab reached peak mean (±SD) serum concentrations (Cmax) of 16.2 ±6.6 mcg/mL by approximately 4 days post dose. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The mean (geometric CV%) volume of distribution at steady-state was 7.11 L (29%) in subjects with plaque psoriasis. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolic pathway of ixekizumab has not been characterized. As a humanized IgG4 monoclonal antibody ixekizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 13 days •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 0.39 L/day •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The most common adverse reactions associated with Ixekizumab treatment are injection site reactions, upper respiratory tract infections, nausea, and tinea infections. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Taltz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ixekizumab is a monoclonal antibody used to treat moderate to severe plaque psoriasis. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Janssen COVID-19 Vaccine interact?

•Drug A: Abatacept •Drug B: Janssen COVID-19 Vaccine •Severity: MODERATE •Description: The therapeutic efficacy of Janssen COVID-19 Vaccine can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found

Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Question: Does Abatacept and Janssen COVID-19 Vaccine interact? Information: •Drug A: Abatacept •Drug B: Janssen COVID-19 Vaccine •Severity: MODERATE •Description: The therapeutic efficacy of Janssen COVID-19 Vaccine can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found Output: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Does Abatacept and Japanese encephalitis virus strain sa 14-14-2 antigen (formaldehyde inactivated) interact?

•Drug A: Abatacept •Drug B: Japanese encephalitis virus strain sa 14-14-2 antigen (formaldehyde inactivated) •Severity: MODERATE •Description: The therapeutic efficacy of Japanese encephalitis virus strain sa 14-14-2 antigen (formaldehyde inactivated) can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found

Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Question: Does Abatacept and Japanese encephalitis virus strain sa 14-14-2 antigen (formaldehyde inactivated) interact? Information: •Drug A: Abatacept •Drug B: Japanese encephalitis virus strain sa 14-14-2 antigen (formaldehyde inactivated) •Severity: MODERATE •Description: The therapeutic efficacy of Japanese encephalitis virus strain sa 14-14-2 antigen (formaldehyde inactivated) can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found Output: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Does Abatacept and Ketamine interact?

•Drug A: Abatacept •Drug B: Ketamine •Severity: MODERATE •Description: The metabolism of Ketamine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ketamine is indicated as an anesthetic agent for recommended diagnostic and surgical procedures. If skeletal muscle relaxation is needed, it should be combined with a muscle relaxant. If the surgical procedure involves visceral pain, it should be supplemented with an agent that obtunds visceral pain. Ketamine can be used for induction of anesthesia prior other general anesthetic agents and as a supplement of low potency agents. Reports have indicated a potential use of ketamine as a therapeutic tool for the management of depression when administered in lower doses. These reports have increased the interest for ketamine in this area and several clinical trials are launched for this indication. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ketamine is a rapid-acting general anesthetic producing an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory depression. The anesthetic state produced by Ketamine has been termed as "dissociative anesthesia" in that it appears to selectively interrupt association pathways of the brain before producing somesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centers and pathways (reticular-activating and limbic systems). Ketamine enhances descending inhibiting serotoninergic pathways and can exert antidepressive effects. These effects are seen in concentrations ten times lower than the needed concentration for anesthetic proposes. The effect of ketamine can be described as analgesic by the prevention of central sensitization in dorsal horn neurons as well as by the inhibition on the synthesis of nitric oxide. Ketamine can present cardiovascular changes and bronchodilatation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ketamine interacts with N-methyl-D-aspartate (NMDA) receptors, opioid receptors, monoaminergic receptors, muscarinic receptors and voltage sensitive Ca ion channels. Unlike other general anaesthetic agents, ketamine does not interact with GABA receptors. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Ketamine absorption is very rapid and the bioavailability is around 93%. After the first pass metabolism, only 17% of the administered dose is absorbed. It distributes very rapidly and presents a distribution half-life of 1.95 min. The Cmax levels at peak reach 0.75 mcg/ml in plasma and 0.2 mcg/ml in cerebrospinal fluid. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of the central compartment and at steady-state are 371.3 ml/kg and 4060.3 ml/kg, respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of ketamine accounts for 53.5% of the administered dose. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ketamine presents a mainly hepatic metabolism and its major metabolite is norketamine. The biotransformation of ketamine corresponds to N-dealkylation, hydroxylation of the cyclohexone ring, conjugation to glucuronic acid and dehydration of the hydroxylated metabolites for the formation of cyclohexene derivatives. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Pharmacokinetic studies have resulted in the recovery of 85-95% of the administered dose in urine mainly in the form of metabolites. Some other routes of elimination of ketamine are bile and feces. When administered intravenously the resultant recovery is distributed by 91% of the administered dose in urine and 3% in feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The reported half-life in preclinical studies for ketamine is 186 min. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance rate of ketamine is high and of around 95 L/h/70kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Preclinical studies related to the blocking of NMDA receptors have shown an increase in apoptosis in the developing brain which results in cognitive deficits when used for longer than 3 hours. Toxicity studies regarding carcinogenesis have not been performed. Regarding mutagenesis and fertility, ketamine showed to be clastogenic and to not have effects on fertility. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ketalar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): DL-ketamine Ketamina Kétamine Ketamine Ketaminum NMDA •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ketamine is a rapid-acting general anesthetic and NMDA receptor antagonist used for induction of anesthesia diagnostic and surgical procedures typically in combination with a muscle relaxant.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Ketamine interact? Information: •Drug A: Abatacept •Drug B: Ketamine •Severity: MODERATE •Description: The metabolism of Ketamine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ketamine is indicated as an anesthetic agent for recommended diagnostic and surgical procedures. If skeletal muscle relaxation is needed, it should be combined with a muscle relaxant. If the surgical procedure involves visceral pain, it should be supplemented with an agent that obtunds visceral pain. Ketamine can be used for induction of anesthesia prior other general anesthetic agents and as a supplement of low potency agents. Reports have indicated a potential use of ketamine as a therapeutic tool for the management of depression when administered in lower doses. These reports have increased the interest for ketamine in this area and several clinical trials are launched for this indication. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ketamine is a rapid-acting general anesthetic producing an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory depression. The anesthetic state produced by Ketamine has been termed as "dissociative anesthesia" in that it appears to selectively interrupt association pathways of the brain before producing somesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centers and pathways (reticular-activating and limbic systems). Ketamine enhances descending inhibiting serotoninergic pathways and can exert antidepressive effects. These effects are seen in concentrations ten times lower than the needed concentration for anesthetic proposes. The effect of ketamine can be described as analgesic by the prevention of central sensitization in dorsal horn neurons as well as by the inhibition on the synthesis of nitric oxide. Ketamine can present cardiovascular changes and bronchodilatation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ketamine interacts with N-methyl-D-aspartate (NMDA) receptors, opioid receptors, monoaminergic receptors, muscarinic receptors and voltage sensitive Ca ion channels. Unlike other general anaesthetic agents, ketamine does not interact with GABA receptors. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Ketamine absorption is very rapid and the bioavailability is around 93%. After the first pass metabolism, only 17% of the administered dose is absorbed. It distributes very rapidly and presents a distribution half-life of 1.95 min. The Cmax levels at peak reach 0.75 mcg/ml in plasma and 0.2 mcg/ml in cerebrospinal fluid. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of the central compartment and at steady-state are 371.3 ml/kg and 4060.3 ml/kg, respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of ketamine accounts for 53.5% of the administered dose. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ketamine presents a mainly hepatic metabolism and its major metabolite is norketamine. The biotransformation of ketamine corresponds to N-dealkylation, hydroxylation of the cyclohexone ring, conjugation to glucuronic acid and dehydration of the hydroxylated metabolites for the formation of cyclohexene derivatives. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Pharmacokinetic studies have resulted in the recovery of 85-95% of the administered dose in urine mainly in the form of metabolites. Some other routes of elimination of ketamine are bile and feces. When administered intravenously the resultant recovery is distributed by 91% of the administered dose in urine and 3% in feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The reported half-life in preclinical studies for ketamine is 186 min. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The clearance rate of ketamine is high and of around 95 L/h/70kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Preclinical studies related to the blocking of NMDA receptors have shown an increase in apoptosis in the developing brain which results in cognitive deficits when used for longer than 3 hours. Toxicity studies regarding carcinogenesis have not been performed. Regarding mutagenesis and fertility, ketamine showed to be clastogenic and to not have effects on fertility. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ketalar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): DL-ketamine Ketamina Kétamine Ketamine Ketaminum NMDA •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ketamine is a rapid-acting general anesthetic and NMDA receptor antagonist used for induction of anesthesia diagnostic and surgical procedures typically in combination with a muscle relaxant. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Does Abatacept and Ketorolac interact?

•Drug A: Abatacept •Drug B: Ketorolac •Severity: MODERATE •Description: The metabolism of Ketorolac can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ketorolac is a Non-steroidal anti-inflammatory drug (NSAID) and has antipyretic, analgesic and anti-inflammatory properties. It is indicated for short term management of acute pain that requires the calibre of pain management offered by opioids. Clinicians may choose to initiate ketorolac to manage post-operative pain, spinal and soft tissue pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, menstrual disorders and headaches among other ailments. Regardless of the etiology of pain, patients should use the lowest possible dose, and avoid using ketorolac for an extended period of time (ideally ≤ 5 days). A benefit of choosing ketorolac over other analgesics with similar potency is that that there does not appear to be a risk of dependence or tolerance with ketorolac use. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ketorolac is a non-selective NSAID and acts by inhibiting both COX-1 and COX-2 enzymes which are normally responsible for converting arachidonic acid to prostaglandins. The COX-1 enzyme is constitutively active and can be found in platelets, gastric mucosa, and vascular endothelium. On the other hand, the COX-2 enzyme is inducible and mediates inflammation, pain and fever. As a result, inhibition of the COX-1 enzyme is linked to an increased risk of bleeding and risk of gastric ulceration, while the desired anti-inflammatory and analgesic properties are linked to inhibition of the COX-2 enzyme. Therefore, despite it's effectiveness in pain management, ketorolac should not be used long-term since this increases the risk of serious adverse effects such as gastrointestinal bleeding, peptic ulcers, and perforations. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ketorolac inhibits key pathways in prostaglandin synthesis which is crucial to it's mechanism of action. Although ketorolac is non-selective and inhibits both COX-1 and COX-2 enzymes, it's clinical efficacy is derived from it's COX-2 inhibition. The COX-2 enzyme is inducible and is responsible for converting arachidonic acid to prostaglandins that mediate inflammation and pain. By blocking this pathway, ketorolac achieves analgesia and reduces inflammation. Ketorolac is administered as a racemic mixture; however, the "S" enantiomer is largely responsible for it's pharmacological activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Ketorolac is rapidly, and completely absorbed after oral administration with a bioavailability of 80% after oral administration. Cmax is attained 20-60 minutes after administration, and after intramuscular administration, the area under the plasma concentration-time curve (AUC) is proportional to the dose administered. After intramuscular administration, ketorolac demonstrates a time to maximal plasma concentration (tmax) of approximately 45-50 minutes, and a tmax of 30-40 minutes after oral administration. The rate of absorption may be reduced by food; however, the extent of absorption remains unaffected. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of ketorolac in healthy human subjects is 0.25 L/kg or less. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): >99% of Ketorolac is plasma protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ketorolac is heavily metabolized via hydroxylation or conjugation in the liver; however, it appears that the key metabolic pathway is glucuronic acid conjugation. Enzymes involved in phase I metabolism include CYP2C8 and CYP2C9, while phase II metabolism is carried out by UDP-glucuronosyltransferase (UGT) 2B7. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Ketorolac is primarily renally eliminated and approximately 92% of the dose can be recovered in the urine with 60% of this proportion recovered unchanged, and 40% recovered as metabolites. In addition 6% of a single dose is eliminated in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Ketorolac tromethamine is administered as a racemic mixture, therefore the half-life of each enantiomer must be considered. The half life of the S-enantiomer is ~2.5 hours, while the half life of the R-enantiomer is ~5 hours. Based on this data, the S enantiomer is cleared about twice as fast as the R enantiomer. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The plasma clearance of ketorolac is 0.021 to 0.037 L/h/kg. Further, studies have illustrated that clearance of oral, IM and IV doses of ketorolac are comparable which suggests linear kinetics. It should also be noted that clearance in children is about double the clearance found in adults. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The rate of adverse effects increases with higher doses of ketorolac. The most frequently observed adverse effects in patients occurring with an incidence of greater than 10% include: abdominal pain, dyspepsia, nausea, and headaches. Most adverse effects associated with short term use are mild in nature, related to the gastrointestinal tract and nervous system, and occur in roughly 39% of patients. Common symptoms of ketorolac overdose include nausea, vomiting, epigastric pain, gastrointestinal bleeding, lethargy and drowsiness. More rare symptoms of overdose include acute renal failure, hypertension, respiratory depression, and coma. Ketorolac is classified as Pregnancy Category C since there is a lack of evidence demonstrating safety in pregnant women. NSAIDs including ketorolac increase the risk of premature closure of the fetal ductus arteriosus in the 3rd trimester; therefore, beginning at 30 weeks gestation, pregnant women should avoid ketorolac. Ketorolac has been shown to be excreted in breast milk, and although available data has not demonstrated any adverse effects in nursing infants, practitioners should proceed with caution when suggesting ketorolac for nursing mothers. The benefits should outweigh the risks and the mother should be counselled to monitor the infant closely and to contact the infant's healthcare provider should any adverse effects arise. Women who are trying to conceive are not advised to take ketorolac since it's effect on prostaglandin synthesis may impair fertility. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Acular, Acuvail, Omidria, Readysharp Anesthetics Plus Ketorolac, Sprix, Toradol, Toronova Suik •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ketorolac is an NSAID used to treat moderate to severe pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, menstrual disorders, and headaches.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Ketorolac interact? Information: •Drug A: Abatacept •Drug B: Ketorolac •Severity: MODERATE •Description: The metabolism of Ketorolac can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Ketorolac is a Non-steroidal anti-inflammatory drug (NSAID) and has antipyretic, analgesic and anti-inflammatory properties. It is indicated for short term management of acute pain that requires the calibre of pain management offered by opioids. Clinicians may choose to initiate ketorolac to manage post-operative pain, spinal and soft tissue pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, menstrual disorders and headaches among other ailments. Regardless of the etiology of pain, patients should use the lowest possible dose, and avoid using ketorolac for an extended period of time (ideally ≤ 5 days). A benefit of choosing ketorolac over other analgesics with similar potency is that that there does not appear to be a risk of dependence or tolerance with ketorolac use. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Ketorolac is a non-selective NSAID and acts by inhibiting both COX-1 and COX-2 enzymes which are normally responsible for converting arachidonic acid to prostaglandins. The COX-1 enzyme is constitutively active and can be found in platelets, gastric mucosa, and vascular endothelium. On the other hand, the COX-2 enzyme is inducible and mediates inflammation, pain and fever. As a result, inhibition of the COX-1 enzyme is linked to an increased risk of bleeding and risk of gastric ulceration, while the desired anti-inflammatory and analgesic properties are linked to inhibition of the COX-2 enzyme. Therefore, despite it's effectiveness in pain management, ketorolac should not be used long-term since this increases the risk of serious adverse effects such as gastrointestinal bleeding, peptic ulcers, and perforations. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Ketorolac inhibits key pathways in prostaglandin synthesis which is crucial to it's mechanism of action. Although ketorolac is non-selective and inhibits both COX-1 and COX-2 enzymes, it's clinical efficacy is derived from it's COX-2 inhibition. The COX-2 enzyme is inducible and is responsible for converting arachidonic acid to prostaglandins that mediate inflammation and pain. By blocking this pathway, ketorolac achieves analgesia and reduces inflammation. Ketorolac is administered as a racemic mixture; however, the "S" enantiomer is largely responsible for it's pharmacological activity. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Ketorolac is rapidly, and completely absorbed after oral administration with a bioavailability of 80% after oral administration. Cmax is attained 20-60 minutes after administration, and after intramuscular administration, the area under the plasma concentration-time curve (AUC) is proportional to the dose administered. After intramuscular administration, ketorolac demonstrates a time to maximal plasma concentration (tmax) of approximately 45-50 minutes, and a tmax of 30-40 minutes after oral administration. The rate of absorption may be reduced by food; however, the extent of absorption remains unaffected. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of ketorolac in healthy human subjects is 0.25 L/kg or less. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): >99% of Ketorolac is plasma protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ketorolac is heavily metabolized via hydroxylation or conjugation in the liver; however, it appears that the key metabolic pathway is glucuronic acid conjugation. Enzymes involved in phase I metabolism include CYP2C8 and CYP2C9, while phase II metabolism is carried out by UDP-glucuronosyltransferase (UGT) 2B7. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Ketorolac is primarily renally eliminated and approximately 92% of the dose can be recovered in the urine with 60% of this proportion recovered unchanged, and 40% recovered as metabolites. In addition 6% of a single dose is eliminated in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Ketorolac tromethamine is administered as a racemic mixture, therefore the half-life of each enantiomer must be considered. The half life of the S-enantiomer is ~2.5 hours, while the half life of the R-enantiomer is ~5 hours. Based on this data, the S enantiomer is cleared about twice as fast as the R enantiomer. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The plasma clearance of ketorolac is 0.021 to 0.037 L/h/kg. Further, studies have illustrated that clearance of oral, IM and IV doses of ketorolac are comparable which suggests linear kinetics. It should also be noted that clearance in children is about double the clearance found in adults. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The rate of adverse effects increases with higher doses of ketorolac. The most frequently observed adverse effects in patients occurring with an incidence of greater than 10% include: abdominal pain, dyspepsia, nausea, and headaches. Most adverse effects associated with short term use are mild in nature, related to the gastrointestinal tract and nervous system, and occur in roughly 39% of patients. Common symptoms of ketorolac overdose include nausea, vomiting, epigastric pain, gastrointestinal bleeding, lethargy and drowsiness. More rare symptoms of overdose include acute renal failure, hypertension, respiratory depression, and coma. Ketorolac is classified as Pregnancy Category C since there is a lack of evidence demonstrating safety in pregnant women. NSAIDs including ketorolac increase the risk of premature closure of the fetal ductus arteriosus in the 3rd trimester; therefore, beginning at 30 weeks gestation, pregnant women should avoid ketorolac. Ketorolac has been shown to be excreted in breast milk, and although available data has not demonstrated any adverse effects in nursing infants, practitioners should proceed with caution when suggesting ketorolac for nursing mothers. The benefits should outweigh the risks and the mother should be counselled to monitor the infant closely and to contact the infant's healthcare provider should any adverse effects arise. Women who are trying to conceive are not advised to take ketorolac since it's effect on prostaglandin synthesis may impair fertility. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Acular, Acuvail, Omidria, Readysharp Anesthetics Plus Ketorolac, Sprix, Toradol, Toronova Suik •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Ketorolac is an NSAID used to treat moderate to severe pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, menstrual disorders, and headaches. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Labetalol interact?

•Drug A: Abatacept •Drug B: Labetalol •Severity: MODERATE •Description: The metabolism of Labetalol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Labetalol injections are indicated to control blood pressure in severe hypertension. Labetalol tablets are indicated alone or in combination with antihypertensives like thiazides and loop diuretics to manage hypertension. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Labetalol antagonizes various adrenergic receptors to decrease blood pressure. The duration of action is long as it is generally given twice daily, and the therapeutic window is wide as patients usually take 200-400mg twice daily. Patients susceptible to bronchospasms should not use labetalol unless they are unresponsive to or intolerant of other antihypertensives. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Labetalol non-selectively antagonizes beta-adrenergic receptors, and selectively antagonizes alpha-1-adrenergic receptors. Following oral administration, labetalol has 3 times the beta-blocking ability than alpha-blocking ability. This increases to 6.9 times following intravenous administration. Antagonism of alpha-1-adrenergic receptors leads to vasodilation and decreased vascular resistance. This leads to a decrease in blood pressure that is most pronounced while standing. Antagonism of beta-1-adrenergic receptors leads to a slight decrease in heart rate. Antagonism of beta-2-adrenergic receptors leads to some of the side effects of labetalol such as bronchospasms, however this may be slightly attenuated by alpha-1-adrenergic antagonism. Labetalol leads to sustained vasodilation over the long term without a significant decrease in cardiac output or stroke volume, and a minimal decrease in heart rate. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): 100mg and 200mg oral doses of labetalol have a T max of 20 minutes to 2 hours. Bioavailability may be as low as 11% or as high as 86% and may increase in older patients or when taken with food. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): In normotensive patients, the volume of distribution is 805L. In hypertensive patients, the volume of distribution is between 188-747L with an average of 392L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Labetalol is approximately 50% protein bound in serum. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of labetalol has not been fully described in the literature but studies in sheep show an N-dealkylation to 3-amino-1-phenyl butane. This metabolite may be further metabolized to benzylacetone and 3-amino-(4-hydroxyphenyl)butane. Labetalol in humans is mainly metabolized to glucuronide metabolites such as the O-phenyl-glucuronide and the N-glucuronide. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Radiolabelled doses of labetalol are 55-60% recovered in the urine and 12-27% recovered in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Labetalol has a half life of 1.7-6.1 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Labetalol has a plasma clearance of approximately 1500mL/min and a whole blood clearance of 1100mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in mice is 600mg/kg and in rats is >2g/kg. The intravenous LD 50 in mice and rats is 50-60mg/kg. Patients experiencing an overdose may present with excessive hypotension and bradycardia. Patients should be placed on their back with their legs raised to maintain perfusion of the brain. Oral overdoses may be treated with gastric lavage or emesis, bradycardia may be treated with atropine or epinephrine, cardiac failure may be treated with digitalis and a diuretic, hypotension may be treated with vasopressors, bronchospasms may be treated with epinephrine or a beta 2 agonist, and seizures may be treated with diazepam. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Trandate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Labetalol Labétalol Labetalolum Labetolol •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Labetalol is an alpha and beta adrenergic antagonist used to treat hypertension, angina, and sympathetic overactivity syndrome.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Labetalol interact? Information: •Drug A: Abatacept •Drug B: Labetalol •Severity: MODERATE •Description: The metabolism of Labetalol can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Labetalol injections are indicated to control blood pressure in severe hypertension. Labetalol tablets are indicated alone or in combination with antihypertensives like thiazides and loop diuretics to manage hypertension. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Labetalol antagonizes various adrenergic receptors to decrease blood pressure. The duration of action is long as it is generally given twice daily, and the therapeutic window is wide as patients usually take 200-400mg twice daily. Patients susceptible to bronchospasms should not use labetalol unless they are unresponsive to or intolerant of other antihypertensives. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Labetalol non-selectively antagonizes beta-adrenergic receptors, and selectively antagonizes alpha-1-adrenergic receptors. Following oral administration, labetalol has 3 times the beta-blocking ability than alpha-blocking ability. This increases to 6.9 times following intravenous administration. Antagonism of alpha-1-adrenergic receptors leads to vasodilation and decreased vascular resistance. This leads to a decrease in blood pressure that is most pronounced while standing. Antagonism of beta-1-adrenergic receptors leads to a slight decrease in heart rate. Antagonism of beta-2-adrenergic receptors leads to some of the side effects of labetalol such as bronchospasms, however this may be slightly attenuated by alpha-1-adrenergic antagonism. Labetalol leads to sustained vasodilation over the long term without a significant decrease in cardiac output or stroke volume, and a minimal decrease in heart rate. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): 100mg and 200mg oral doses of labetalol have a T max of 20 minutes to 2 hours. Bioavailability may be as low as 11% or as high as 86% and may increase in older patients or when taken with food. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): In normotensive patients, the volume of distribution is 805L. In hypertensive patients, the volume of distribution is between 188-747L with an average of 392L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Labetalol is approximately 50% protein bound in serum. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of labetalol has not been fully described in the literature but studies in sheep show an N-dealkylation to 3-amino-1-phenyl butane. This metabolite may be further metabolized to benzylacetone and 3-amino-(4-hydroxyphenyl)butane. Labetalol in humans is mainly metabolized to glucuronide metabolites such as the O-phenyl-glucuronide and the N-glucuronide. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Radiolabelled doses of labetalol are 55-60% recovered in the urine and 12-27% recovered in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Labetalol has a half life of 1.7-6.1 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Labetalol has a plasma clearance of approximately 1500mL/min and a whole blood clearance of 1100mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in mice is 600mg/kg and in rats is >2g/kg. The intravenous LD 50 in mice and rats is 50-60mg/kg. Patients experiencing an overdose may present with excessive hypotension and bradycardia. Patients should be placed on their back with their legs raised to maintain perfusion of the brain. Oral overdoses may be treated with gastric lavage or emesis, bradycardia may be treated with atropine or epinephrine, cardiac failure may be treated with digitalis and a diuretic, hypotension may be treated with vasopressors, bronchospasms may be treated with epinephrine or a beta 2 agonist, and seizures may be treated with diazepam. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Trandate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Labetalol Labétalol Labetalolum Labetolol •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Labetalol is an alpha and beta adrenergic antagonist used to treat hypertension, angina, and sympathetic overactivity syndrome. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Lacosamide interact?

•Drug A: Abatacept •Drug B: Lacosamide •Severity: MODERATE •Description: The metabolism of Lacosamide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): In the US and Europe, lacosamide is indicated for the treatment of partial-onset seizures in children and adults. In Canada, it is reserved for use in adults. It is also used as an adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients four years of age and older. The extended-release capsules of lacosamide are indicated for the treatment of partial-onset seizures in adults and in pediatric patients weighing at least 50 kg. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Lacosamide is an antiepileptic drug with high oral potency, stereoselectivity, and anticonvulsant effects. By blocking sensory neuronal voltage-gated sodium channels that mediate neuropathic pain responses, lacosamide was shown to possess analgesic activity. Lacosamide is a chiral functionalized amino acid. The S-stereoisomer does not exhibit antiepileptic activity. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Caused by neuronal hyperexcitability, seizures in epilepsy involve sustained firing of sodium-dependent action potentials. The slow inactivation process, intrinsic to voltage-gated sodium channel functioning, has been implicated in the paroxysmal depolarizing shifts associated with epileptic activity. The exact mechanism of action of lacosamide is not fully known; however, in vitro electrophysiological studies have shown that lacosamide selectively enhances the slow inactivation of voltage-gated sodium channels, shifting the slow inactivation curve to more hyperpolarized potentials and augmenting the maximal fraction of channels in the slow inactivated state. This results in the stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. Lacosamide does not affect the fast component of voltage-gated sodium currents, unlike traditional sodium channel blockers. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Lacosamide is completely absorbed after oral administration with negligible first-pass effect. It has a high absolute bioavailability of approximately 100%. Food does not affect the rate and extent of absorption. The T max ranges from one to four hours. Steady-state plasma concentrations are achieved after three days of twice-daily repeated administration. The pharmacokinetics of lacosamide are dose-proportional over the dose range between 100 and 800 mg, and time-invariant, with low inter- and intra-subject variability. The major O-desmethyl metabolite of lacosamide has a longer T max that ranges from 0.5 to 12 hours. After intravenous administration, C max is reached at the end of infusion. The 30- and 60-minute intravenous infusions are bioequivalent to the oral tablet. For the 15-minute intravenous infusion, bioequivalence was met for AUC 0-tz but not for C max. The point estimate of C max was 20% higher than C max for oral tablet and the 90% CI for C max exceeded the upper boundary of the bioequivalence range. In a trial comparing the oral tablet with an oral solution containing 10 mg/mL lacosamide, bioequivalence between both formulations was shown. A single loading dose of 200 mg approximates steady-state concentrations comparable to the 100 mg twice-daily oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Lacosamide is less than 15% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Lacosamide is metabolized by CYP3A4, CYP2C9, and CYP2C19 to form O-desmethyl lacosamide, which is a major, pharmacologically inactive metabolite in humans. There is no enantiomeric interconversion of lacosamide. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation. After oral and intravenous administration of 100 mg radiolabeled lacosamide, approximately 95% of the radioactivity was recovered in the urine and less than 0.5 % in the feces. The major compounds excreted were unchanged lacosamide (approximately 40% of the dose), its O-desmethyl metabolite (approximately 30%), and a structurally unknown polar fraction (~20%). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration. The major O-desmethyl metabolite of lacosamide has an elimination half-life ranging from 15 to 23 hours). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in rats is 253 mg/kg. Dizziness, nausea, and seizures (generalized tonic-clonic seizures, status epilepticus) were observed at doses greater than 800 mg, which is twice the maximum recommended daily dose. Cardiac conduction disorders, confusion, decreased level of consciousness, cardiogenic shock, cardiac arrest, and coma have also been observed. Fatal overdoses have occurred with lacosamide. As there is no specific antidote for overdose with lacosamide, standard decontamination procedures should be followed. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of patient. Standard hemodialysis procedures result in significant clearance of lacosamide (reduction of systemic exposure by 50% in four hours). Hemodialysis may be indicated based on the patient's clinical state or in patients with significant renal impairment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Motpoly, Vimpat •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lacosamide is an antiepileptic drug used to treat partial-onset seizures and primary generalized tonic-clonic seizures.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Lacosamide interact? Information: •Drug A: Abatacept •Drug B: Lacosamide •Severity: MODERATE •Description: The metabolism of Lacosamide can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): In the US and Europe, lacosamide is indicated for the treatment of partial-onset seizures in children and adults. In Canada, it is reserved for use in adults. It is also used as an adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients four years of age and older. The extended-release capsules of lacosamide are indicated for the treatment of partial-onset seizures in adults and in pediatric patients weighing at least 50 kg. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Lacosamide is an antiepileptic drug with high oral potency, stereoselectivity, and anticonvulsant effects. By blocking sensory neuronal voltage-gated sodium channels that mediate neuropathic pain responses, lacosamide was shown to possess analgesic activity. Lacosamide is a chiral functionalized amino acid. The S-stereoisomer does not exhibit antiepileptic activity. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Caused by neuronal hyperexcitability, seizures in epilepsy involve sustained firing of sodium-dependent action potentials. The slow inactivation process, intrinsic to voltage-gated sodium channel functioning, has been implicated in the paroxysmal depolarizing shifts associated with epileptic activity. The exact mechanism of action of lacosamide is not fully known; however, in vitro electrophysiological studies have shown that lacosamide selectively enhances the slow inactivation of voltage-gated sodium channels, shifting the slow inactivation curve to more hyperpolarized potentials and augmenting the maximal fraction of channels in the slow inactivated state. This results in the stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. Lacosamide does not affect the fast component of voltage-gated sodium currents, unlike traditional sodium channel blockers. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Lacosamide is completely absorbed after oral administration with negligible first-pass effect. It has a high absolute bioavailability of approximately 100%. Food does not affect the rate and extent of absorption. The T max ranges from one to four hours. Steady-state plasma concentrations are achieved after three days of twice-daily repeated administration. The pharmacokinetics of lacosamide are dose-proportional over the dose range between 100 and 800 mg, and time-invariant, with low inter- and intra-subject variability. The major O-desmethyl metabolite of lacosamide has a longer T max that ranges from 0.5 to 12 hours. After intravenous administration, C max is reached at the end of infusion. The 30- and 60-minute intravenous infusions are bioequivalent to the oral tablet. For the 15-minute intravenous infusion, bioequivalence was met for AUC 0-tz but not for C max. The point estimate of C max was 20% higher than C max for oral tablet and the 90% CI for C max exceeded the upper boundary of the bioequivalence range. In a trial comparing the oral tablet with an oral solution containing 10 mg/mL lacosamide, bioequivalence between both formulations was shown. A single loading dose of 200 mg approximates steady-state concentrations comparable to the 100 mg twice-daily oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Lacosamide is less than 15% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Lacosamide is metabolized by CYP3A4, CYP2C9, and CYP2C19 to form O-desmethyl lacosamide, which is a major, pharmacologically inactive metabolite in humans. There is no enantiomeric interconversion of lacosamide. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation. After oral and intravenous administration of 100 mg radiolabeled lacosamide, approximately 95% of the radioactivity was recovered in the urine and less than 0.5 % in the feces. The major compounds excreted were unchanged lacosamide (approximately 40% of the dose), its O-desmethyl metabolite (approximately 30%), and a structurally unknown polar fraction (~20%). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration. The major O-desmethyl metabolite of lacosamide has an elimination half-life ranging from 15 to 23 hours). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in rats is 253 mg/kg. Dizziness, nausea, and seizures (generalized tonic-clonic seizures, status epilepticus) were observed at doses greater than 800 mg, which is twice the maximum recommended daily dose. Cardiac conduction disorders, confusion, decreased level of consciousness, cardiogenic shock, cardiac arrest, and coma have also been observed. Fatal overdoses have occurred with lacosamide. As there is no specific antidote for overdose with lacosamide, standard decontamination procedures should be followed. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of patient. Standard hemodialysis procedures result in significant clearance of lacosamide (reduction of systemic exposure by 50% in four hours). Hemodialysis may be indicated based on the patient's clinical state or in patients with significant renal impairment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Motpoly, Vimpat •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lacosamide is an antiepileptic drug used to treat partial-onset seizures and primary generalized tonic-clonic seizures. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Lansoprazole interact?

•Drug A: Abatacept •Drug B: Lansoprazole •Severity: MODERATE •Description: The metabolism of Lansoprazole can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Lansoprazole is used to reduce gastric acid secretion and is approved for short term treatment of active gastric ulcers, active duodenal ulcers, erosive reflux oesophagitis, symptomatic gastroesophageal reflux disease, and non-steroidal anti-inflammatory drug (NSAID) induced gastric and duodenal ulcers. It may be used in the maintenance and healing of several gastric conditions including duodenal ulcers, NSAID related gastric ulcers, and erosive esophagitis. Lansoprazole prevents recurrence of gastric ulcers in patients who have a documented history of gastric ulcers who also use NSAIDs chronically. Predictably, it is also useful in the management of hypersecretory conditions including Zollinger-Ellison syndrome. Lansoprazole is effective at eradicating H. pylori when used in conjunction with amoxicillin and clarithromycin (triple therapy) or with amoxicillin alone (dual therapy). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Lansoprazole decreases gastric acid secretion by targeting H+,K+-ATPase, which is the enzyme that catalyzes the final step in the acid secretion pathway in parietal cells. Conveniently, lansoprazole administered any time of day is able to inhibit both daytime and nocturnal acid secretion. The result is that lansoprazole is effective at healing duodenal ulcers, reduces ulcer-related pain, and offers relief from symptoms of heartburn Lansoprazole also reduces pepsin secretion, making it a useful treatment option for hypersecretory conditions such as Zollinger-Ellison syndrome. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): As a PPI, lansoprazole is a prodrug and requires protonation via an acidic environment to become activated. Once protonated, lansoprazole is able to react with cysteine residues, specifically Cys813 and Cys321, on parietal H+,K+-ATPase resulting in stable disulfides. PPI's in general are able to provide prolonged inhibition of acid secretion due to their ability to bind covalently to their targets. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The oral bioavailability of lansoprazole is reported to be 80-90% and the peak plasma concentration(Cmax) is achieved about 1.7 hours after oral dosing. Food reduces the absorption of lansoprazole (both Cmax and AUC are reduced by 50-70%); therefore, patients should be instructed to take lansoprazole before meals. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of lansoprazole is 0.4 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 97% of lansoprazole is plasma protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Lansoprazole is predominantly metabolized in the liver by CYP3A4 and CYP2C19. The resulting major metabolites are 5-hydroxy lansoprazole and the sulfone derivative of lansoprazole. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): A reported 14-23% of a lansoprazole is eliminated in the urine with this percentage range including both conjugated and unconjugated hydroxylated metabolites. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): One source reports the half life of lansoprazole to be 0.9 - 1.6 hours, while another source cites 0.9 - 2.1 hours. The general consensus is that lansoprazole has a short half life and is approximately 2 hours or less. These numbers may be misleading since it suggests that lansoprazole has a short duration of action when in practice, lansoprazole can effectively inhibit acid secretion for ~24 hours due to it's mechanism of action. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The reported clearance of lansoprazole is 400-650 mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The most commonly reported adverse events occurring more frequently in lansoprazole treated patients compared to placebo include abdominal pain, constipation, diarrhea, and nausea. There is a case report of toxic epidermal necrolysis (TEN), which is a rare but very serious cutaneous reaction, caused by lansoprazole. The previously healthy patient presented with symptoms of TEN 15 days after starting lansoprazole to manage peptic disease. Although the use of PPI's is rarely associated with TEN, causation should be considered if a patient presents with TEN shortly after newly commencing a PPI. In a single case report, a patient ingested 600 mg of lansoprazole and did not experience any adverse effects or symptoms of overdose. Overall, lansoprazole is well tolerated with relatively few adverse effects. Lansoprazole is classified as Pregnancy Category B. Although there are animal studies that suggest lansoprazole does not cause harm to the fetus, there is still a paucity of human data. Hence, lansoprazole should only be administered to pregnant women if other options with more safety data have been exhausted. It is unknown if lansoprazole is excreted in human breast milk. It is worth mentioning that lansoprazole has been used safely in infants, and is therefore likely safe to use during breastfeeding. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Prevacid, Prevpac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lansoprazole is a proton pump inhibitor used to help gastrointestinal ulcers heal, to treat symptoms of gastroesophageal reflux disease (GERD), to eradicate Helicobacter pylori, and to treat hypersecretory conditions such as Zollinger-Ellison Syndrome.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Lansoprazole interact? Information: •Drug A: Abatacept •Drug B: Lansoprazole •Severity: MODERATE •Description: The metabolism of Lansoprazole can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Lansoprazole is used to reduce gastric acid secretion and is approved for short term treatment of active gastric ulcers, active duodenal ulcers, erosive reflux oesophagitis, symptomatic gastroesophageal reflux disease, and non-steroidal anti-inflammatory drug (NSAID) induced gastric and duodenal ulcers. It may be used in the maintenance and healing of several gastric conditions including duodenal ulcers, NSAID related gastric ulcers, and erosive esophagitis. Lansoprazole prevents recurrence of gastric ulcers in patients who have a documented history of gastric ulcers who also use NSAIDs chronically. Predictably, it is also useful in the management of hypersecretory conditions including Zollinger-Ellison syndrome. Lansoprazole is effective at eradicating H. pylori when used in conjunction with amoxicillin and clarithromycin (triple therapy) or with amoxicillin alone (dual therapy). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Lansoprazole decreases gastric acid secretion by targeting H+,K+-ATPase, which is the enzyme that catalyzes the final step in the acid secretion pathway in parietal cells. Conveniently, lansoprazole administered any time of day is able to inhibit both daytime and nocturnal acid secretion. The result is that lansoprazole is effective at healing duodenal ulcers, reduces ulcer-related pain, and offers relief from symptoms of heartburn Lansoprazole also reduces pepsin secretion, making it a useful treatment option for hypersecretory conditions such as Zollinger-Ellison syndrome. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): As a PPI, lansoprazole is a prodrug and requires protonation via an acidic environment to become activated. Once protonated, lansoprazole is able to react with cysteine residues, specifically Cys813 and Cys321, on parietal H+,K+-ATPase resulting in stable disulfides. PPI's in general are able to provide prolonged inhibition of acid secretion due to their ability to bind covalently to their targets. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The oral bioavailability of lansoprazole is reported to be 80-90% and the peak plasma concentration(Cmax) is achieved about 1.7 hours after oral dosing. Food reduces the absorption of lansoprazole (both Cmax and AUC are reduced by 50-70%); therefore, patients should be instructed to take lansoprazole before meals. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of lansoprazole is 0.4 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 97% of lansoprazole is plasma protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Lansoprazole is predominantly metabolized in the liver by CYP3A4 and CYP2C19. The resulting major metabolites are 5-hydroxy lansoprazole and the sulfone derivative of lansoprazole. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): A reported 14-23% of a lansoprazole is eliminated in the urine with this percentage range including both conjugated and unconjugated hydroxylated metabolites. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): One source reports the half life of lansoprazole to be 0.9 - 1.6 hours, while another source cites 0.9 - 2.1 hours. The general consensus is that lansoprazole has a short half life and is approximately 2 hours or less. These numbers may be misleading since it suggests that lansoprazole has a short duration of action when in practice, lansoprazole can effectively inhibit acid secretion for ~24 hours due to it's mechanism of action. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The reported clearance of lansoprazole is 400-650 mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The most commonly reported adverse events occurring more frequently in lansoprazole treated patients compared to placebo include abdominal pain, constipation, diarrhea, and nausea. There is a case report of toxic epidermal necrolysis (TEN), which is a rare but very serious cutaneous reaction, caused by lansoprazole. The previously healthy patient presented with symptoms of TEN 15 days after starting lansoprazole to manage peptic disease. Although the use of PPI's is rarely associated with TEN, causation should be considered if a patient presents with TEN shortly after newly commencing a PPI. In a single case report, a patient ingested 600 mg of lansoprazole and did not experience any adverse effects or symptoms of overdose. Overall, lansoprazole is well tolerated with relatively few adverse effects. Lansoprazole is classified as Pregnancy Category B. Although there are animal studies that suggest lansoprazole does not cause harm to the fetus, there is still a paucity of human data. Hence, lansoprazole should only be administered to pregnant women if other options with more safety data have been exhausted. It is unknown if lansoprazole is excreted in human breast milk. It is worth mentioning that lansoprazole has been used safely in infants, and is therefore likely safe to use during breastfeeding. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Prevacid, Prevpac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lansoprazole is a proton pump inhibitor used to help gastrointestinal ulcers heal, to treat symptoms of gastroesophageal reflux disease (GERD), to eradicate Helicobacter pylori, and to treat hypersecretory conditions such as Zollinger-Ellison Syndrome. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Lapatinib interact?

•Drug A: Abatacept •Drug B: Lapatinib •Severity: MODERATE •Description: The metabolism of Lapatinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress the human epidermal receptor type 2 (HER2) protein and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Lapatinib is a small molecule and a member of the 4-anilinoquinazoline class of kinase inhibitors. An anti-cancer drug, lapatinib was developed by GlaxoSmithKline (GSK) as a treatment for solid tumours such as breast and lung cancer. It was approved by the FDA on March 13, 2007, for use in patients with advanced metastatic breast cancer in conjunction with the chemotherapy drug capecitabine. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both epidermal growth factor receptor (HER1/EGFR/ERBB1) and human epidermal growth factor receptor type 2 (HER2/ERBB2)with a dissociation half-life of ≥300 minutes. Lapatinib inhibits ERBB-driven tumor cell growth in vitro and in various animal models. An additive effect was demonstrated in an in vitro study when lapatinib and 5-florouracil (the active metabolite of capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non-cross-resistance between these two agents. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption following oral administration of lapatinib is incomplete and variable. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Highly bound (>99%) to albumin and alpha-1 acid glycoprotein •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Single-dose terminal half life: 14.2 hours Effective multiple-dose half life: 24 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There has been a report of one patient who took 3,000 mg of lapatinib for 10 days. This patient had grade 3 diarrhea and vomiting on day 10. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tykerb, Tyverb •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lapatinib •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lapatinib is an antineoplastic agent and tyrosine kinase inhibitor used for the treatment of advanced or metastatic HER-positive breast cancer in patients who received prior chemotherapeutic treatments.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Lapatinib interact? Information: •Drug A: Abatacept •Drug B: Lapatinib •Severity: MODERATE •Description: The metabolism of Lapatinib can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress the human epidermal receptor type 2 (HER2) protein and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Lapatinib is a small molecule and a member of the 4-anilinoquinazoline class of kinase inhibitors. An anti-cancer drug, lapatinib was developed by GlaxoSmithKline (GSK) as a treatment for solid tumours such as breast and lung cancer. It was approved by the FDA on March 13, 2007, for use in patients with advanced metastatic breast cancer in conjunction with the chemotherapy drug capecitabine. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both epidermal growth factor receptor (HER1/EGFR/ERBB1) and human epidermal growth factor receptor type 2 (HER2/ERBB2)with a dissociation half-life of ≥300 minutes. Lapatinib inhibits ERBB-driven tumor cell growth in vitro and in various animal models. An additive effect was demonstrated in an in vitro study when lapatinib and 5-florouracil (the active metabolite of capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non-cross-resistance between these two agents. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption following oral administration of lapatinib is incomplete and variable. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Highly bound (>99%) to albumin and alpha-1 acid glycoprotein •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Single-dose terminal half life: 14.2 hours Effective multiple-dose half life: 24 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): There has been a report of one patient who took 3,000 mg of lapatinib for 10 days. This patient had grade 3 diarrhea and vomiting on day 10. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tykerb, Tyverb •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lapatinib •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lapatinib is an antineoplastic agent and tyrosine kinase inhibitor used for the treatment of advanced or metastatic HER-positive breast cancer in patients who received prior chemotherapeutic treatments. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Lefamulin interact?

•Drug A: Abatacept •Drug B: Lefamulin •Severity: MODERATE •Description: The metabolism of Lefamulin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Lefamulin is indicated to treat adults diagnosed with community-acquired bacterial pneumonia (CABP) that is caused by susceptible bacteria. Its use should be reserved for confirmed susceptible organisms or a high probability of infection with susceptible organisms. The list of susceptible bacteria includes Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible), Legionella pneumophila, Haemophilus influenza, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Lefamulin demonstrates strong antibacterial activity against several microbes that are found to be common in both acute bacterial skin and skin structure infections as well as community-acquired bacterial pneumonia. It shows antibacterial activity against gram-positive and atypical microbes (for example, Streptococcus pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, Haemophilus influenzae, and Chlamydophila pneumoniae). Lefamulin also exerts activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium. It does not treat Pseudomonas aeruginosa infections. During in vitro studies, drug has also has demonstrated activity against Neisseria gonorrhoeae and Mycoplasma genitalium. A note on QT prolongation and Clostridium difficile According to the FDA label, lefamulin may have cardiac QT interval prolonging effects and advises against the administration of this drug in patients with diagnosed QT prolongation or ventricular arrhythmias. The administration of lefamulin should also be avoided in patients being administered antiarrhythmic agents and other drugs that prolong the QT interval. As with other antibiotics, the risk of Clostridium difficile associated diarrhea is increased with lefamulin use. Any case of diarrhea should be evaluated for C. difficile. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Lefamulin inhibits prokaryotic ribosomal protein synthesis via its binding to the peptidyl transferase center (PTC) of the ribosomal bacterial 50S subunit. It inhibits protein translation through binding to both the A and P sites of the PTC via four hydrogen bonds, resulting in the interruption of peptide bond formation. Lefamulin's tricyclic mutilin core is the common moiety for binding of all members of its drug class, the pleuromutilins. Although the tricyclic motilin core doesn’t form any hydrogen bonds with the PTC nucleotides, it is stabilized or anchored by hydrophobic and Van der Waals interactions. Lefamulin exerts a selective inhibition of protein translation in eukaryotes, however, does not affect ribosomal translation of eukaryotes. Lefamulin demonstrates a unique induced-fit type of action that closes the binding pocket within a ribosome, conferring close contact of the drug to its target, therefore improving therapeutic efficacy. Because of its mechanism of action that differs from that of other antimicrobials, cross-resistance to other antibiotic classes is less likely. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In a pharmacokinetic study of healthy subjects, lefamulin was rapidly absorbed after oral administration. The median Tmax was measured at 1.00 h for the intravenous preparation and 1.76 h for the tablet preparation. At steady-state doses, the Cmax of oral lefamulin is 37.1 mcg/mL. The AUC at steady-state concentrations of this drug is 49.2 mcg·h/mL. The estimated bioavailability of the oral tablets is 25%. Clinical studies have found that the AUC of lefamulin is decreased by about 10-28% in the fed state. To optimize absorption, this drug should be administered a minimum of 1 hour before a meal or, at minimum, 2 hours after a meal with water. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The average volume of distribution of lefamulin is 86.1 L in patients with community-acquired bacterial pneumonia, but can range from 34.2 to 153 L. During clinical studies, lefamulin has been shown to significantly concentrate in the lung tissue, likely increasing its effectiveness in treating pneumonia. After lefamulin is administered, penetration into various tissues is observed, and is about 6 times greater in concentration in the fluid of the pulmonary epithelium, when compared with concentrations in the plasma. Animal studies demonstrate that lefamulin crosses the placenta. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The average plasma protein binding of lefamulin is between 94.8 to 97.1% in healthy adults. A systematic review identifies the plasma protein binding at 80-87%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): CYP3A4 is the main enzyme responsible for the metabolism of lefamulin. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Lefamulin is largely excreted by the gastrointestinal tract and about 14% excreted by the kidneys. In healthy adult volunteers during clinical trials, a radiolabeled dose of lefamulin was administered. The total radioactivity found to be excreted in the feces was 77.3% on average with 4.2% to 9.1% as unchanged drug when the drug was administered via the intravenous route. A total radioactivity of 88.5% was measured in the feces with 7.8-24.8% as unchanged drug after a dose administered via the oral route. In the urine, it was found to be 15.5% with 9.6-14.1% excretd as unchanged drug after an intravenous dose and 5.3% after an oral dose. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The average elimination half-life of lefamulin is about 8 hours in patients diagnosed with community-acquired bacterial pneumonia. One pharmacokinetic study of healthy volunteers revealed a mean half-life of 13.2 hours after an intravenous infusion of lefamulin. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The total body clearance of lefamulin has been determined to range from 2.94 to 30.0 L/h after an injected dose. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In the case of overdose with lefamulin, the patient should be monitored closely and provided with supportive treatment, according to symptoms and signs. This drug and its active metabolite are not removable by dialysis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Xenleta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lefamulin is a pleuromutilin antibacterial used to treat community-acquired bacterial pneumonia (CABP).

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Lefamulin interact? Information: •Drug A: Abatacept •Drug B: Lefamulin •Severity: MODERATE •Description: The metabolism of Lefamulin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Lefamulin is indicated to treat adults diagnosed with community-acquired bacterial pneumonia (CABP) that is caused by susceptible bacteria. Its use should be reserved for confirmed susceptible organisms or a high probability of infection with susceptible organisms. The list of susceptible bacteria includes Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible), Legionella pneumophila, Haemophilus influenza, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Lefamulin demonstrates strong antibacterial activity against several microbes that are found to be common in both acute bacterial skin and skin structure infections as well as community-acquired bacterial pneumonia. It shows antibacterial activity against gram-positive and atypical microbes (for example, Streptococcus pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae, Haemophilus influenzae, and Chlamydophila pneumoniae). Lefamulin also exerts activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium. It does not treat Pseudomonas aeruginosa infections. During in vitro studies, drug has also has demonstrated activity against Neisseria gonorrhoeae and Mycoplasma genitalium. A note on QT prolongation and Clostridium difficile According to the FDA label, lefamulin may have cardiac QT interval prolonging effects and advises against the administration of this drug in patients with diagnosed QT prolongation or ventricular arrhythmias. The administration of lefamulin should also be avoided in patients being administered antiarrhythmic agents and other drugs that prolong the QT interval. As with other antibiotics, the risk of Clostridium difficile associated diarrhea is increased with lefamulin use. Any case of diarrhea should be evaluated for C. difficile. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Lefamulin inhibits prokaryotic ribosomal protein synthesis via its binding to the peptidyl transferase center (PTC) of the ribosomal bacterial 50S subunit. It inhibits protein translation through binding to both the A and P sites of the PTC via four hydrogen bonds, resulting in the interruption of peptide bond formation. Lefamulin's tricyclic mutilin core is the common moiety for binding of all members of its drug class, the pleuromutilins. Although the tricyclic motilin core doesn’t form any hydrogen bonds with the PTC nucleotides, it is stabilized or anchored by hydrophobic and Van der Waals interactions. Lefamulin exerts a selective inhibition of protein translation in eukaryotes, however, does not affect ribosomal translation of eukaryotes. Lefamulin demonstrates a unique induced-fit type of action that closes the binding pocket within a ribosome, conferring close contact of the drug to its target, therefore improving therapeutic efficacy. Because of its mechanism of action that differs from that of other antimicrobials, cross-resistance to other antibiotic classes is less likely. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In a pharmacokinetic study of healthy subjects, lefamulin was rapidly absorbed after oral administration. The median Tmax was measured at 1.00 h for the intravenous preparation and 1.76 h for the tablet preparation. At steady-state doses, the Cmax of oral lefamulin is 37.1 mcg/mL. The AUC at steady-state concentrations of this drug is 49.2 mcg·h/mL. The estimated bioavailability of the oral tablets is 25%. Clinical studies have found that the AUC of lefamulin is decreased by about 10-28% in the fed state. To optimize absorption, this drug should be administered a minimum of 1 hour before a meal or, at minimum, 2 hours after a meal with water. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The average volume of distribution of lefamulin is 86.1 L in patients with community-acquired bacterial pneumonia, but can range from 34.2 to 153 L. During clinical studies, lefamulin has been shown to significantly concentrate in the lung tissue, likely increasing its effectiveness in treating pneumonia. After lefamulin is administered, penetration into various tissues is observed, and is about 6 times greater in concentration in the fluid of the pulmonary epithelium, when compared with concentrations in the plasma. Animal studies demonstrate that lefamulin crosses the placenta. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The average plasma protein binding of lefamulin is between 94.8 to 97.1% in healthy adults. A systematic review identifies the plasma protein binding at 80-87%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): CYP3A4 is the main enzyme responsible for the metabolism of lefamulin. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Lefamulin is largely excreted by the gastrointestinal tract and about 14% excreted by the kidneys. In healthy adult volunteers during clinical trials, a radiolabeled dose of lefamulin was administered. The total radioactivity found to be excreted in the feces was 77.3% on average with 4.2% to 9.1% as unchanged drug when the drug was administered via the intravenous route. A total radioactivity of 88.5% was measured in the feces with 7.8-24.8% as unchanged drug after a dose administered via the oral route. In the urine, it was found to be 15.5% with 9.6-14.1% excretd as unchanged drug after an intravenous dose and 5.3% after an oral dose. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The average elimination half-life of lefamulin is about 8 hours in patients diagnosed with community-acquired bacterial pneumonia. One pharmacokinetic study of healthy volunteers revealed a mean half-life of 13.2 hours after an intravenous infusion of lefamulin. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The total body clearance of lefamulin has been determined to range from 2.94 to 30.0 L/h after an injected dose. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In the case of overdose with lefamulin, the patient should be monitored closely and provided with supportive treatment, according to symptoms and signs. This drug and its active metabolite are not removable by dialysis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Xenleta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lefamulin is a pleuromutilin antibacterial used to treat community-acquired bacterial pneumonia (CABP). Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Does Abatacept and Leflunomide interact?

•Drug A: Abatacept •Drug B: Leflunomide •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Leflunomide. •Extended Description: The immunosuppressive effects of leflunomide may be augmented by the concurrent administration of immunosuppressive agents, leading to an increased risk of serious infection and/or lymphoproliferative disorders resulting from bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the management of the signs and symptoms of active rheumatoid arthritis (RA) to improve physical function and to slow the progression of structural damage associated with the disease. Has also been used for the prevention of acute and chronic rejection in recipients of solid organ trasnplants and is designated by the FDA as an orphan drug for this use. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Leflunomide is a pyrimidine synthesis inhibitor indicated in adults for the treatment of active rheumatoid arthritis (RA). RA is an auto-immune disease characterized by high T-cell activity. T cells have two pathways to synthesize pyrimidines: the salvage pathways and the de novo synthesis. At rest, T lymphocytes meet their metabolic requirements by the salvage pathway. Activated lymphocytes need to expand their pyrimidine pool 7- to 8-fold, while the purine pool is expanded only 2- to 3-fold. To meet the need for more pyrimidines, activated T cells use the de novo pathway for pyrimidine synthesis. Therefore, activated T cells, which are dependent on de novo pyrimidine synthesis, will be more affected by leflunomide's inhibition of dihydroorotate dehydrogenase than other cell types that use the salvage pathway of pyrimidine synthesis. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Leflunomide is a prodrug that is rapidly and almost completely metabolized following oral administration to its pharmacologically active metabolite, A77 1726. This metabolite is responsible for essentially all of the drug's activity in-vivo. The mechanism of action of leflunomide has not been fully determined, but appears to primarily involve regulation of autoimmune lymphocytes. It has been suggested that leflunomide exerts its immunomodulating effects by preventing the expansion of activated autoimmune lymphocytes via interferences with cell cycle progression. In-vitro data indicates that leflunomide interferes with cell cycle progression by inhibiting dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine ribonucleotide uridine monophosphate (rUMP)synthesis) and has antiproliferative activity. Human dihydroorotate dehydrogenase consists of 2 domains: an α/β-barrel domain containing the active site and an α-helical domain that forms a tunnel leading to the active site. A77 1726 binds to the hydrophobic tunnel at a site near the flavin mononucleotide. Inhibition of dihydroorotate dehydrogenase by A77 1726 prevents production of rUMP by the de novo pathway; such inhibition leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest. It is through this action that leflunomide inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells. Since salvage pathways are expected to sustain cells arrested in the G1 phase, the activity of leflunomide is cytostatic rather than cytotoxic. Other effects that result from reduced rUMP levels include interference with adhesion of activated lymphocytes to the synovial vascular endothelial cells, and increased synthesis of immunosuppressive cytokines such as transforming growth factor-β (TGF-β). Leflunomide is also a tyrosine kinase inhibitor. Tyrosine kinases activate signalling pathways leading to DNA repair, apoptosis and cell proliferation. Inhibition of tyrosine kinases can help to treating cancer by preventing repair of tumor cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Well absorbed, peak plasma concentrations appear 6-12 hours after dosing •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 0.13 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): >99.3% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic. Leflunomide is converted to its active form following oral intake. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The active metabolite is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. It is not known whether leflunomide is excreted in human milk. Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from leflunomide. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 2 weeks •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 =100-250 mg/kg (acute oral toxicity) •Brand Names (Drug A): Orencia •Brand Names (Drug B): Arava •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 4-ISOXAZOLECARBOXAMIDE, 5-METHYL-N-(4-(TRIFLUOROMETHYL)PHENYL)- Leflunomida Leflunomide Léflunomide Leflunomidum N-(4-(TRIFLUOROMETHYL)PHENYL) 5 METHYLISOXAZOLE-4-CARBOXAMIDE N-[4-(trifluoromethyl)phenyl] 5 methylisoxazole-4-carboxamide •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Leflunomide is a pyrimidine synthesis inhibitor indicated to treat rheumatoid arthritis.

The immunosuppressive effects of leflunomide may be augmented by the concurrent administration of immunosuppressive agents, leading to an increased risk of serious infection and/or lymphoproliferative disorders resulting from bone marrow suppression. The severity of the interaction is moderate.

Question: Does Abatacept and Leflunomide interact? Information: •Drug A: Abatacept •Drug B: Leflunomide •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Leflunomide. •Extended Description: The immunosuppressive effects of leflunomide may be augmented by the concurrent administration of immunosuppressive agents, leading to an increased risk of serious infection and/or lymphoproliferative disorders resulting from bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the management of the signs and symptoms of active rheumatoid arthritis (RA) to improve physical function and to slow the progression of structural damage associated with the disease. Has also been used for the prevention of acute and chronic rejection in recipients of solid organ trasnplants and is designated by the FDA as an orphan drug for this use. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Leflunomide is a pyrimidine synthesis inhibitor indicated in adults for the treatment of active rheumatoid arthritis (RA). RA is an auto-immune disease characterized by high T-cell activity. T cells have two pathways to synthesize pyrimidines: the salvage pathways and the de novo synthesis. At rest, T lymphocytes meet their metabolic requirements by the salvage pathway. Activated lymphocytes need to expand their pyrimidine pool 7- to 8-fold, while the purine pool is expanded only 2- to 3-fold. To meet the need for more pyrimidines, activated T cells use the de novo pathway for pyrimidine synthesis. Therefore, activated T cells, which are dependent on de novo pyrimidine synthesis, will be more affected by leflunomide's inhibition of dihydroorotate dehydrogenase than other cell types that use the salvage pathway of pyrimidine synthesis. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Leflunomide is a prodrug that is rapidly and almost completely metabolized following oral administration to its pharmacologically active metabolite, A77 1726. This metabolite is responsible for essentially all of the drug's activity in-vivo. The mechanism of action of leflunomide has not been fully determined, but appears to primarily involve regulation of autoimmune lymphocytes. It has been suggested that leflunomide exerts its immunomodulating effects by preventing the expansion of activated autoimmune lymphocytes via interferences with cell cycle progression. In-vitro data indicates that leflunomide interferes with cell cycle progression by inhibiting dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine ribonucleotide uridine monophosphate (rUMP)synthesis) and has antiproliferative activity. Human dihydroorotate dehydrogenase consists of 2 domains: an α/β-barrel domain containing the active site and an α-helical domain that forms a tunnel leading to the active site. A77 1726 binds to the hydrophobic tunnel at a site near the flavin mononucleotide. Inhibition of dihydroorotate dehydrogenase by A77 1726 prevents production of rUMP by the de novo pathway; such inhibition leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest. It is through this action that leflunomide inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells. Since salvage pathways are expected to sustain cells arrested in the G1 phase, the activity of leflunomide is cytostatic rather than cytotoxic. Other effects that result from reduced rUMP levels include interference with adhesion of activated lymphocytes to the synovial vascular endothelial cells, and increased synthesis of immunosuppressive cytokines such as transforming growth factor-β (TGF-β). Leflunomide is also a tyrosine kinase inhibitor. Tyrosine kinases activate signalling pathways leading to DNA repair, apoptosis and cell proliferation. Inhibition of tyrosine kinases can help to treating cancer by preventing repair of tumor cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Well absorbed, peak plasma concentrations appear 6-12 hours after dosing •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 0.13 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): >99.3% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic. Leflunomide is converted to its active form following oral intake. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The active metabolite is eliminated by further metabolism and subsequent renal excretion as well as by direct biliary excretion. In a 28 day study of drug elimination (n=3) using a single dose of radiolabeled compound, approximately 43% of the total radioactivity was eliminated in the urine and 48% was eliminated in the feces. It is not known whether leflunomide is excreted in human milk. Many drugs are excreted in human milk, and there is a potential for serious adverse reactions in nursing infants from leflunomide. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 2 weeks •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 =100-250 mg/kg (acute oral toxicity) •Brand Names (Drug A): Orencia •Brand Names (Drug B): Arava •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 4-ISOXAZOLECARBOXAMIDE, 5-METHYL-N-(4-(TRIFLUOROMETHYL)PHENYL)- Leflunomida Leflunomide Léflunomide Leflunomidum N-(4-(TRIFLUOROMETHYL)PHENYL) 5 METHYLISOXAZOLE-4-CARBOXAMIDE N-[4-(trifluoromethyl)phenyl] 5 methylisoxazole-4-carboxamide •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Leflunomide is a pyrimidine synthesis inhibitor indicated to treat rheumatoid arthritis. Output: The immunosuppressive effects of leflunomide may be augmented by the concurrent administration of immunosuppressive agents, leading to an increased risk of serious infection and/or lymphoproliferative disorders resulting from bone marrow suppression. The severity of the interaction is moderate.

Does Abatacept and Lemborexant interact?

•Drug A: Abatacept •Drug B: Lemborexant •Severity: MODERATE •Description: The metabolism of Lemborexant can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Lemborexant is indicated for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Lemborexant promotes sleep by antagonizing the actions of wake-promoting chemicals in the brain. Episodes of complex sleep behaviors (e.g. eating food, having sex, making phone calls) have been reported in patients using lemborexant - these events may occur in hypnotic-naive and hyponotic-experienced patients, and patients are unlikely to remember these events. Patients exhibiting complex sleep behaviors should discontinue lemborexant immediately. Lemborexant may carry some risk of abuse, and should be used with caution in patients with a history of alcohol or drug addiction. Its controlled substance schedule is currently under review by the Drug Enforcement Administration. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The orexin neuropeptide signaling system is involved in many physiologic functions, including sleep/wake control. Orexin-A and orexin-B activate post-synaptic G-protein coupled orexin-1 receptors (OX1R) and orexin-2 receptors (OX2R), which are found on neurons in the hypothalamus that project to numerous wake-controlling nuclei. Each receptor carries slightly different activity - activation of OX1R appears to suppress the onset of rapid eye movement (REM) sleep, whereas activation of OX2R appears to suppress non-REM sleep. Lemborexant is an competitive antagonist of OX1R and OX2R. By blocking the binding of wake-promoting orexin-A and -B at these receptors, lemborexant suppresses the wake-drive, thereby promoting sleep. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Animal models of lemborexant disposition have demonstrated rapid absorption following oral administration. The T max of lemborexant is approximately 1-3 hours, or 3-5 hours following administration of a high-fat, high-calorie meal. C max and AUC 0-24h increase at a rate slightly less than proportionate to the given dose. Following administration of a high-fat, high-calorie meal, C max is decreased by 23% and AUC 0-inf is increased by 18%. AUC, C max, and terminal half-life are increased in the presence of moderate hepatic impairment, and AUC (but not half-life) is increased in the presence of mild hepatic impairment. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of lemborexant is 1970 L, indicating extensive tissue distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Lemborexant is approximately 94% protein-bound in vitro, though the specific proteins to which it binds in plasma have not been elucidated. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Given that less than 1% of an administered dose is recovered unchanged in the urine, it is likely that lemborexant is extensively metabolized - this has been confirmed in rat and monkey models, but its metabolism in humans has not been fully characterized. Prescribing information states that it is predominantly metabolized by CYP3A4, with a smaller contribution by CYP3A5. The major circulating metabolite is lemborexant's M10 metabolite, which is pharmacologically active and binds to orexin receptors with a similar affinity to the parent drug. The M10 metabolite has the potential to induce CYP3A and CYP2B6 enzymes, weakly inhibit CYP3A enzymes, and is a substrate of P-gp transporters. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration, 57.4% of the dose is found in the feces and 29.1% in the urine. Less than 1% of the dose recovered in the urine exists as unchanged parent drug, suggesting extensive metabolism. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life for lemborexant at doses of 5mg and 10mg is 17 and 19 hours, respectively. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Clinical experience with lemborexant overdose is limited. In clinical studies, healthy patients receiving doses up to 10x the recommended maximum dose experienced dose-dependent increases in the frequency of adverse effects such as somnolence - it is likely, then, that symptoms of overdose will be consistent with lemborexant's adverse effect profile. In the event of an overdosage, implement supportive measures and consult the nearest poison control center for the most up to date management strategies. As lemborexant is highly protein-bound, hemodialysis is likely to be of little use in overdose situations. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Dayvigo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lemborexant is a dual orexin antagonist indicated for the treatment of sleep-onset and/or sleep maintenance insomnia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Lemborexant interact? Information: •Drug A: Abatacept •Drug B: Lemborexant •Severity: MODERATE •Description: The metabolism of Lemborexant can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Lemborexant is indicated for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Lemborexant promotes sleep by antagonizing the actions of wake-promoting chemicals in the brain. Episodes of complex sleep behaviors (e.g. eating food, having sex, making phone calls) have been reported in patients using lemborexant - these events may occur in hypnotic-naive and hyponotic-experienced patients, and patients are unlikely to remember these events. Patients exhibiting complex sleep behaviors should discontinue lemborexant immediately. Lemborexant may carry some risk of abuse, and should be used with caution in patients with a history of alcohol or drug addiction. Its controlled substance schedule is currently under review by the Drug Enforcement Administration. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): The orexin neuropeptide signaling system is involved in many physiologic functions, including sleep/wake control. Orexin-A and orexin-B activate post-synaptic G-protein coupled orexin-1 receptors (OX1R) and orexin-2 receptors (OX2R), which are found on neurons in the hypothalamus that project to numerous wake-controlling nuclei. Each receptor carries slightly different activity - activation of OX1R appears to suppress the onset of rapid eye movement (REM) sleep, whereas activation of OX2R appears to suppress non-REM sleep. Lemborexant is an competitive antagonist of OX1R and OX2R. By blocking the binding of wake-promoting orexin-A and -B at these receptors, lemborexant suppresses the wake-drive, thereby promoting sleep. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Animal models of lemborexant disposition have demonstrated rapid absorption following oral administration. The T max of lemborexant is approximately 1-3 hours, or 3-5 hours following administration of a high-fat, high-calorie meal. C max and AUC 0-24h increase at a rate slightly less than proportionate to the given dose. Following administration of a high-fat, high-calorie meal, C max is decreased by 23% and AUC 0-inf is increased by 18%. AUC, C max, and terminal half-life are increased in the presence of moderate hepatic impairment, and AUC (but not half-life) is increased in the presence of mild hepatic impairment. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of lemborexant is 1970 L, indicating extensive tissue distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Lemborexant is approximately 94% protein-bound in vitro, though the specific proteins to which it binds in plasma have not been elucidated. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Given that less than 1% of an administered dose is recovered unchanged in the urine, it is likely that lemborexant is extensively metabolized - this has been confirmed in rat and monkey models, but its metabolism in humans has not been fully characterized. Prescribing information states that it is predominantly metabolized by CYP3A4, with a smaller contribution by CYP3A5. The major circulating metabolite is lemborexant's M10 metabolite, which is pharmacologically active and binds to orexin receptors with a similar affinity to the parent drug. The M10 metabolite has the potential to induce CYP3A and CYP2B6 enzymes, weakly inhibit CYP3A enzymes, and is a substrate of P-gp transporters. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration, 57.4% of the dose is found in the feces and 29.1% in the urine. Less than 1% of the dose recovered in the urine exists as unchanged parent drug, suggesting extensive metabolism. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life for lemborexant at doses of 5mg and 10mg is 17 and 19 hours, respectively. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Clinical experience with lemborexant overdose is limited. In clinical studies, healthy patients receiving doses up to 10x the recommended maximum dose experienced dose-dependent increases in the frequency of adverse effects such as somnolence - it is likely, then, that symptoms of overdose will be consistent with lemborexant's adverse effect profile. In the event of an overdosage, implement supportive measures and consult the nearest poison control center for the most up to date management strategies. As lemborexant is highly protein-bound, hemodialysis is likely to be of little use in overdose situations. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Dayvigo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lemborexant is a dual orexin antagonist indicated for the treatment of sleep-onset and/or sleep maintenance insomnia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Lenalidomide interact?

•Drug A: Abatacept •Drug B: Lenalidomide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Lenalidomide is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Lenalidomide is indicated for the treatment of adult patients with multiple myeloma (MM) in combination with dexamethasone. It is also indicated as maintenance therapy in multiple myeloma following autologous hematopoietic stem cell transplantation (auto-HSCT). It is indicated for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Lenalidomide is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. In combination with a rituximab product, lenalidomide is indicated for the treatment of adult patients with previously treated follicular lymphoma (FL) or previously treated marginal zone lymphoma (MZL). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In hematological malignancies, the immune system is deregulated in the form of altered cytokine networks in the tumour microenvironment, defective T cell regulation of host-tumour immune interactions, and diminished NK cell activity. Lenalidomide is an immunomodulatory agent with antineoplastic, antiangiogenic, and anti-inflammatory properties. Lenalidomide exerts direct cytotoxicity by increasing apoptosis and inhibiting the proliferation of hematopoietic malignant cells. It delays tumour growth in nonclinical hematopoietic tumour models in vivo, including multiple myeloma. Lenalidomide also works to limit the invasion or metastasis of tumour cells and inhibits angiogenesis. Lenalidomide also mediates indirect antitumour effects via its immunomodulatory actions: it inhibits the production of pro-inflammatory cytokines, which are implicated in various hematologic malignancies. Lenalidomide enhances the host immunity by stimulating T cell proliferation and enhancing the activity of natural killer (NK) cells. Lenalidomide is about 100–1000 times more potent in stimulating T cell proliferation than thalidomide. In vitro, it enhances antibody-dependent cell-mediated cytotoxicity (ADCC), which is even more pronounced when used in combination with rituximab. Due to its anti-inflammatory properties, lenalidomide has been investigated in the context of inflammatory and autoimmune diseases, such as amyotrophic lateral sclerosis. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Lenalidomide is a drug with multiple mechanisms of action. Lenalidomide exerts immunomodulating effects by altering cytokine production, regulating T cell co-stimulation, and enhancing the NK cell-mediated cytotoxicity. Lenalidomide directly inhibits the cullin ring E3 ubiquitin ligase complex: upon binding to cereblon, a substrate adaptor of the complex, lenalidomide modulates substrate specificity of the complex to recruit substrate proteins of the ligase, including Ikaros (IKZF1), Aiolos (IKZF3), and CK1α. These substrates are then tagged for ubiquitination and subsequent proteasomal degradation. IKZF1 and IKZF3 are B-cell transcription factors that are essential for B-cell differentiation and survival of malignant cells. IKZF3 also regulates the expression of interferon regulatory factor 4 (IRF4), which is a transcription factor that regulates the aberrant myeloma-specific gene. The immunomodulatory actions of lenalidomide can be partly explained by the degradation of IKZF3, since it is a repressor of the interleukin 2 gene (IL2): as lenalidomide decreases the level of IKZF3, the production of IL-2 increases, thereby increasing the proliferation of natural killer (NK), NKT cells, and CD4+ T cells. Lenalidomide inhibits the production of pro-inflammatory cytokines TNF-α, IL-1, IL-6, and IL-12, while elevating the production of anti-inflammatory cytokine IL-10. Lenalidomide acts as a T-cell co-stimulatory molecule that promotes CD3 T-cell proliferation and increases the production of IL-2 and IFN-γ in T lymphocytes, which enhances NK cell cytotoxicity and ADCC. It inhibits the expression and function of T-regulatory cells, which are often overabundant in some hematological malignancies. Lenalidomide directly exerts antitumour effects by inhibiting the proliferation and inducing apoptosis of tumour cells. Lenalidomide triggers the activation of pro-apoptotic caspase-8, enhances tumour cell sensitivity to FAS-induced apoptosis, and downregulates NF-κB, an anti-apoptotic protein. Independent of its immunomodulatory effects, lenalidomide mediates anti-angiogenic effects by inhibiting angiogenic growth factors released by tumour cells, such as vascular endothelial growth factor (VEGF), basic fibroblastic-growth factor (BFGF), and hepatocyte-growth factor. In vitro, lenalidomide inhibits cell adhesion molecules such as ICAM-1, LFA-1, β2 and β3 integrins, as well as gap-junction function, thereby preventing metastasis of malignant cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following oral administration, lenalidomide is rapidly absorbed with high bioavailability. It has a T max ranging from 0.5 to six hours. Lenalidomide exhibits a linear pharmacokinetic profile, with its AUC and C max increasing proportionally with dose. Multiple dosing does not result in drug accumulation. In healthy male subjects, the C max was 413 ± 77 ng/ml and the AUC infinity was 1319 ± 162 h x ng/ml. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): In healthy male subjects, the apparent volume of distribution was 75.8 ± 7.3 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, about 30% of lenalidomide was bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Lenalidomide is not subject to extensive hepatic metabolism involving CYP enzymes and metabolism contributes to a very minor extent to the clearance of lenalidomide in humans. Lenalidomide undergoes hydrolysis in human plasma to form 5-hydroxy-lenalidomide and N-acetyl-lenalidomide. Unchanged lenalidomide is the predominant circulating drug form, with metabolites accounting for less than five percent of the parent drug levels in the circulation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Lenalidomide is eliminated predominantly via urinary excretion in the unchanged form. Following oral administration of 25 mg of radiolabeled lenalidomide in healthy subjects, about 90% of the dose (4.59% as metabolites) was eliminated in urine and 4% of the dose (1.83% as metabolites) was eliminated in feces within ten days post-dose. Approximately 85% of the dose was excreted as lenalidomide in the urine within 24 hours. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In healthy subjects, the mean half-life of lenalidomide is three hours in the clinically relevant dose range (5–50 mg). Half-life can range from three to five hours in patients with multiple myeloma, myelodysplastic syndromes, or mantle cell lymphoma. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The renal clearance of lenalidomide exceeds the glomerular filtration rate. In healthy male subjects, the oral clearance was 318 ± 41 mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The lowest lethal dose (LDLo) in rats is >2000 mg/kg following oral administration and >40 mg/kg following intravenous administration. The oral Lowest published toxic dose (TDLo) in humans is 9 mg/kg/4W (intermittent). There is limited clinical experience in managing lenalidomide overdose. In single-dose studies, healthy subjects have been exposed to doses up to 400 mg. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia. Toxicities associated with lenalidomide, some leading to fatality, include embryo-fetal toxicity, neutropenia, thrombocytopenia, venous (deep vein thrombosis and pulmonary embolism) and arterial thromboembolic events (myocardial infarction and stroke), serious adverse cardiovascular reactions, second primary malignancies, hepatotoxicity, severe cutaneous reactions, tumour lysis syndrome, tumour flare reaction, hypothyroidism, and hyperthyroidism. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Revlimid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lenalidomida Lenalidomide •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lenalidomide is a thalidomide derivative used to treat multiple myeloma and anemia in low to intermediate risk myelodysplastic syndrome.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Lenalidomide interact? Information: •Drug A: Abatacept •Drug B: Lenalidomide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Lenalidomide is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Lenalidomide is indicated for the treatment of adult patients with multiple myeloma (MM) in combination with dexamethasone. It is also indicated as maintenance therapy in multiple myeloma following autologous hematopoietic stem cell transplantation (auto-HSCT). It is indicated for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Lenalidomide is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. In combination with a rituximab product, lenalidomide is indicated for the treatment of adult patients with previously treated follicular lymphoma (FL) or previously treated marginal zone lymphoma (MZL). •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): In hematological malignancies, the immune system is deregulated in the form of altered cytokine networks in the tumour microenvironment, defective T cell regulation of host-tumour immune interactions, and diminished NK cell activity. Lenalidomide is an immunomodulatory agent with antineoplastic, antiangiogenic, and anti-inflammatory properties. Lenalidomide exerts direct cytotoxicity by increasing apoptosis and inhibiting the proliferation of hematopoietic malignant cells. It delays tumour growth in nonclinical hematopoietic tumour models in vivo, including multiple myeloma. Lenalidomide also works to limit the invasion or metastasis of tumour cells and inhibits angiogenesis. Lenalidomide also mediates indirect antitumour effects via its immunomodulatory actions: it inhibits the production of pro-inflammatory cytokines, which are implicated in various hematologic malignancies. Lenalidomide enhances the host immunity by stimulating T cell proliferation and enhancing the activity of natural killer (NK) cells. Lenalidomide is about 100–1000 times more potent in stimulating T cell proliferation than thalidomide. In vitro, it enhances antibody-dependent cell-mediated cytotoxicity (ADCC), which is even more pronounced when used in combination with rituximab. Due to its anti-inflammatory properties, lenalidomide has been investigated in the context of inflammatory and autoimmune diseases, such as amyotrophic lateral sclerosis. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Lenalidomide is a drug with multiple mechanisms of action. Lenalidomide exerts immunomodulating effects by altering cytokine production, regulating T cell co-stimulation, and enhancing the NK cell-mediated cytotoxicity. Lenalidomide directly inhibits the cullin ring E3 ubiquitin ligase complex: upon binding to cereblon, a substrate adaptor of the complex, lenalidomide modulates substrate specificity of the complex to recruit substrate proteins of the ligase, including Ikaros (IKZF1), Aiolos (IKZF3), and CK1α. These substrates are then tagged for ubiquitination and subsequent proteasomal degradation. IKZF1 and IKZF3 are B-cell transcription factors that are essential for B-cell differentiation and survival of malignant cells. IKZF3 also regulates the expression of interferon regulatory factor 4 (IRF4), which is a transcription factor that regulates the aberrant myeloma-specific gene. The immunomodulatory actions of lenalidomide can be partly explained by the degradation of IKZF3, since it is a repressor of the interleukin 2 gene (IL2): as lenalidomide decreases the level of IKZF3, the production of IL-2 increases, thereby increasing the proliferation of natural killer (NK), NKT cells, and CD4+ T cells. Lenalidomide inhibits the production of pro-inflammatory cytokines TNF-α, IL-1, IL-6, and IL-12, while elevating the production of anti-inflammatory cytokine IL-10. Lenalidomide acts as a T-cell co-stimulatory molecule that promotes CD3 T-cell proliferation and increases the production of IL-2 and IFN-γ in T lymphocytes, which enhances NK cell cytotoxicity and ADCC. It inhibits the expression and function of T-regulatory cells, which are often overabundant in some hematological malignancies. Lenalidomide directly exerts antitumour effects by inhibiting the proliferation and inducing apoptosis of tumour cells. Lenalidomide triggers the activation of pro-apoptotic caspase-8, enhances tumour cell sensitivity to FAS-induced apoptosis, and downregulates NF-κB, an anti-apoptotic protein. Independent of its immunomodulatory effects, lenalidomide mediates anti-angiogenic effects by inhibiting angiogenic growth factors released by tumour cells, such as vascular endothelial growth factor (VEGF), basic fibroblastic-growth factor (BFGF), and hepatocyte-growth factor. In vitro, lenalidomide inhibits cell adhesion molecules such as ICAM-1, LFA-1, β2 and β3 integrins, as well as gap-junction function, thereby preventing metastasis of malignant cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Following oral administration, lenalidomide is rapidly absorbed with high bioavailability. It has a T max ranging from 0.5 to six hours. Lenalidomide exhibits a linear pharmacokinetic profile, with its AUC and C max increasing proportionally with dose. Multiple dosing does not result in drug accumulation. In healthy male subjects, the C max was 413 ± 77 ng/ml and the AUC infinity was 1319 ± 162 h x ng/ml. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): In healthy male subjects, the apparent volume of distribution was 75.8 ± 7.3 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, about 30% of lenalidomide was bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Lenalidomide is not subject to extensive hepatic metabolism involving CYP enzymes and metabolism contributes to a very minor extent to the clearance of lenalidomide in humans. Lenalidomide undergoes hydrolysis in human plasma to form 5-hydroxy-lenalidomide and N-acetyl-lenalidomide. Unchanged lenalidomide is the predominant circulating drug form, with metabolites accounting for less than five percent of the parent drug levels in the circulation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Lenalidomide is eliminated predominantly via urinary excretion in the unchanged form. Following oral administration of 25 mg of radiolabeled lenalidomide in healthy subjects, about 90% of the dose (4.59% as metabolites) was eliminated in urine and 4% of the dose (1.83% as metabolites) was eliminated in feces within ten days post-dose. Approximately 85% of the dose was excreted as lenalidomide in the urine within 24 hours. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In healthy subjects, the mean half-life of lenalidomide is three hours in the clinically relevant dose range (5–50 mg). Half-life can range from three to five hours in patients with multiple myeloma, myelodysplastic syndromes, or mantle cell lymphoma. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The renal clearance of lenalidomide exceeds the glomerular filtration rate. In healthy male subjects, the oral clearance was 318 ± 41 mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The lowest lethal dose (LDLo) in rats is >2000 mg/kg following oral administration and >40 mg/kg following intravenous administration. The oral Lowest published toxic dose (TDLo) in humans is 9 mg/kg/4W (intermittent). There is limited clinical experience in managing lenalidomide overdose. In single-dose studies, healthy subjects have been exposed to doses up to 400 mg. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia. Toxicities associated with lenalidomide, some leading to fatality, include embryo-fetal toxicity, neutropenia, thrombocytopenia, venous (deep vein thrombosis and pulmonary embolism) and arterial thromboembolic events (myocardial infarction and stroke), serious adverse cardiovascular reactions, second primary malignancies, hepatotoxicity, severe cutaneous reactions, tumour lysis syndrome, tumour flare reaction, hypothyroidism, and hyperthyroidism. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Revlimid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lenalidomida Lenalidomide •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lenalidomide is a thalidomide derivative used to treat multiple myeloma and anemia in low to intermediate risk myelodysplastic syndrome. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Lercanidipine interact?

•Drug A: Abatacept •Drug B: Lercanidipine •Severity: MODERATE •Description: The metabolism of Lercanidipine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of Hypertension, management of angina pectoris and Raynaud's syndrome •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Lercanidipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Lercanidipine is similar to other peripheral vasodilators. Lercanidipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Lercanidipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lercanidipine is a calcium channel blocker for the management of hypertension.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Lercanidipine interact? Information: •Drug A: Abatacept •Drug B: Lercanidipine •Severity: MODERATE •Description: The metabolism of Lercanidipine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of Hypertension, management of angina pectoris and Raynaud's syndrome •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Lercanidipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Lercanidipine is similar to other peripheral vasodilators. Lercanidipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Lercanidipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): No half-life available •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lercanidipine is a calcium channel blocker for the management of hypertension. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Letrozole interact?

•Drug A: Abatacept •Drug B: Letrozole •Severity: MODERATE •Description: The metabolism of Letrozole can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Letrozole is indicated to treat postmenopausal women with hormone receptor (HR) positive early breast cancer, postmenopausal women with early breast cancer who have periviously been treated with tamoxifen, and postmenopausal women with HR+ or unknown advanced breast cancer. Letrozole, given with ribociclib, is indicated to treat pre, peri, and postmenopausal women with HR+ and human epidermal growth factor 2 (HER2) negative advanced or metastatic breast cancer. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Letrozole is an aromatase inhibitor used in the treatment of breast cancer. Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue. Letrozole is a third generation type II aromatase inhibitor used to treat estrogen dependant breast cancers. It has a long duration of action as it has a half life of over 42 hours in breast cancer patients. Patients should be counselled regarding the risk of interstitial lung disease, pneumonitis, QT prolongation, elevated transaminase levels, neutropenia, and embryo-fetal toxicity. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Letrozole is a non-steroidal type II aromatase inhibitor. It blocks the active site, and therefore the electron transfer chain of CYP19A1. This competitive inhibition prevents the conversion of androgens to estrogen. This action leads to a reduction in uterine weight and elevated leuteinizing hormone. In postmenopausal women, the action of aromatase is responsible for the majority of estrogen production. With reduced availability of estrogen, estrogen-dependant tumors regress. Third generation aromatase inhibitors do not significantly affect cortisol, aldosterone, and thyroxine levels. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Letrozole is 99.9% orally bioavailable. A 2.5mg oral dose reaches a C max of 104nmol/L with a T max of 8.10h, and an AUC of 7387nmol*h/L. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of letrozole is 1.87L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Letrozole is 60% bound to proteins. 55% is bound to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Letrozole is metabolized by CYP2A6 to a ketone analog metabolite, which is further metabolized by CYP3A4 and CYP2A6 to 4,4'-(hydroxymethylene)dibenzonitrile. 4,4'-(hydroxymethylene)dibenzonitrile is glucuronidated by UGT2B7. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Letrozole is 90% eliminated in the urine. 75% of the dose is recovered as a glucuronide metabolite, 9% is in the form of the ketone and carbinol metabolites, and 6% is recovered in urine as unchanged letrozole. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half life of letrozole is approximately 42h in healthy volunteers, but longer in breast cancer patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The average clearance after a single dose of letrozole was 1.52L/h and at steady state was 1.20L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Overdose data in humans is not readily available, however 1 reported case was not associated with serious adverse reactions. Animal studies do not report serious adverse effects with high dose treatment. Patients experiencing and overdose should be treated with symptomatic and supportive measures. Oral doses over 2000mg/kg were associated with reduced motor activity, ataxia, dyspnea, and death in mice and rats. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Femara, Kisqali Femara Co-pack •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Letrozole is an aromatase inhibitor used to treat breast cancer in postmenopausal women.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Letrozole interact? Information: •Drug A: Abatacept •Drug B: Letrozole •Severity: MODERATE •Description: The metabolism of Letrozole can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Letrozole is indicated to treat postmenopausal women with hormone receptor (HR) positive early breast cancer, postmenopausal women with early breast cancer who have periviously been treated with tamoxifen, and postmenopausal women with HR+ or unknown advanced breast cancer. Letrozole, given with ribociclib, is indicated to treat pre, peri, and postmenopausal women with HR+ and human epidermal growth factor 2 (HER2) negative advanced or metastatic breast cancer. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Letrozole is an aromatase inhibitor used in the treatment of breast cancer. Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue. Letrozole is a third generation type II aromatase inhibitor used to treat estrogen dependant breast cancers. It has a long duration of action as it has a half life of over 42 hours in breast cancer patients. Patients should be counselled regarding the risk of interstitial lung disease, pneumonitis, QT prolongation, elevated transaminase levels, neutropenia, and embryo-fetal toxicity. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Letrozole is a non-steroidal type II aromatase inhibitor. It blocks the active site, and therefore the electron transfer chain of CYP19A1. This competitive inhibition prevents the conversion of androgens to estrogen. This action leads to a reduction in uterine weight and elevated leuteinizing hormone. In postmenopausal women, the action of aromatase is responsible for the majority of estrogen production. With reduced availability of estrogen, estrogen-dependant tumors regress. Third generation aromatase inhibitors do not significantly affect cortisol, aldosterone, and thyroxine levels. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Letrozole is 99.9% orally bioavailable. A 2.5mg oral dose reaches a C max of 104nmol/L with a T max of 8.10h, and an AUC of 7387nmol*h/L. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of letrozole is 1.87L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Letrozole is 60% bound to proteins. 55% is bound to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Letrozole is metabolized by CYP2A6 to a ketone analog metabolite, which is further metabolized by CYP3A4 and CYP2A6 to 4,4'-(hydroxymethylene)dibenzonitrile. 4,4'-(hydroxymethylene)dibenzonitrile is glucuronidated by UGT2B7. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Letrozole is 90% eliminated in the urine. 75% of the dose is recovered as a glucuronide metabolite, 9% is in the form of the ketone and carbinol metabolites, and 6% is recovered in urine as unchanged letrozole. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal elimination half life of letrozole is approximately 42h in healthy volunteers, but longer in breast cancer patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The average clearance after a single dose of letrozole was 1.52L/h and at steady state was 1.20L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Overdose data in humans is not readily available, however 1 reported case was not associated with serious adverse reactions. Animal studies do not report serious adverse effects with high dose treatment. Patients experiencing and overdose should be treated with symptomatic and supportive measures. Oral doses over 2000mg/kg were associated with reduced motor activity, ataxia, dyspnea, and death in mice and rats. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Femara, Kisqali Femara Co-pack •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Letrozole is an aromatase inhibitor used to treat breast cancer in postmenopausal women. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Does Abatacept and Levamlodipine interact?

•Drug A: Abatacept •Drug B: Levamlodipine •Severity: MODERATE •Description: The metabolism of Levamlodipine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Levamlodipine is indicated alone or in combination to treat hypertension in adults and children. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Levamlodipine inhibits L-type calcium channels in vascular smooth muscle, reducing peripheral vascular resistance and blood pressure. It is given once daily in doses of 1.25-2.5mg in children and 2.5-5mg in adults. Patients should be counselled regarding the risk of symptomatic hypotension, worsening angina, and myocardial infarction. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Levamlodipine blocks the transmembrane influx of calcium through L-type calcium channels into the vascular and cardiac smooth muscles resulting in vasodilation and a subsequent decrease in blood pressure. Levamlodipine inhibits calcium influx in vascular smooth muscle to a greater degree than in cardiac muscle, leading to decreased peripheral vascular resistance and lowered blood pressure. In vitro studies have shown a negative inotropic effect but this is unlikely to be clinically relevant. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Oral levamlodipine has a T max of 6-12h and a bioavailability of 64-90%. Absorption of levamlodipine is not significantly affected by food. 20mg or oral s-amlodipine besylate reaches a C max of 6.13±1.29ng/mL with a T max of 8.4±3.6h and an AUC of 351±72h*ng/mL. 20mg or oral s-amlodipine maleate reaches a C max of 5.07±1.09ng/mL with a T max of 10.7±3.4h and an AUC of 330±88h*ng/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of levamlodipine is similar to amlodipine. The volume of distribution of amlodipine is 21L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Levamlodipine is 93% protein bound in plasma, largely to human serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Levamlodipine is 90% metabolized to inactive metabolites. Incubation with liver microsomes has shown that this metabolism is primarily mediated by CYP3A4. Levamlodipine's dehydrogenation to a pyridine metabolite (M9) is the most important metabolic pathway in human liver microsomes. This derivative can be further oxidatively deaminated or O-dealkylated, but does not appear to undergo O-demethylation like racemic amlodipine. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Levamlodipine is 60% eliminated in urine with 10% eliminated as the unmetabolized drug. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Levamlodipine has a half life of 30-50h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The oral clearance of S-amlodipine besylate is 6.9±1.6mL/min/kg and the oral clearance of S-amlodipine maleate is 7.3±2.1mL/min/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Patients experiencing an overdose may present with hypotension and reflex tachycardia. Treat overdose with cardiac and respiratory monitoring, frequent blood pressure measurement, elevation of extremities to treat hypotension, and possible administration of vasopressors. Hemodialysis is not expected to be useful as levamlodipine is highly protein bound. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Conjupri •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Levamlodipine is a calcium channel blocker used to treat hypertension.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Levamlodipine interact? Information: •Drug A: Abatacept •Drug B: Levamlodipine •Severity: MODERATE •Description: The metabolism of Levamlodipine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Levamlodipine is indicated alone or in combination to treat hypertension in adults and children. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Levamlodipine inhibits L-type calcium channels in vascular smooth muscle, reducing peripheral vascular resistance and blood pressure. It is given once daily in doses of 1.25-2.5mg in children and 2.5-5mg in adults. Patients should be counselled regarding the risk of symptomatic hypotension, worsening angina, and myocardial infarction. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Levamlodipine blocks the transmembrane influx of calcium through L-type calcium channels into the vascular and cardiac smooth muscles resulting in vasodilation and a subsequent decrease in blood pressure. Levamlodipine inhibits calcium influx in vascular smooth muscle to a greater degree than in cardiac muscle, leading to decreased peripheral vascular resistance and lowered blood pressure. In vitro studies have shown a negative inotropic effect but this is unlikely to be clinically relevant. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Oral levamlodipine has a T max of 6-12h and a bioavailability of 64-90%. Absorption of levamlodipine is not significantly affected by food. 20mg or oral s-amlodipine besylate reaches a C max of 6.13±1.29ng/mL with a T max of 8.4±3.6h and an AUC of 351±72h*ng/mL. 20mg or oral s-amlodipine maleate reaches a C max of 5.07±1.09ng/mL with a T max of 10.7±3.4h and an AUC of 330±88h*ng/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of levamlodipine is similar to amlodipine. The volume of distribution of amlodipine is 21L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Levamlodipine is 93% protein bound in plasma, largely to human serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Levamlodipine is 90% metabolized to inactive metabolites. Incubation with liver microsomes has shown that this metabolism is primarily mediated by CYP3A4. Levamlodipine's dehydrogenation to a pyridine metabolite (M9) is the most important metabolic pathway in human liver microsomes. This derivative can be further oxidatively deaminated or O-dealkylated, but does not appear to undergo O-demethylation like racemic amlodipine. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Levamlodipine is 60% eliminated in urine with 10% eliminated as the unmetabolized drug. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Levamlodipine has a half life of 30-50h. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The oral clearance of S-amlodipine besylate is 6.9±1.6mL/min/kg and the oral clearance of S-amlodipine maleate is 7.3±2.1mL/min/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Patients experiencing an overdose may present with hypotension and reflex tachycardia. Treat overdose with cardiac and respiratory monitoring, frequent blood pressure measurement, elevation of extremities to treat hypotension, and possible administration of vasopressors. Hemodialysis is not expected to be useful as levamlodipine is highly protein bound. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Conjupri •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Levamlodipine is a calcium channel blocker used to treat hypertension. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Levobupivacaine interact?

•Drug A: Abatacept •Drug B: Levobupivacaine •Severity: MODERATE •Description: The metabolism of Levobupivacaine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the production of local or regional anesthesia for surgery and obstetrics, and for post-operative pain management •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Levobupivacaine, a local anesthetic agent, is indicated for the production of local or regional anesthesia or analgesia for surgery, for oral surgery procedures, for diagnostic and therapeutic procedures, and for obstetrical procedures. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Local anesthetics such as Levobupivacaine block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Specifically, the drug binds to the intracellular portion of sodium channels and blocks sodium influx into nerve cells, which prevents depolarization. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The plasma concentration of levobupivacaine following therapeutic administration depends on dose and also on route of administration, because absorption from the site of administration is affected by the vascularity of the tissue. Peak levels in blood were reached approximately 30 minutes after epidural administration, and doses up to 150 mg resulted in mean C max levels of up to 1.2 µg/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 66.91 ±18.23 L [after intravenous administration of 40 mg in healthy volunteers] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): >97% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Levobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine or feces. In vitro studies using [14 C] levobupivacaine showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. In vivo, the 3-hydroxy levobupivacaine appears to undergo further transformation to glucuronide and sulfate conjugates. Metabolic inversion of levobupivacaine to R(+)-bupivacaine was not evident both in vitro and in vivo. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following intravenous administration, recovery of the radiolabelled dose of levobupivacaine was essentially quantitative with a mean total of about 95% being recovered in urine and feces in 48 hours. Of this 95%, about 71% was in urine while 24% was in feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 3.3 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 39.06 ±13.29 L/h [after intravenous administration of 40 mg in healthy volunteers] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50: 5.1mg/kg in rabbit, intravenous; 18mg/kg in rabbit, oral; 207mg/kg in rabbit, parenteral; 63mg/kg in rat, subcutaneous (Archives Internationales de Pharmacodynamie et de Therapie. Vol. 200, Pg. 359, 1972.) Levobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine, despite being in higher concentrations. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-bupivacaine Levobupivacaína Levobupivacaine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Levobupivacaine is a drug used for nerve block and anesthesia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Levobupivacaine interact? Information: •Drug A: Abatacept •Drug B: Levobupivacaine •Severity: MODERATE •Description: The metabolism of Levobupivacaine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the production of local or regional anesthesia for surgery and obstetrics, and for post-operative pain management •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Levobupivacaine, a local anesthetic agent, is indicated for the production of local or regional anesthesia or analgesia for surgery, for oral surgery procedures, for diagnostic and therapeutic procedures, and for obstetrical procedures. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Local anesthetics such as Levobupivacaine block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Specifically, the drug binds to the intracellular portion of sodium channels and blocks sodium influx into nerve cells, which prevents depolarization. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The plasma concentration of levobupivacaine following therapeutic administration depends on dose and also on route of administration, because absorption from the site of administration is affected by the vascularity of the tissue. Peak levels in blood were reached approximately 30 minutes after epidural administration, and doses up to 150 mg resulted in mean C max levels of up to 1.2 µg/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 66.91 ±18.23 L [after intravenous administration of 40 mg in healthy volunteers] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): >97% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Levobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine or feces. In vitro studies using [14 C] levobupivacaine showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. In vivo, the 3-hydroxy levobupivacaine appears to undergo further transformation to glucuronide and sulfate conjugates. Metabolic inversion of levobupivacaine to R(+)-bupivacaine was not evident both in vitro and in vivo. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following intravenous administration, recovery of the radiolabelled dose of levobupivacaine was essentially quantitative with a mean total of about 95% being recovered in urine and feces in 48 hours. Of this 95%, about 71% was in urine while 24% was in feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 3.3 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): 39.06 ±13.29 L/h [after intravenous administration of 40 mg in healthy volunteers] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD50: 5.1mg/kg in rabbit, intravenous; 18mg/kg in rabbit, oral; 207mg/kg in rabbit, parenteral; 63mg/kg in rat, subcutaneous (Archives Internationales de Pharmacodynamie et de Therapie. Vol. 200, Pg. 359, 1972.) Levobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine, despite being in higher concentrations. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-bupivacaine Levobupivacaína Levobupivacaine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Levobupivacaine is a drug used for nerve block and anesthesia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Levonorgestrel interact?

•Drug A: Abatacept •Drug B: Levonorgestrel •Severity: MODERATE •Description: The metabolism of Levonorgestrel can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Emergency contraception Levonorgestrel, in the single-agent emergency contraceptive form, is indicated for the prevention of pregnancy after the confirmed or suspected failure of contraception methods or following unprotected intercourse. It is distributed by prescription for patients under 17, and over the counter for those above this age. This levonorgestrel-only form of contraception is not indicated for regular contraception and must be taken as soon as possible within 72 hours after intercourse. It has shown a lower efficacy when it is used off label within 96 hours. Long-term contraception or nonemergency contraception In addition to the above indication in emergency contraception, levonorgestrel is combined with other contraceptives in contraceptive formulations designed for regular use, for example with ethinyl estradiol. It is used in various hormone-releasing intrauterine devices for long-term contraception ranging for a duration of 3-5 years. Product labeling for Mirena specifically mentions that it is recommended in women who have had at least 1 child and can be indicated for the prevention of pregnancy for up to 8 years. A subdermal implant is also available for the prevention of pregnancy for up to 5 years. Hormone therapy and off-label uses Levonorgestrel is prescribed in combination with estradiol as hormone therapy during menopause to manage vasomotor symptoms and to prevent osteoporosis. Off-label, levonorgestrel may be used to treat menorrhagia, endometrial hyperplasia, and endometriosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Levonorgestrel prevents pregnancy by interfering with ovulation, fertilization, and implantation. The levonorgestrel-only containing emergency contraceptive tablet is 89% effective if it is used according to prescribing information within 72 hours after intercourse. The intrauterine and implantable devices releasing levonorgestrel are more than 99% in preventing pregnancy. Levonorgestrel utilized as a component of hormonal therapy helps to prevent endometrial carcinoma associated with unopposed estrogen administration. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Mechanism of action on ovulation Oral contraceptives containing levonorgestrel suppress gonadotropins, inhibiting ovulation. Specifically, levonorgestrel binds to progesterone and androgen receptors and slows the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. This process results in the suppression of the normal physiological luteinizing hormone (LH) surge that precedes ovulation. It inhibits the rupture of follicles and viable egg release from the ovaries. Levonorgestrel has been proven to be more effective when administered before ovulation. Mechanism of action in cervical mucus changes Similar to other levonorgestrel-containing contraceptives, the intrauterine (IUD) forms of levonorgestrel likely prevent pregnancy by increasing the thickness of cervical mucus, interfering with the movement and survival of sperm, and inducing changes in the endometrium, where a fertilized ovum is usually implanted. Levonorgestrel is reported to alter the consistency of mucus in the cervix, which interferes with sperm migration into the uterus for fertilization. Levonorgestrel is not effective after implantation has occurred. Interestingly, recent evidence has refuted the commonly believed notion that levonorgestrel changes the consistency of cervical mucus when it is taken over a short-term period, as in emergency contraception. Over a long-term period, however, levonorgestrel has been proven to thicken cervical mucus. The exact mechanism of action of levonorgestrel is not completely understood and remains a topic of controversy and ongoing investigation. Effects on implantation * The effects of levonorgestrel on endometrial receptivity are unclear, and the relevance of this mechanism to the therapeutic efficacy of levonorgestrel is contentious. Prescribing information for levonorgestrel IUDs state that they exert local morphological changes to the endometrium (e.g. stromal pseudodecidualization, glandular atrophy) that may play a role in their contraceptive activity. Mechanism of action in hormone therapy When combined with estrogens for the treatment of menopausal symptoms and prevention of osteoporosis, levonorgestrel serves to lower the carcinogenic risk of unopposed estrogen therapy via the inhibition of endometrial proliferation. Unregulated endometrial proliferation sometimes leads to endometrial cancer after estrogen use. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Orally administered levonorgestrel is absorbed in the gastrointestinal tract while levonorgestrel administered through an IUD device is absorbed in the endometrium. Levonorgestrel is absorbed immediately in the interstitial fluids when it is inserted as a subdermal implant. After insertion of the subdermal implant, the Cmax of levonorgestrel is attained within 2-3 days. The Cmax following one dose of 0.75 mg of oral levonorgestrel is reached within the hour after administration, according to one reference. In a pharmacokinetic study of 1.5 mg of levonorgestrel in women with a normal BMI and those considered to be obese (BMI>30), mean Cmax was found to be 16.2 ng/mL and 10.5 ng/mL respectively. Tmax was found to be 2 hours for those with normal BMI and 2.5 hours for patients with increased BMI. The bioavailability of levonorgestrel approaches 100%. Mean AUC has been shown to be higher in patients with a normal BMI, measuring at 360.1 h × ng/mL versus a range of 197.28 to 208.1 h × ng/mL in an obese group of patients. Obesity may contribute to decreased efficacy of levonorgestrel in contraception. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): One pharmacokinetic study determined a mean steady-state volume of distribution of 1.5 mg of levonorgestrel to be 162.2 L in those with normal BMI and in the range of 404.7 L to 466.4 L in obese patients with a body mass index of at least 30. Mean volume of distribution in 16 patients receiving 0.75 mg of levonorgestrel in another pharmacokinetic study was 260 L. The Plan B one-step FDA label reports an apparent volume of distribution of 1.8 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of levonorgestrel ranges from 97.5-99%, and it is mainly bound to sex hormone-binding globulin (SHBG). Levonorgestrel is also bound to albumin. The prescribing information for the implanted levonorgestrel indicates that the concentration of sex hormone-binding globulin (SHBG) is reduced in the span of a few days after levonorgestrel administration, decreasing the levels of the drug. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): After absorption of the oral emergency contraceptive preparation, levonorgestrel is conjugated and forms a large number of sulfate conjugates. In addition, glucuronide conjugates have been identified in the plasma. High levels of conjugated and unconjugated 3α, 5β-tetrahydrolevonorgestrel are found in the plasma. The entire metabolic pathway for levonorgestrel has not been studied, however, 16β-hydroxylation is one pathway that has been identified. Small quantities of 3α, 5α­ tetrahydrolevonorgestrel and 16βhydroxylevonorgestrel are also formed. No active metabolites have been identified. The rate of metabolism may be considerably different according to the patient and may explain a wide variation in levonorgestrel clearance. Liver CYP3A4 and CYP3A5 hepatic enzymes are reported to be involved in the metabolism of levonorgestrel. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 45% of an oral levonorgestrel dose and its conjugated or sulfate metabolites are found to be excreted in the urine. Approximately 32% of an orally ingested dose is found excreted in feces, primarily in the form of glucuronide conjugates of levonorgestrel. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of a 0.75 mg dose of 1.5 mg of levonorgestrel ranges between 20-60 hours post-administration. A pharmacokinetic study of women with a normal BMI and BMI over revealed an elimination half-life of 29.7 h and 41.0-46.4 hours, respectively. Another pharmacokinetic study revealed a mean elimination half-life of 24.4 hours after a 0.75 mg dose of levonorgestrel was administered to 16 patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Clearance was found to 4.8 L/h in healthy female volunteers with a normal BMI, and 7.70-8.51 L/h in obese patients after a single 1.5 mg dose. After a 0.75 mg dose of levonorgestrel in 16 patients in another pharmacokinetic study, mean clearance was calculated at 7.06 L/h. Following levonorgestrel implant removal, the serum concentration falls below 100 pg/mL within the first 96 hours and further falls below the sensitivity of detection within the range of 5 days to 2 weeks. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD50 in rats is greater than 5000 mg/kg. An overdose of this drug, like other contraceptives, may cause nausea and withdrawal bleeding. Provide symptomatic treatment in the case of a levonorgestrel overdose and contact the local poison control center. There is no specific antidote for a levonorgestrel overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Afirmelle 28 Day, Aftera, Alesse, Altavera 28 Day, Amethia 91 Day, Amethyst, Ashlyna 91 Day, Aubra 28 Day, Aviane 28, Ayuna 28 Day Pack, Balcoltra 28 Day, Bionafem, Camrese 91 Day, Camreselo 91 Day, Chateal 28 Day, Climara Pro, Curae, Daysee 91 Day, Delyla 28 Day, Dolishale 28 Day, Econtra, Enpresse 28 Day, Fallback Solo, Falmina 28 Day, Fayosim 91 Day, Her Style, Iclevia 91 Day, Indayo, Introvale 91 Day, Jaimiess 91 Day, Jolessa 91 Day, Joyeaux 28 Day, Kurvelo, Kyleena, Levonest 28 Day, Levora 0.15/30 28 Day, Liletta, Lo Simpesse, LoJaimiess, Loseasonique, Lutera 28 Day, Marlissa 28 Day, Min-ovral, Mirena, Morning After, My Choice, My Way, Myzilra 28 Day, New Day, Next Choice, Next Choice One Dose, Opcicon One-step, Option 2, Orsythia 28 Day, Plan B, Plan B One-step, Portia 28 Day, Preventeza, Quartette 91 Day Pack, React, Rivelsa 91 Day, Seasonale, Seasonique, Setlakin 91 Day, Simpesse, Skyla, Sronyx 28 Day, Take Action, Triquilar, Trivora 28 Day, Twirla 3 Count Weekly Patch, Tyblume 28 Day, Vienva 28 Day •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 18-Methylnorethisterone Levonorgestrel Lèvonorgestrel Levonorgestrelum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Levonorgestrel is a progestin found in oral and IUD contraceptives and at higher doses in emergency contraceptives.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Levonorgestrel interact? Information: •Drug A: Abatacept •Drug B: Levonorgestrel •Severity: MODERATE •Description: The metabolism of Levonorgestrel can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Emergency contraception Levonorgestrel, in the single-agent emergency contraceptive form, is indicated for the prevention of pregnancy after the confirmed or suspected failure of contraception methods or following unprotected intercourse. It is distributed by prescription for patients under 17, and over the counter for those above this age. This levonorgestrel-only form of contraception is not indicated for regular contraception and must be taken as soon as possible within 72 hours after intercourse. It has shown a lower efficacy when it is used off label within 96 hours. Long-term contraception or nonemergency contraception In addition to the above indication in emergency contraception, levonorgestrel is combined with other contraceptives in contraceptive formulations designed for regular use, for example with ethinyl estradiol. It is used in various hormone-releasing intrauterine devices for long-term contraception ranging for a duration of 3-5 years. Product labeling for Mirena specifically mentions that it is recommended in women who have had at least 1 child and can be indicated for the prevention of pregnancy for up to 8 years. A subdermal implant is also available for the prevention of pregnancy for up to 5 years. Hormone therapy and off-label uses Levonorgestrel is prescribed in combination with estradiol as hormone therapy during menopause to manage vasomotor symptoms and to prevent osteoporosis. Off-label, levonorgestrel may be used to treat menorrhagia, endometrial hyperplasia, and endometriosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Levonorgestrel prevents pregnancy by interfering with ovulation, fertilization, and implantation. The levonorgestrel-only containing emergency contraceptive tablet is 89% effective if it is used according to prescribing information within 72 hours after intercourse. The intrauterine and implantable devices releasing levonorgestrel are more than 99% in preventing pregnancy. Levonorgestrel utilized as a component of hormonal therapy helps to prevent endometrial carcinoma associated with unopposed estrogen administration. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Mechanism of action on ovulation Oral contraceptives containing levonorgestrel suppress gonadotropins, inhibiting ovulation. Specifically, levonorgestrel binds to progesterone and androgen receptors and slows the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. This process results in the suppression of the normal physiological luteinizing hormone (LH) surge that precedes ovulation. It inhibits the rupture of follicles and viable egg release from the ovaries. Levonorgestrel has been proven to be more effective when administered before ovulation. Mechanism of action in cervical mucus changes Similar to other levonorgestrel-containing contraceptives, the intrauterine (IUD) forms of levonorgestrel likely prevent pregnancy by increasing the thickness of cervical mucus, interfering with the movement and survival of sperm, and inducing changes in the endometrium, where a fertilized ovum is usually implanted. Levonorgestrel is reported to alter the consistency of mucus in the cervix, which interferes with sperm migration into the uterus for fertilization. Levonorgestrel is not effective after implantation has occurred. Interestingly, recent evidence has refuted the commonly believed notion that levonorgestrel changes the consistency of cervical mucus when it is taken over a short-term period, as in emergency contraception. Over a long-term period, however, levonorgestrel has been proven to thicken cervical mucus. The exact mechanism of action of levonorgestrel is not completely understood and remains a topic of controversy and ongoing investigation. Effects on implantation * The effects of levonorgestrel on endometrial receptivity are unclear, and the relevance of this mechanism to the therapeutic efficacy of levonorgestrel is contentious. Prescribing information for levonorgestrel IUDs state that they exert local morphological changes to the endometrium (e.g. stromal pseudodecidualization, glandular atrophy) that may play a role in their contraceptive activity. Mechanism of action in hormone therapy When combined with estrogens for the treatment of menopausal symptoms and prevention of osteoporosis, levonorgestrel serves to lower the carcinogenic risk of unopposed estrogen therapy via the inhibition of endometrial proliferation. Unregulated endometrial proliferation sometimes leads to endometrial cancer after estrogen use. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Orally administered levonorgestrel is absorbed in the gastrointestinal tract while levonorgestrel administered through an IUD device is absorbed in the endometrium. Levonorgestrel is absorbed immediately in the interstitial fluids when it is inserted as a subdermal implant. After insertion of the subdermal implant, the Cmax of levonorgestrel is attained within 2-3 days. The Cmax following one dose of 0.75 mg of oral levonorgestrel is reached within the hour after administration, according to one reference. In a pharmacokinetic study of 1.5 mg of levonorgestrel in women with a normal BMI and those considered to be obese (BMI>30), mean Cmax was found to be 16.2 ng/mL and 10.5 ng/mL respectively. Tmax was found to be 2 hours for those with normal BMI and 2.5 hours for patients with increased BMI. The bioavailability of levonorgestrel approaches 100%. Mean AUC has been shown to be higher in patients with a normal BMI, measuring at 360.1 h × ng/mL versus a range of 197.28 to 208.1 h × ng/mL in an obese group of patients. Obesity may contribute to decreased efficacy of levonorgestrel in contraception. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): One pharmacokinetic study determined a mean steady-state volume of distribution of 1.5 mg of levonorgestrel to be 162.2 L in those with normal BMI and in the range of 404.7 L to 466.4 L in obese patients with a body mass index of at least 30. Mean volume of distribution in 16 patients receiving 0.75 mg of levonorgestrel in another pharmacokinetic study was 260 L. The Plan B one-step FDA label reports an apparent volume of distribution of 1.8 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of levonorgestrel ranges from 97.5-99%, and it is mainly bound to sex hormone-binding globulin (SHBG). Levonorgestrel is also bound to albumin. The prescribing information for the implanted levonorgestrel indicates that the concentration of sex hormone-binding globulin (SHBG) is reduced in the span of a few days after levonorgestrel administration, decreasing the levels of the drug. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): After absorption of the oral emergency contraceptive preparation, levonorgestrel is conjugated and forms a large number of sulfate conjugates. In addition, glucuronide conjugates have been identified in the plasma. High levels of conjugated and unconjugated 3α, 5β-tetrahydrolevonorgestrel are found in the plasma. The entire metabolic pathway for levonorgestrel has not been studied, however, 16β-hydroxylation is one pathway that has been identified. Small quantities of 3α, 5α­ tetrahydrolevonorgestrel and 16βhydroxylevonorgestrel are also formed. No active metabolites have been identified. The rate of metabolism may be considerably different according to the patient and may explain a wide variation in levonorgestrel clearance. Liver CYP3A4 and CYP3A5 hepatic enzymes are reported to be involved in the metabolism of levonorgestrel. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 45% of an oral levonorgestrel dose and its conjugated or sulfate metabolites are found to be excreted in the urine. Approximately 32% of an orally ingested dose is found excreted in feces, primarily in the form of glucuronide conjugates of levonorgestrel. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of a 0.75 mg dose of 1.5 mg of levonorgestrel ranges between 20-60 hours post-administration. A pharmacokinetic study of women with a normal BMI and BMI over revealed an elimination half-life of 29.7 h and 41.0-46.4 hours, respectively. Another pharmacokinetic study revealed a mean elimination half-life of 24.4 hours after a 0.75 mg dose of levonorgestrel was administered to 16 patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Clearance was found to 4.8 L/h in healthy female volunteers with a normal BMI, and 7.70-8.51 L/h in obese patients after a single 1.5 mg dose. After a 0.75 mg dose of levonorgestrel in 16 patients in another pharmacokinetic study, mean clearance was calculated at 7.06 L/h. Following levonorgestrel implant removal, the serum concentration falls below 100 pg/mL within the first 96 hours and further falls below the sensitivity of detection within the range of 5 days to 2 weeks. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD50 in rats is greater than 5000 mg/kg. An overdose of this drug, like other contraceptives, may cause nausea and withdrawal bleeding. Provide symptomatic treatment in the case of a levonorgestrel overdose and contact the local poison control center. There is no specific antidote for a levonorgestrel overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Afirmelle 28 Day, Aftera, Alesse, Altavera 28 Day, Amethia 91 Day, Amethyst, Ashlyna 91 Day, Aubra 28 Day, Aviane 28, Ayuna 28 Day Pack, Balcoltra 28 Day, Bionafem, Camrese 91 Day, Camreselo 91 Day, Chateal 28 Day, Climara Pro, Curae, Daysee 91 Day, Delyla 28 Day, Dolishale 28 Day, Econtra, Enpresse 28 Day, Fallback Solo, Falmina 28 Day, Fayosim 91 Day, Her Style, Iclevia 91 Day, Indayo, Introvale 91 Day, Jaimiess 91 Day, Jolessa 91 Day, Joyeaux 28 Day, Kurvelo, Kyleena, Levonest 28 Day, Levora 0.15/30 28 Day, Liletta, Lo Simpesse, LoJaimiess, Loseasonique, Lutera 28 Day, Marlissa 28 Day, Min-ovral, Mirena, Morning After, My Choice, My Way, Myzilra 28 Day, New Day, Next Choice, Next Choice One Dose, Opcicon One-step, Option 2, Orsythia 28 Day, Plan B, Plan B One-step, Portia 28 Day, Preventeza, Quartette 91 Day Pack, React, Rivelsa 91 Day, Seasonale, Seasonique, Setlakin 91 Day, Simpesse, Skyla, Sronyx 28 Day, Take Action, Triquilar, Trivora 28 Day, Twirla 3 Count Weekly Patch, Tyblume 28 Day, Vienva 28 Day •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 18-Methylnorethisterone Levonorgestrel Lèvonorgestrel Levonorgestrelum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Levonorgestrel is a progestin found in oral and IUD contraceptives and at higher doses in emergency contraceptives. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Lidocaine interact?

•Drug A: Abatacept •Drug B: Lidocaine •Severity: MODERATE •Description: The metabolism of Lidocaine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Lidocaine is an anesthetic of the amide group indicated for production of local or regional anesthesia by infiltration techniques such as percutaneous injection and intravenous regional anesthesia by peripheral nerve block techniques such as brachial plexus and intercostal and by central neural techniques such as lumbar and caudal epidural blocks. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Excessive blood levels of lidocaine can cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to the block of autonomic fibers, a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system, and/or the beta-adrenergic receptor stimulating action of epinephrine when present. The net effect is normally a modest hypotension when the recommended dosages are not exceeded. In particular, such cardiac effects are likely associated with the principal effect that lidocaine elicits when it binds and blocks sodium channels, inhibiting the ionic fluxes required for the initiation and conduction of electrical action potential impulses necessary to facilitate muscle contraction. Subsequently, in cardiac myocytes, lidocaine can potentially block or otherwise slow the rise of cardiac action potentials and their associated cardiac myocyte contractions, resulting in possible effects like hypotension, bradycardia, myocardial depression, cardiac arrhythmias, and perhaps cardiac arrest or circulatory collapse. Moreover, lidocaine possesses a dissociation constant (pKa) of 7.7 and is considered a weak base. As a result, about 25% of lidocaine molecules will be un-ionized and available at the physiological pH of 7.4 to translocate inside nerve cells, which means lidocaine elicits an onset of action more rapidly than other local anesthetics that have higher pKa values. This rapid onset of action is demonstrated in about one minute following intravenous injection and fifteen minutes following intramuscular injection. The administered lidocaine subsequently spreads rapidly through the surrounding tissues and the anesthetic effect lasts approximately ten to twenty minutes when given intravenously and about sixty to ninety minutes after intramuscular injection. Nevertheless, it appears that the efficacy of lidocaine may be minimized in the presence of inflammation. This effect could be due to acidosis decreasing the amount of un-ionized lidocaine molecules, a more rapid reduction in lidocaine concentration as a result of increased blood flow, or potentially also because of increased production of inflammatory mediators like peroxynitrite that elicit direct actions on sodium channels. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Lidocaine is a local anesthetic of the amide type. It is used to provide local anesthesia by nerve blockade at various sites in the body. It does so by stabilizing the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. In particular, the lidocaine agent acts on sodium ion channels located on the internal surface of nerve cell membranes. At these channels, neutral uncharged lidocaine molecules diffuse through neural sheaths into the axoplasm where they are subsequently ionized by joining with hydrogen ions. The resultant lidocaine cations are then capable of reversibly binding the sodium channels from the inside, keeping them locked in an open state that prevents nerve depolarization. As a result, with sufficient blockage, the membrane of the postsynaptic neuron will ultimately not depolarize and will thus fail to transmit an action potential. This facilitates an anesthetic effect by not merely preventing pain signals from propagating to the brain but by aborting their generation in the first place. In addition to blocking conduction in nerve axons in the peripheral nervous system, lidocaine has important effects on the central nervous system and cardiovascular system. After absorption, lidocaine may cause stimulation of the CNS followed by depression and in the cardiovascular system, it acts primarily on the myocardium where it may produce decreases in electrical excitability, conduction rate, and force of contraction. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In general, lidocaine is readily absorbed across mucous membranes and damaged skin but poorly through intact skin. The agent is quickly absorbed from the upper airway, tracheobronchial tree, and alveoli into the bloodstream. And although lidocaine is also well absorbed across the gastrointestinal tract the oral bioavailability is only about 35% as a result of a high degree of first-pass metabolism. After injection into tissues, lidocaine is also rapidly absorbed and the absorption rate is affected by both vascularity and the presence of tissue and fat capable of binding lidocaine in the particular tissues. The concentration of lidocaine in the blood is subsequently affected by a variety of aspects, including its rate of absorption from the site of injection, the rate of tissue distribution, and the rate of metabolism and excretion. Subsequently, the systemic absorption of lidocaine is determined by the site of injection, the dosage given, and its pharmacological profile. The maximum blood concentration occurs following intercostal nerve blockade followed in order of decreasing concentration, the lumbar epidural space, brachial plexus site, and subcutaneous tissue. The total dose injected regardless of the site is the primary determinant of the absorption rate and blood levels achieved. There is a linear relationship between the amount of lidocaine injected and the resultant peak anesthetic blood levels. Nevertheless, it has been observed that lidocaine hydrochloride is completely absorbed following parenteral administration, its rate of absorption depending also on lipid solubility and the presence or absence of a vasoconstrictor agent. Except for intravascular administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration. Additionally, lidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution determined for lidocaine is 0.7 to 1.5 L/kg. In particular, lidocaine is distributed throughout the total body water. Its rate of disappearance from the blood can be described by a two or possibly even three-compartment model. There is a rapid disappearance (alpha phase) which is believed to be related to uptake by rapidly equilibrating tissues (tissues with high vascular perfusion, for example). The slower phase is related to distribution to slowly equilibrating tissues (beta phase) and to its metabolism and excretion (gamma phase). Lidocaine's distribution is ultimately throughout all body tissues. In general, the more highly perfused organs will show higher concentrations of the agent. The highest percentage of this drug will be found in skeletal muscle, mainly due to the mass of muscle rather than an affinity. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding recorded for lidocaine is about 60 to 80% and is dependent upon the plasma concentration of alpha-1-acid glycoprotein. Such percentage protein binding bestows lidocaine with a medium duration of action when placed in comparison to other local anesthetic agents. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Lidocaine is metabolized predominantly and rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The pharmacological/toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine HCl. Approximately 90% of lidocaine HCl administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The excretion of unchanged lidocaine and its metabolites occurs predominantly via the kidney with less than 5% in the unchanged form appearing in the urine. The renal clearance is inversely related to its protein binding affinity and the pH of the urine. This suggests by the latter that excretion of lidocaine occurs by non-ionic diffusion. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of lidocaine hydrochloride following an intravenous bolus injection is typically 1.5 to 2.0 hours. Because of the rapid rate at which lidocaine hydrochloride is metabolized, any condition that affects liver function may alter lidocaine HCl kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean systemic clearance observed for intravenously administered lidocaine in a study of 15 adults was approximately 0.64 +/- 0.18 L/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose and/or acute systemic toxicity involves central nervous system toxicity that presents with symptoms of increasing severity. Patients may present initially with circumoral paraesthesia, numbness of the tongue, light-headedness, hyperacusis, and tinnitus. Visual disturbance and muscular tremors or muscle twitching are more serious and precede the onset of generalized convulsions. These signs must not be mistaken for neurotic behavior. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercapnia occur rapidly following convulsions due to increased muscular activity, together with the interference with normal respiration and loss of the airway. In severe cases, apnoea may occur. Acidosis increases the toxic effects of local anesthetics. Effects on the cardiovascular system may be seen in severe cases. Hypotension, bradycardia, arrhythmia and cardiac arrest may occur as a result of high systemic concentrations, with potentially fatal outcome. Pregnancy Category B has been established for the use of lidocaine in pregnancy, although there are no formal, adequate, and well-controlled studies in pregnant women. General consideration should be given to this fact before administering lidocaine to women of childbearing potential, especially during early pregnancy when maximum organogenesis takes place. Ultimately, although animal studies have revealed no evidence of harm to the fetus, lidocaine should not be administered during early pregnancy unless the benefits are considered to outweigh the risks. Lidocaine readily crosses the placental barrier after epidural or intravenous administration to the mother. The ratio of umbilical to maternal venous concentration is 0.5 to 0.6. The fetus appears to be capable of metabolizing lidocaine at term. The elimination half-life in the newborn of the drug received in utero is about three hours, compared with 100 minutes in the adult. Elevated lidocaine levels may persist in the newborn for at least 48 hours after delivery. Fetal bradycardia or tachycardia, neonatal bradycardia, hypotonia or respiratory depression may occur. Local anesthetics rapidly cross the placenta and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity. The potential for toxicity depends upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural, spinal, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. However, spinal and epidural anesthesia have also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown. Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical nerve block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. The physician should weigh the possible advantages against risks when considering a paracervical block in prematurity, toxemia of pregnancy, and fetal distress. Careful adherence to the recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and often manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when lidocaine is administered to a nursing woman. Dosages in children should be reduced, commensurate with age, body weight and physical condition. The oral LD 50 of lidocaine HCl in non-fasted female rats is 459 (346-773) mg/kg (as the salt) and 214 (159-324) mg/kg (as the salt) in fasted female rats. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Agoneaze, Akten, Alivio, Anestacon, Anodyne Lpt, Astero, Cathejell, Curacaine, Depo-medrol With Lidocaine, Dermacinrx Lido V Pak, Dermacinrx Phn Pak, Dermacinrx Prikaan, Diphen, Emla, Fortacin, Glydo, Instillagel, Kenalog, Lido Bdk, Lido-prilo Caine Pack, Lidocan, Lidodan, Lidoderm, Lidopac, Lidopril, Lidopro, Lidosol, Lidothol, Lidotral, Lignospan, Marcaine, Max-freeze, Medi-derm With Lidocaine, Neo-bex, Octocaine, Octocaine With Epinephrine, Oraqix, P-care, P-care X, Pliaglis, Prilolid, Prizotral, Procomycin, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Relador, Synera, Triple Antibiotic, Venipuncture Px1, Viadur, Xylocaine, Xylocaine With Epinephrine, Xylocard, Xylonor, Zingo, Ztlido •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lidocaína Lidocaina Lidocaine Lidocainum Lignocaine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lidocaine is a local anesthetic used in a wide variety of superficial and invasive procedures.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Lidocaine interact? Information: •Drug A: Abatacept •Drug B: Lidocaine •Severity: MODERATE •Description: The metabolism of Lidocaine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Lidocaine is an anesthetic of the amide group indicated for production of local or regional anesthesia by infiltration techniques such as percutaneous injection and intravenous regional anesthesia by peripheral nerve block techniques such as brachial plexus and intercostal and by central neural techniques such as lumbar and caudal epidural blocks. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Excessive blood levels of lidocaine can cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to the block of autonomic fibers, a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system, and/or the beta-adrenergic receptor stimulating action of epinephrine when present. The net effect is normally a modest hypotension when the recommended dosages are not exceeded. In particular, such cardiac effects are likely associated with the principal effect that lidocaine elicits when it binds and blocks sodium channels, inhibiting the ionic fluxes required for the initiation and conduction of electrical action potential impulses necessary to facilitate muscle contraction. Subsequently, in cardiac myocytes, lidocaine can potentially block or otherwise slow the rise of cardiac action potentials and their associated cardiac myocyte contractions, resulting in possible effects like hypotension, bradycardia, myocardial depression, cardiac arrhythmias, and perhaps cardiac arrest or circulatory collapse. Moreover, lidocaine possesses a dissociation constant (pKa) of 7.7 and is considered a weak base. As a result, about 25% of lidocaine molecules will be un-ionized and available at the physiological pH of 7.4 to translocate inside nerve cells, which means lidocaine elicits an onset of action more rapidly than other local anesthetics that have higher pKa values. This rapid onset of action is demonstrated in about one minute following intravenous injection and fifteen minutes following intramuscular injection. The administered lidocaine subsequently spreads rapidly through the surrounding tissues and the anesthetic effect lasts approximately ten to twenty minutes when given intravenously and about sixty to ninety minutes after intramuscular injection. Nevertheless, it appears that the efficacy of lidocaine may be minimized in the presence of inflammation. This effect could be due to acidosis decreasing the amount of un-ionized lidocaine molecules, a more rapid reduction in lidocaine concentration as a result of increased blood flow, or potentially also because of increased production of inflammatory mediators like peroxynitrite that elicit direct actions on sodium channels. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Lidocaine is a local anesthetic of the amide type. It is used to provide local anesthesia by nerve blockade at various sites in the body. It does so by stabilizing the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. In particular, the lidocaine agent acts on sodium ion channels located on the internal surface of nerve cell membranes. At these channels, neutral uncharged lidocaine molecules diffuse through neural sheaths into the axoplasm where they are subsequently ionized by joining with hydrogen ions. The resultant lidocaine cations are then capable of reversibly binding the sodium channels from the inside, keeping them locked in an open state that prevents nerve depolarization. As a result, with sufficient blockage, the membrane of the postsynaptic neuron will ultimately not depolarize and will thus fail to transmit an action potential. This facilitates an anesthetic effect by not merely preventing pain signals from propagating to the brain but by aborting their generation in the first place. In addition to blocking conduction in nerve axons in the peripheral nervous system, lidocaine has important effects on the central nervous system and cardiovascular system. After absorption, lidocaine may cause stimulation of the CNS followed by depression and in the cardiovascular system, it acts primarily on the myocardium where it may produce decreases in electrical excitability, conduction rate, and force of contraction. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): In general, lidocaine is readily absorbed across mucous membranes and damaged skin but poorly through intact skin. The agent is quickly absorbed from the upper airway, tracheobronchial tree, and alveoli into the bloodstream. And although lidocaine is also well absorbed across the gastrointestinal tract the oral bioavailability is only about 35% as a result of a high degree of first-pass metabolism. After injection into tissues, lidocaine is also rapidly absorbed and the absorption rate is affected by both vascularity and the presence of tissue and fat capable of binding lidocaine in the particular tissues. The concentration of lidocaine in the blood is subsequently affected by a variety of aspects, including its rate of absorption from the site of injection, the rate of tissue distribution, and the rate of metabolism and excretion. Subsequently, the systemic absorption of lidocaine is determined by the site of injection, the dosage given, and its pharmacological profile. The maximum blood concentration occurs following intercostal nerve blockade followed in order of decreasing concentration, the lumbar epidural space, brachial plexus site, and subcutaneous tissue. The total dose injected regardless of the site is the primary determinant of the absorption rate and blood levels achieved. There is a linear relationship between the amount of lidocaine injected and the resultant peak anesthetic blood levels. Nevertheless, it has been observed that lidocaine hydrochloride is completely absorbed following parenteral administration, its rate of absorption depending also on lipid solubility and the presence or absence of a vasoconstrictor agent. Except for intravascular administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration. Additionally, lidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution determined for lidocaine is 0.7 to 1.5 L/kg. In particular, lidocaine is distributed throughout the total body water. Its rate of disappearance from the blood can be described by a two or possibly even three-compartment model. There is a rapid disappearance (alpha phase) which is believed to be related to uptake by rapidly equilibrating tissues (tissues with high vascular perfusion, for example). The slower phase is related to distribution to slowly equilibrating tissues (beta phase) and to its metabolism and excretion (gamma phase). Lidocaine's distribution is ultimately throughout all body tissues. In general, the more highly perfused organs will show higher concentrations of the agent. The highest percentage of this drug will be found in skeletal muscle, mainly due to the mass of muscle rather than an affinity. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding recorded for lidocaine is about 60 to 80% and is dependent upon the plasma concentration of alpha-1-acid glycoprotein. Such percentage protein binding bestows lidocaine with a medium duration of action when placed in comparison to other local anesthetic agents. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Lidocaine is metabolized predominantly and rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The pharmacological/toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine HCl. Approximately 90% of lidocaine HCl administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The excretion of unchanged lidocaine and its metabolites occurs predominantly via the kidney with less than 5% in the unchanged form appearing in the urine. The renal clearance is inversely related to its protein binding affinity and the pH of the urine. This suggests by the latter that excretion of lidocaine occurs by non-ionic diffusion. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life of lidocaine hydrochloride following an intravenous bolus injection is typically 1.5 to 2.0 hours. Because of the rapid rate at which lidocaine hydrochloride is metabolized, any condition that affects liver function may alter lidocaine HCl kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): The mean systemic clearance observed for intravenously administered lidocaine in a study of 15 adults was approximately 0.64 +/- 0.18 L/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overdose and/or acute systemic toxicity involves central nervous system toxicity that presents with symptoms of increasing severity. Patients may present initially with circumoral paraesthesia, numbness of the tongue, light-headedness, hyperacusis, and tinnitus. Visual disturbance and muscular tremors or muscle twitching are more serious and precede the onset of generalized convulsions. These signs must not be mistaken for neurotic behavior. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercapnia occur rapidly following convulsions due to increased muscular activity, together with the interference with normal respiration and loss of the airway. In severe cases, apnoea may occur. Acidosis increases the toxic effects of local anesthetics. Effects on the cardiovascular system may be seen in severe cases. Hypotension, bradycardia, arrhythmia and cardiac arrest may occur as a result of high systemic concentrations, with potentially fatal outcome. Pregnancy Category B has been established for the use of lidocaine in pregnancy, although there are no formal, adequate, and well-controlled studies in pregnant women. General consideration should be given to this fact before administering lidocaine to women of childbearing potential, especially during early pregnancy when maximum organogenesis takes place. Ultimately, although animal studies have revealed no evidence of harm to the fetus, lidocaine should not be administered during early pregnancy unless the benefits are considered to outweigh the risks. Lidocaine readily crosses the placental barrier after epidural or intravenous administration to the mother. The ratio of umbilical to maternal venous concentration is 0.5 to 0.6. The fetus appears to be capable of metabolizing lidocaine at term. The elimination half-life in the newborn of the drug received in utero is about three hours, compared with 100 minutes in the adult. Elevated lidocaine levels may persist in the newborn for at least 48 hours after delivery. Fetal bradycardia or tachycardia, neonatal bradycardia, hypotonia or respiratory depression may occur. Local anesthetics rapidly cross the placenta and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity. The potential for toxicity depends upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural, spinal, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. However, spinal and epidural anesthesia have also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown. Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical nerve block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. The physician should weigh the possible advantages against risks when considering a paracervical block in prematurity, toxemia of pregnancy, and fetal distress. Careful adherence to the recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and often manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when lidocaine is administered to a nursing woman. Dosages in children should be reduced, commensurate with age, body weight and physical condition. The oral LD 50 of lidocaine HCl in non-fasted female rats is 459 (346-773) mg/kg (as the salt) and 214 (159-324) mg/kg (as the salt) in fasted female rats. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Agoneaze, Akten, Alivio, Anestacon, Anodyne Lpt, Astero, Cathejell, Curacaine, Depo-medrol With Lidocaine, Dermacinrx Lido V Pak, Dermacinrx Phn Pak, Dermacinrx Prikaan, Diphen, Emla, Fortacin, Glydo, Instillagel, Kenalog, Lido Bdk, Lido-prilo Caine Pack, Lidocan, Lidodan, Lidoderm, Lidopac, Lidopril, Lidopro, Lidosol, Lidothol, Lidotral, Lignospan, Marcaine, Max-freeze, Medi-derm With Lidocaine, Neo-bex, Octocaine, Octocaine With Epinephrine, Oraqix, P-care, P-care X, Pliaglis, Prilolid, Prizotral, Procomycin, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Relador, Synera, Triple Antibiotic, Venipuncture Px1, Viadur, Xylocaine, Xylocaine With Epinephrine, Xylocard, Xylonor, Zingo, Ztlido •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lidocaína Lidocaina Lidocaine Lidocainum Lignocaine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Lidocaine is a local anesthetic used in a wide variety of superficial and invasive procedures. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Linagliptin interact?

•Drug A: Abatacept •Drug B: Linagliptin •Severity: MODERATE •Description: The metabolism of Linagliptin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Linagliptin is indicated for the treatment of type II diabetes in addition to diet and exercise. It should not be used to treat type I diabetes or in diabetic ketoacidosis. An extended-release combination product containing empagliflozin, linagliptin, and metformin was approved by the FDA in January 2020 for the improvement of glycemic control in adults with type 2 diabetes mellitus when used adjunctively with diet and exercise. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): A 5mg oral dose of linagliptin results in >80% inhibition of dipeptidyl peptidase 4 (DPP-4) for ≥24 hours. Inhibition of DPP-4 increases the concentration of glucagon-like peptide 1 (GLP-1), leading to decreased glycosylated hemoglobin and fasting plasma glucose. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Linagliptin is a competitive, reversible DPP-4 inhibitor. Inhibition of this enzyme slows the breakdown of GLP-1 and glucose-dependant insulinotropic polypeptide (GIP). GLP-1 and GIP stimulate the release of insulin from beta cells in the pancreas while inhibiting release of glucagon from pancreatic beta cells. These effects together reduce the breakdown of glycogen in the liver and increase insulin release in response to glucose. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Oral bioavailability of linagliptin is 30%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): A single intravenous dose of 5mg results in a volume of distribution of 1110L. However an intravenous infusion of 0.5-10mg results in a volume of distribution of 380-1540L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Linagliptin is 99% protein bound at a concentration of 1nmol/L and 75-89% protein bound at a concentration of >30nmol/L. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): An oral dose of linagliptin is excreted primarily in the feces. 90% of an oral dose is excreted unchanged in the urine and feces. The predominant metabolite in the plasma is CD1790 and the predominant metabolite recovered after excretion was M489(1). Other metabolites are produced through oxidation, oxidative degradation, N-acetylation, glucuronidation, and cysteine adduct formation. Other metabolites have been identified through mass spectrometry though no structures were determined. Metabolism of linagliptin is mediated by cytochrome P450 3A4, aldo-keto reductases, and carbonyl reductases. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 84.7% of linagliptin is eliminated in the feces and 5.4% is eliminated in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal half life of linagliptin is 155 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Total clearance of linagliptin is 374mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No dosage adjustment is necessary based on race, age, weight, sex, renal impairment, or hepatic impairment. Studies of efficacy and safety in pediatric populations were not included in the original drug approval but recent clinical trials show linagliptin to be well tolerated in patients 10 to 18 years old. Animal studies showed an increased risk of lymphoma in female rats at over 200 times the clinical dose. Aside from this effect, linagliptin was not shown to be mutagenic, clastogenic, or have an effect on fertility. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Glyxambi, Jentadueto, Tradjenta, Trajenta, Trijardy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Linagliptin Linagliptina •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used to manage hyperglycemia in patients with type 2 diabetes mellitus.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Linagliptin interact? Information: •Drug A: Abatacept •Drug B: Linagliptin •Severity: MODERATE •Description: The metabolism of Linagliptin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Linagliptin is indicated for the treatment of type II diabetes in addition to diet and exercise. It should not be used to treat type I diabetes or in diabetic ketoacidosis. An extended-release combination product containing empagliflozin, linagliptin, and metformin was approved by the FDA in January 2020 for the improvement of glycemic control in adults with type 2 diabetes mellitus when used adjunctively with diet and exercise. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): A 5mg oral dose of linagliptin results in >80% inhibition of dipeptidyl peptidase 4 (DPP-4) for ≥24 hours. Inhibition of DPP-4 increases the concentration of glucagon-like peptide 1 (GLP-1), leading to decreased glycosylated hemoglobin and fasting plasma glucose. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Linagliptin is a competitive, reversible DPP-4 inhibitor. Inhibition of this enzyme slows the breakdown of GLP-1 and glucose-dependant insulinotropic polypeptide (GIP). GLP-1 and GIP stimulate the release of insulin from beta cells in the pancreas while inhibiting release of glucagon from pancreatic beta cells. These effects together reduce the breakdown of glycogen in the liver and increase insulin release in response to glucose. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Oral bioavailability of linagliptin is 30%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): A single intravenous dose of 5mg results in a volume of distribution of 1110L. However an intravenous infusion of 0.5-10mg results in a volume of distribution of 380-1540L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Linagliptin is 99% protein bound at a concentration of 1nmol/L and 75-89% protein bound at a concentration of >30nmol/L. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): An oral dose of linagliptin is excreted primarily in the feces. 90% of an oral dose is excreted unchanged in the urine and feces. The predominant metabolite in the plasma is CD1790 and the predominant metabolite recovered after excretion was M489(1). Other metabolites are produced through oxidation, oxidative degradation, N-acetylation, glucuronidation, and cysteine adduct formation. Other metabolites have been identified through mass spectrometry though no structures were determined. Metabolism of linagliptin is mediated by cytochrome P450 3A4, aldo-keto reductases, and carbonyl reductases. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 84.7% of linagliptin is eliminated in the feces and 5.4% is eliminated in the urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The terminal half life of linagliptin is 155 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Total clearance of linagliptin is 374mL/min. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No dosage adjustment is necessary based on race, age, weight, sex, renal impairment, or hepatic impairment. Studies of efficacy and safety in pediatric populations were not included in the original drug approval but recent clinical trials show linagliptin to be well tolerated in patients 10 to 18 years old. Animal studies showed an increased risk of lymphoma in female rats at over 200 times the clinical dose. Aside from this effect, linagliptin was not shown to be mutagenic, clastogenic, or have an effect on fertility. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Glyxambi, Jentadueto, Tradjenta, Trajenta, Trijardy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Linagliptin Linagliptina •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used to manage hyperglycemia in patients with type 2 diabetes mellitus. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Does Abatacept and Linezolid interact?

•Drug A: Abatacept •Drug B: Linezolid •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Linezolid is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Linezolid is indicated in adults and children for the treatment of infections caused by susceptible Gram-positive bacteria, including nosocomial pneumonia, community-acquired pneumonia, skin and skin structure infections, and vancomycin-resistant Enterococcus faecium infections. Examples of susceptible bacteria include Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae. Linezolid is not indicated for the treatment of Gram-negative infections, nor has it been evaluated for use longer than 28 days. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Linezolid is an oxazolidinone antibacterial agent effective against most strains of aerobic Gram-positive bacteria and mycobacteria. It appears to be bacteriostatic against both staphylococci and enterococci and bactericidal against most isolates of streptococci. Linezolid has shown some in vitro activity against Gram-negative and anaerobic bacteria but is not considered efficacious against these organisms. Linezolid is a reversible and non-selective inhibitor of monoamine oxidase (MAO) enzymes and can therefore contribute to the development of serotonin syndrome when administered alongside serotonergic agents such as selective serotonin re-uptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs). Linezolid should not be used for the treatment of catheter-related bloodstream infections or catheter-site infections, as the risk of therapy appears to outweigh its benefits under these circumstances. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Linezolid exerts its antibacterial effects by interfering with bacterial protein translation. It binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is essential for bacterial reproduction, thereby preventing bacteria from dividing. Point mutations in the bacterial 23S rRNA can lead to linezolid resistance, and the development of linezolid-resistant Enterococcus faecium and Staphylococcus aureus have been documented during its clinical use. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Linezolid is extensively absorbed following oral administration and has an absolute bioavailability of approximately 100%. Maximum plasma concentrations are reached within approximately 1 to 2 hours after dosing (T max ) and range from 8.1-12.9 mcg/mL after single doses and 11.0-21.2 mcg/mL after multiple dosing. The absorption of orally administered linezolid is not significantly affected by co-administration with food and it may therefore be given without regard to the timing of meals. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): At steady-state, the volume of distribution of linezolid in healthy adults is approximately 40-50 liters. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of linezolid is approximately 31% - primarily to serum albumin - and is concentration-dependent. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Linezolid is primarily metabolized to two inactive metabolites: an aminoethoxyacetic acid metabolite (PNU-142300) and a hydroxyethyl glycine metabolite (PNU-142586), both of which are the result of morpholine ring oxidation. The hydroxyethyl glycine metabolite - the most abundant of the two metabolites - is likely generated via non-enzymatic processes, though further detail has not been elucidated. While the specific enzymes responsible for the biotransformation of linezolid are unclear, it does not appear to be subject to metabolism via the CYP450 enzyme system, nor does it meaningfully inhibit or induce these enzymes. Linezolid is, however, a reversible and non-selective inhibitor of monoamine oxidase enzymes. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Urinary excretion is the primary means by which linezolid and its metabolic products are excreted. Following the administration of a radiolabeled dose of linezolid under steady-state conditions, approximately 84% of radioactivity was recovered in the urine, of which approximately 30% is unchanged parent drug, 40% is the hydroxyethyl glycine metabolite, and 10% is the aminoethoxyacetic acid metabolite. Fecal elimination is comparatively minor, with no parent drug observed in feces and only 6% and 3% of an administered dose found in the feces as the hydroxyethyl glycine metabolite and the aminoethoxyacetic acid metabolite, respectively. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life is estimated to be between 5 and 7 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Total clearance of linezolid is estimated to be 100-200 mL/min, the majority of which appears to be non-renal. Mean renal clearance is approximately 40 mL/min, which suggests net tubular reabsorption, while non-renal clearance is estimated to account for roughly 65% of total clearance, or 70-150 mL/min on average. Variability in linezolid clearance is high, particularly for non-renal clearance. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Clinical signs of overdosage observed in rats were decreased activity and ataxia (2000 mg/kg/day) and in dogs were vomiting and tremors (3000 mg/kg/day). Treatment of overdose should involve symptomatic and supportive measures and may include hemodialysis if clinically necessary. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Zyvox, Zyvoxam •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Linezolid Linezolide Linezolidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Linezolid is an oxazolidinone antibiotic used to treat infections by susceptible strains of aerobic Gram-positive bacteria.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Linezolid interact? Information: •Drug A: Abatacept •Drug B: Linezolid •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Linezolid is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Linezolid is indicated in adults and children for the treatment of infections caused by susceptible Gram-positive bacteria, including nosocomial pneumonia, community-acquired pneumonia, skin and skin structure infections, and vancomycin-resistant Enterococcus faecium infections. Examples of susceptible bacteria include Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae. Linezolid is not indicated for the treatment of Gram-negative infections, nor has it been evaluated for use longer than 28 days. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Linezolid is an oxazolidinone antibacterial agent effective against most strains of aerobic Gram-positive bacteria and mycobacteria. It appears to be bacteriostatic against both staphylococci and enterococci and bactericidal against most isolates of streptococci. Linezolid has shown some in vitro activity against Gram-negative and anaerobic bacteria but is not considered efficacious against these organisms. Linezolid is a reversible and non-selective inhibitor of monoamine oxidase (MAO) enzymes and can therefore contribute to the development of serotonin syndrome when administered alongside serotonergic agents such as selective serotonin re-uptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs). Linezolid should not be used for the treatment of catheter-related bloodstream infections or catheter-site infections, as the risk of therapy appears to outweigh its benefits under these circumstances. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Linezolid exerts its antibacterial effects by interfering with bacterial protein translation. It binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is essential for bacterial reproduction, thereby preventing bacteria from dividing. Point mutations in the bacterial 23S rRNA can lead to linezolid resistance, and the development of linezolid-resistant Enterococcus faecium and Staphylococcus aureus have been documented during its clinical use. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Linezolid is extensively absorbed following oral administration and has an absolute bioavailability of approximately 100%. Maximum plasma concentrations are reached within approximately 1 to 2 hours after dosing (T max ) and range from 8.1-12.9 mcg/mL after single doses and 11.0-21.2 mcg/mL after multiple dosing. The absorption of orally administered linezolid is not significantly affected by co-administration with food and it may therefore be given without regard to the timing of meals. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): At steady-state, the volume of distribution of linezolid in healthy adults is approximately 40-50 liters. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of linezolid is approximately 31% - primarily to serum albumin - and is concentration-dependent. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Linezolid is primarily metabolized to two inactive metabolites: an aminoethoxyacetic acid metabolite (PNU-142300) and a hydroxyethyl glycine metabolite (PNU-142586), both of which are the result of morpholine ring oxidation. The hydroxyethyl glycine metabolite - the most abundant of the two metabolites - is likely generated via non-enzymatic processes, though further detail has not been elucidated. While the specific enzymes responsible for the biotransformation of linezolid are unclear, it does not appear to be subject to metabolism via the CYP450 enzyme system, nor does it meaningfully inhibit or induce these enzymes. Linezolid is, however, a reversible and non-selective inhibitor of monoamine oxidase enzymes. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Urinary excretion is the primary means by which linezolid and its metabolic products are excreted. Following the administration of a radiolabeled dose of linezolid under steady-state conditions, approximately 84% of radioactivity was recovered in the urine, of which approximately 30% is unchanged parent drug, 40% is the hydroxyethyl glycine metabolite, and 10% is the aminoethoxyacetic acid metabolite. Fecal elimination is comparatively minor, with no parent drug observed in feces and only 6% and 3% of an administered dose found in the feces as the hydroxyethyl glycine metabolite and the aminoethoxyacetic acid metabolite, respectively. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The elimination half-life is estimated to be between 5 and 7 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Total clearance of linezolid is estimated to be 100-200 mL/min, the majority of which appears to be non-renal. Mean renal clearance is approximately 40 mL/min, which suggests net tubular reabsorption, while non-renal clearance is estimated to account for roughly 65% of total clearance, or 70-150 mL/min on average. Variability in linezolid clearance is high, particularly for non-renal clearance. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Clinical signs of overdosage observed in rats were decreased activity and ataxia (2000 mg/kg/day) and in dogs were vomiting and tremors (3000 mg/kg/day). Treatment of overdose should involve symptomatic and supportive measures and may include hemodialysis if clinically necessary. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Zyvox, Zyvoxam •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Linezolid Linezolide Linezolidum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Linezolid is an oxazolidinone antibiotic used to treat infections by susceptible strains of aerobic Gram-positive bacteria. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Magnesium interact?

•Drug A: Abatacept •Drug B: Magnesium •Severity: MODERATE •Description: The serum concentration of Magnesium can be decreased when it is combined with Abatacept. •Extended Description: Co-administration of magnesium with certain immunosuppressive agents (cyclosporin, ritodrine) may lead to a decrease in serum concentrations of magnesium. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Healthy levels of magnesium can be achieved through a well balanced diet, but if food sources are insufficient, magnesium supplements can be used to prevent and treat magnesium deficiencies. In medicine, various magnesium salts may be used in laxative and antacid products. For example, magnesium citrate is available over-the-counter and may be used to manage occasional constipation. Magnesium sulfate may be used on its own or with total parenteral nutrition to treat hypomagnesemia. Magnesium sulfate is also indicated to prevent seizures in pregnant women with pre-eclampsia, and to manage seizures associated with eclampsia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Magnesium is important for many biochemical processes and is therefore quite common in humans. The majority of magnesium is stored in the bones (>50%), while the remainder is stored in muscle, soft tissue, red blood cells and serum. This is functionally important since the bones behave as a magnesium exchange reservoir and help maintain healthy levels of magnesium. Magnesium plays an important role in the regulation of several bodily processes including blood pressure, insulin metabolism, muscular contraction, vasomotor tone, cardiac excitability, nerve transmission and neuromuscular conduction. Disruptions in homeostatic levels of magnesium (often times hypomagnesemia) can impact the nervous system, muscles, or can lead to cardiac abnormalities. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Magnesium is a cofactor for at least 300 enzymes and is important for several functions in the body with some key processes identified below. Enzymes that rely on magnesium to operate help produce energy through oxidative phosphorylation, glycolysis and ATP metabolism. They are also involved in nerve function, muscle contraction, blood glucose control, hormone receptor binding, protein synthesis, cardiac excitability, blood pressure control, gating of calcium channels and transmembrane ion flux. The mitochondrial intracellular space is rich in magnesium, since it is required to produce the active form of ATP (adenosine triphosphate) from ADP (adenosine diphosphate) and inorganic phosphate, and behaves as a counter ion for the energy rich molecule. Additionally, magnesium is essential for ATP metabolism. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Approximately 24-76% of ingested magnesium is absorbed in the gastrointestinal tract, primarily via passive paracellular absorption in the small intestine. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): According to a pharmacokinetic review, the volume of distribution of magnesium sulphate when used to manage patients with pre-eclampsia and eclampsia ranged from 13.65 to 49.00 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 20% of the magnesium found in human serum is protein bound. Approximately 60-70% of this fraction is bound to albumin while the remainder is bound to globulin proteins. Magnesium has the ability to bind to 3751 human proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Magnesium does not appear to be metabolized. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The majority of magnesium is excreted renally. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Magnesiums biologic half-life is reported to be approximately 1000 hours or 42 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The recommended dietary allowance of magnesium ranges from 30 mg for infants to 420 mg for males between the age of 31 and 50. According to the institute of Medicine (IOM), the majority of adults can tolerate 350 mg of magnesium per day without experiencing adverse effects. Symptoms of magnesium toxicity include diarrhea and other gastrointestinal effects, thirst, muscle weakness, drowsiness, severe back and pelvic pain, hypotension, dizziness, confusion, difficulty breathing, lethargy, and deterioration of kidney function. Other more severe symptoms associated with magnesium overdose include loss of consciousness, respiratory arrest, cardiac arrhythmias and cardiac arrest. Regular use of laxatives containing magnesium may lead to severe and even fatal hypermagnesemia. Discontinuation of magnesium products including supplements, laxatives, and antacids is usually sufficient to manage mild cases of magnesium overdose; however, patients should also be screened for renal impairment. In severe cases of magnesium overdose, patients may require supportive care and interventions including intravenous fluids and furosemide, IV calcium chloride or calcium gluconate, renal dialysis and artificial respiratory support. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Vitafol-one •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Magnesio Magnésium Magnesium metallicum Magnesium powder •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Magnesium is a medication used for many purposes including constipation, indigestion, magnesium deficiency, and pre-eclampsia.

Co-administration of magnesium with certain immunosuppressive agents (cyclosporin, ritodrine) may lead to a decrease in serum concentrations of magnesium. The severity of the interaction is moderate.

Question: Does Abatacept and Magnesium interact? Information: •Drug A: Abatacept •Drug B: Magnesium •Severity: MODERATE •Description: The serum concentration of Magnesium can be decreased when it is combined with Abatacept. •Extended Description: Co-administration of magnesium with certain immunosuppressive agents (cyclosporin, ritodrine) may lead to a decrease in serum concentrations of magnesium. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Healthy levels of magnesium can be achieved through a well balanced diet, but if food sources are insufficient, magnesium supplements can be used to prevent and treat magnesium deficiencies. In medicine, various magnesium salts may be used in laxative and antacid products. For example, magnesium citrate is available over-the-counter and may be used to manage occasional constipation. Magnesium sulfate may be used on its own or with total parenteral nutrition to treat hypomagnesemia. Magnesium sulfate is also indicated to prevent seizures in pregnant women with pre-eclampsia, and to manage seizures associated with eclampsia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Magnesium is important for many biochemical processes and is therefore quite common in humans. The majority of magnesium is stored in the bones (>50%), while the remainder is stored in muscle, soft tissue, red blood cells and serum. This is functionally important since the bones behave as a magnesium exchange reservoir and help maintain healthy levels of magnesium. Magnesium plays an important role in the regulation of several bodily processes including blood pressure, insulin metabolism, muscular contraction, vasomotor tone, cardiac excitability, nerve transmission and neuromuscular conduction. Disruptions in homeostatic levels of magnesium (often times hypomagnesemia) can impact the nervous system, muscles, or can lead to cardiac abnormalities. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Magnesium is a cofactor for at least 300 enzymes and is important for several functions in the body with some key processes identified below. Enzymes that rely on magnesium to operate help produce energy through oxidative phosphorylation, glycolysis and ATP metabolism. They are also involved in nerve function, muscle contraction, blood glucose control, hormone receptor binding, protein synthesis, cardiac excitability, blood pressure control, gating of calcium channels and transmembrane ion flux. The mitochondrial intracellular space is rich in magnesium, since it is required to produce the active form of ATP (adenosine triphosphate) from ADP (adenosine diphosphate) and inorganic phosphate, and behaves as a counter ion for the energy rich molecule. Additionally, magnesium is essential for ATP metabolism. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Approximately 24-76% of ingested magnesium is absorbed in the gastrointestinal tract, primarily via passive paracellular absorption in the small intestine. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): According to a pharmacokinetic review, the volume of distribution of magnesium sulphate when used to manage patients with pre-eclampsia and eclampsia ranged from 13.65 to 49.00 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 20% of the magnesium found in human serum is protein bound. Approximately 60-70% of this fraction is bound to albumin while the remainder is bound to globulin proteins. Magnesium has the ability to bind to 3751 human proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Magnesium does not appear to be metabolized. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The majority of magnesium is excreted renally. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Magnesiums biologic half-life is reported to be approximately 1000 hours or 42 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The recommended dietary allowance of magnesium ranges from 30 mg for infants to 420 mg for males between the age of 31 and 50. According to the institute of Medicine (IOM), the majority of adults can tolerate 350 mg of magnesium per day without experiencing adverse effects. Symptoms of magnesium toxicity include diarrhea and other gastrointestinal effects, thirst, muscle weakness, drowsiness, severe back and pelvic pain, hypotension, dizziness, confusion, difficulty breathing, lethargy, and deterioration of kidney function. Other more severe symptoms associated with magnesium overdose include loss of consciousness, respiratory arrest, cardiac arrhythmias and cardiac arrest. Regular use of laxatives containing magnesium may lead to severe and even fatal hypermagnesemia. Discontinuation of magnesium products including supplements, laxatives, and antacids is usually sufficient to manage mild cases of magnesium overdose; however, patients should also be screened for renal impairment. In severe cases of magnesium overdose, patients may require supportive care and interventions including intravenous fluids and furosemide, IV calcium chloride or calcium gluconate, renal dialysis and artificial respiratory support. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Vitafol-one •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Magnesio Magnésium Magnesium metallicum Magnesium powder •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Magnesium is a medication used for many purposes including constipation, indigestion, magnesium deficiency, and pre-eclampsia. Output: Co-administration of magnesium with certain immunosuppressive agents (cyclosporin, ritodrine) may lead to a decrease in serum concentrations of magnesium. The severity of the interaction is moderate.

Does Abatacept and Maprotiline interact?

•Drug A: Abatacept •Drug B: Maprotiline •Severity: MODERATE •Description: The metabolism of Maprotiline can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For treatment of depression, including the depressed phase of bipolar depression, psychotic depression, and involutional melancholia, and may also be helpful in treating certain patients suffering severe depressive neurosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Maprotiline is a tetracyclic antidepressant. Although its main therapeutic use is in the treatment of depression, it has also been shown to exert a sedative effect on the anxiety component that often accompanies depression. In one sleep study, it was shown that maprotiline increases the duration of the REM sleep phase in depressed patients, compared to imipramine which reduced the REM sleep phase. Maprotiline is a strong inhibitor of noradrenaline reuptake in the brain and peripheral tissues, however it is worthy to note that it is a weak inhibitor of serotonergic uptake. In addition, it displays strong antihistaminic action (which may explain its sedative effects) as well as weak anticholinergic action. Maprotiline also has lower alpha adrenergic blocking activity than amitriptyline. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Maprotiline exerts its antidepressant action by inhibition of presynaptic uptake of catecholamines, thereby increasing their concentration at the synaptic clefts of the brain. In single doses, the effect of maprotiline on the EEG revealed a rise in the alpha-wave density, a reduction of the alpha-wave frequency and an increase in the alpha-wave amplitude. However, as with other tricyclic antidepressants, maprotiline lowers the convulsive threshold. Maprotiline acts as an antagonist at central presynaptic α 2 -adrenergic inhibitory autoreceptors and hetero-receptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity. Maprotiline is also a moderate peripheral α 1 adrenergic antagonist, which may explain the occasional orthostatic hypotension reported in association with its use. Maprotiline also inhibits the amine transporter, delaying the reuptake of noradrenaline and norepinephrine. Lastly, maprotiline is a strong inhibitor of the histamine H 1 receptor, which explains its sedative actions. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Slowly, but completely absorbed from the GI tract following oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Maprotiline and its metabolites may be detected in the lungs, liver, brain, and kidneys; lower concentrations may be found in the adrenal glands, heart and muscle. Maprotiline is readily distributed into breast milk to similar concentrations as those in maternal blood. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 88% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Maprotiline is metabolized by N -demethylation, deamination, aliphatic and aromatic hydroxylations and by formation of aromatic methoxy derivatives. It is slowly metabolized primarily to desmethylmaprotiline, a pharmacologically active metabolite. Desmethylmaprotiline may undergo further metabolism to maprotiline- N -oxide. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 60% of a single orally administered dose is excreted in urine as conjugated metabolites within 21 days; 30% is eliminated in feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Average ~ 51 hours (range: 27-58 hours) •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 =~900 mg/kg (Orally in rats); LD 50 =90 mg/kg (Orally in women); Signs of overdose include motor unrest, muscular twitching and rigidity, tremor, ataxia, convulsions, hyperpyrexia, vertigo, mydriasis, vomiting, cyanosis, hypotension, shock, tachycardia, cardiac arrhythmias, impaired cardiac conduction, respiratory depression, and disturbances of consciousness up to deep coma. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Maprotiline is a tetracyclic antidepressant used to treat depressive illness, major depressive disorder, bipolar disorder, and anxiety associated with depression.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Maprotiline interact? Information: •Drug A: Abatacept •Drug B: Maprotiline •Severity: MODERATE •Description: The metabolism of Maprotiline can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For treatment of depression, including the depressed phase of bipolar depression, psychotic depression, and involutional melancholia, and may also be helpful in treating certain patients suffering severe depressive neurosis. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Maprotiline is a tetracyclic antidepressant. Although its main therapeutic use is in the treatment of depression, it has also been shown to exert a sedative effect on the anxiety component that often accompanies depression. In one sleep study, it was shown that maprotiline increases the duration of the REM sleep phase in depressed patients, compared to imipramine which reduced the REM sleep phase. Maprotiline is a strong inhibitor of noradrenaline reuptake in the brain and peripheral tissues, however it is worthy to note that it is a weak inhibitor of serotonergic uptake. In addition, it displays strong antihistaminic action (which may explain its sedative effects) as well as weak anticholinergic action. Maprotiline also has lower alpha adrenergic blocking activity than amitriptyline. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Maprotiline exerts its antidepressant action by inhibition of presynaptic uptake of catecholamines, thereby increasing their concentration at the synaptic clefts of the brain. In single doses, the effect of maprotiline on the EEG revealed a rise in the alpha-wave density, a reduction of the alpha-wave frequency and an increase in the alpha-wave amplitude. However, as with other tricyclic antidepressants, maprotiline lowers the convulsive threshold. Maprotiline acts as an antagonist at central presynaptic α 2 -adrenergic inhibitory autoreceptors and hetero-receptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity. Maprotiline is also a moderate peripheral α 1 adrenergic antagonist, which may explain the occasional orthostatic hypotension reported in association with its use. Maprotiline also inhibits the amine transporter, delaying the reuptake of noradrenaline and norepinephrine. Lastly, maprotiline is a strong inhibitor of the histamine H 1 receptor, which explains its sedative actions. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Slowly, but completely absorbed from the GI tract following oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Maprotiline and its metabolites may be detected in the lungs, liver, brain, and kidneys; lower concentrations may be found in the adrenal glands, heart and muscle. Maprotiline is readily distributed into breast milk to similar concentrations as those in maternal blood. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 88% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Maprotiline is metabolized by N -demethylation, deamination, aliphatic and aromatic hydroxylations and by formation of aromatic methoxy derivatives. It is slowly metabolized primarily to desmethylmaprotiline, a pharmacologically active metabolite. Desmethylmaprotiline may undergo further metabolism to maprotiline- N -oxide. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 60% of a single orally administered dose is excreted in urine as conjugated metabolites within 21 days; 30% is eliminated in feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Average ~ 51 hours (range: 27-58 hours) •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): LD 50 =~900 mg/kg (Orally in rats); LD 50 =90 mg/kg (Orally in women); Signs of overdose include motor unrest, muscular twitching and rigidity, tremor, ataxia, convulsions, hyperpyrexia, vertigo, mydriasis, vomiting, cyanosis, hypotension, shock, tachycardia, cardiac arrhythmias, impaired cardiac conduction, respiratory depression, and disturbances of consciousness up to deep coma. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Maprotiline is a tetracyclic antidepressant used to treat depressive illness, major depressive disorder, bipolar disorder, and anxiety associated with depression. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Mavacamten interact?

•Drug A: Abatacept •Drug B: Mavacamten •Severity: MODERATE •Description: The metabolism of Mavacamten can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Mavacamten is indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms by the FDA, Health Canada, and the EMA. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Mavacamten is a myosin inhibitor to prevent muscle hypercontractility. It binds to myosin and inhibits myosin interaction with actin at various stages of the thermomechanical cycle. Mechanistic studies show that mavacamten can inhibit myosin in both its active and relaxed form, thus effectively alleviating excess sarcomere power, a hallmark of hypertrophic cardiomyopathy. In the EXPLORER-HCM trial, patients achieved reductions in mean resting and provoked (Valsalva) LVOT gradient by Week 4 which were sustained throughout the 30-week trial. At Week 30, the mean (SD) changes from baseline in resting and Valsalva LVOT gradients were -39 (29) mmHg and -49 (34) mmHg, respectively, for the CAMZYOS group and -6 (28) mmHg and -12 (31) mmHg, respectively, for the placebo group. The reductions in the Valsalva LVOT gradient were accompanied by decreases in LVEF, generally within the normal range. Eight weeks after discontinuation of CAMZYOS, mean LVEF and Valsalva LVOT gradients were similar to baseline. Echocardiographic measurements of the cardiac structure showed a mean (SD) reduction from baseline at Week 30 in left ventricular mass index (LVMI) in the mavacamten group (-7.4 [17.8] g/m2) versus an increase in LVMI in the placebo group (8.9 [15.3] g/m2). There was also a mean (SD) reduction from baseline in left atrial volume index (LAVI) in the mavacamten group(-7.5 [7.8] mL/m2) versus no change in the placebo group (-0.1 [8.7] mL/m2). The clinical significance of these findings is unknown. A reduction in a biomarker of cardiac wall stress, NT-proBNP, was observed by Week 4 and sustained through the end of treatment. At Week 30 compared with baseline, the reduction in NT-proBNP after mavacamten treatment was 80% greater than for placebo (proportion of geometric mean ratio between the two groups, 0.20 [95% CI: 0.17, 0.24]). The clinical significance of these findings is unknown. In healthy volunteers receiving multiple doses of mavacamten, a concentration-dependent increase in the QTc interval was observed at doses up to 25 mg once daily. No acute QTc changes have been observed at similar exposures during single-dose studies. The mechanism of the QT prolongation effect is not known. A meta-analysis across clinical studies in HCM patients does not suggest clinically relevant increases in the QTc interval in the therapeutic exposure range. In HCM, the QT interval may be intrinsically prolonged due to the underlying disease, in association with ventricular pacing, or in association with drugs with the potential for QT prolongation commonly used in the HCM population. The effect of coadministration of mavacamten with QT-prolonging drugs or in patients with potassium channel variants resulting in a long QT interval has not been characterized. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Myosin is a family of enzymes that can produce mechanical output by an ATP-mediated cyclic interaction with actin. When ATP is bound to the myosin head, it is hydrolyzed into ADP and organophosphate by myosin ATPase activity, and the energy produced from the reaction is stored in the myosin head. As the organophosphate dissociates from myosin, it shifts myosin into a strong binding state to actin, thus creating a myosin-actin complex otherwise known as "cross-bridging". Dissociation of the organophosphate also causes a conformation change in myosin that creates strain in the actin-myosin bridge that can only be released once the actin and myosin filaments slide past each other, thus shortening the sarcomere and create a muscle contraction. Once the sliding is completed, ADP is released to create further movement of the myosin head. Although this ADP release-induced movement is minor and unlikely to contribute to the sarcomere movement, researchers have hypothesized that this movement is likely essential in limiting the sliding velocity of actin. Finally, myosin then bind to a new ATP molecule to initiate the chemomechanical cycle again. Mavacamten reduces sarcomere hypercontractility by acting as an allosteric and reversible modulator of the beta-cardiac isoform of myosin to reduce its ATPase activity, thus reducing actin-myosin cross bridging. Specifically, mavacamten inhibits the phosphate release, the cycle's rate-limiting step, without affecting the ADP release rate in actin-bound myosin. Also, mavacamten inhibits binding of ADP-bound myosin to actin as well as ADP release to prime the myosin head to initiate turnover. Recently, it was also discovered when myosin is not in its active state to interact with actin, it exists in equilibrium between 2 energy sparing states: a disordered relaxed state, where interaction between actin and myosin by the thin filament regulatory proteins, and a super relaxed state, where significant myosin head-to-head interaction lengthen ATP turnover rate.. Mavacamten's binding to myosin can shift the equilibrium toward the super relaxed state, effectively exerting both a basal and actin-activated ATP inhibition. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Mavacamten has an estimated oral bioavailability of at least 85% and T max of 1 hour. Mavacamten exposures (AUC) increased up to 220% in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. The effect of severe (Child-Pugh C) hepatic impairment is unknown. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Through the use of a simple 4-species (mouse, rat, dog, and cynomolgus monkey) allometric scaling of unbound blood steady-state volume of distribution, the human volume of distribution of mavacamten is predicted to be 9.5 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of mavacamten is between 97 and 98%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Mavacamten is extensively metabolized, primarily through CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single 25 mg dose of radiolabeled mavacamten, 7% of the dose was recovered in feces (1% unchanged) and 85% in urine (3% unchanged). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Mavacamten has a variable terminal t1/2 that depends on CYP2C19 metabolic status. Mavacamten's terminal half-life is 6-9 days in CYP2C19 normal metabolizers (NMs), which is prolonged in CYP2C19 poor metabolizers (PMs) to 23 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Mavacamten demonstrates a long terminal half-life and thus low clearance, with an estimated plasma clearance using human hepatocytes of less than 4.9 mL/min/kg. Assuming a one-compartment model, using simple allometric scaling of unbound blood clearance of mouse, rat, dog, and cynomolgus monkey, human plasma clearance of mavacamten is estimated to be 0.51 mL/min/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Human experience of overdose with CAMZYOS is limited. CAMZYOS has been given as a single dose of up to 144 mg in patients with HCM. One subject administered a single dose of 144 mg experienced serious adverse events including vasovagal reaction, hypotension, and asystole, but the subject recovered. In healthy subjects, doses of up to 25 mg have been administered for up to 25 days, with 3 of 8 participants treated at the 25-mg dose level experiencing 20% or greater reductions in LVEF. An infant's death was reported after accidental ingestion of three 15-mg capsules. Systolic dysfunction is the most likely result of overdosage of CAMZYOS. Treatment of overdose with CAMZYOS consists of discontinuation of CAMZYOS treatment as well as medically supportive measures to maintain hemodynamic stability, including close monitoring of vital signs and LVEF and management of the clinical status of the patient. Overdose in humans can be life-threatening and result in asystole refractory to any medical intervention. Mavacamten was not genotoxic in a bacterial reverse mutation test (Ames test), a human in vitro lymphocyte clastogenicity assay, or a rat in vivo micronucleus assay. There was no evidence of carcinogenicity seen in a 6-month rasH2 transgenic mouse study at mavacamten doses of up to 2.0 mg/kg/day in males and 3.0 mg/kg/day in females, which resulted in exposures (AUC) that were 1.8- and 3-fold in males and females, respectively, compared to AUC exposures in humans at the MRHD. In reproductive toxicity studies, there was no evidence of the effects of mavacamten on mating and fertility in male or female rats at doses up to 1.2 mg/kg/day, or on the viability and fertility of offspring of dams dosed up to 1.5 mg/kg/day. Plasma exposure (AUC) of mavacamten at the highest dose tested was the same as in humans at the MRHD. The safety of mavacamten has been evaluated in rats and dogs at multiple dose levels (0.06 to 10 mg/kg/day) orally. Noted toxicities, including echocardiographic findings, reduction in systolic function, cardiac dilation, and death, as well as increased heart weights in rats, were consistent with mavacamten’s mechanism of action and primary pharmacological activity. Other findings included cardiac osseous metaplasia in rats and QTc prolongation in dogs. Plasma exposures (AUC) at the NOAEL in rats and dogs were 0.1 and 0.3 times, respectively, human exposure (AUC) at the MRHD. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Camzyos •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Mavacamten MYK-461 •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Mavacamten is a myosin inhibitor used to treat obstructive hypertrophic cardiomyopathy.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Mavacamten interact? Information: •Drug A: Abatacept •Drug B: Mavacamten •Severity: MODERATE •Description: The metabolism of Mavacamten can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Mavacamten is indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms by the FDA, Health Canada, and the EMA. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Mavacamten is a myosin inhibitor to prevent muscle hypercontractility. It binds to myosin and inhibits myosin interaction with actin at various stages of the thermomechanical cycle. Mechanistic studies show that mavacamten can inhibit myosin in both its active and relaxed form, thus effectively alleviating excess sarcomere power, a hallmark of hypertrophic cardiomyopathy. In the EXPLORER-HCM trial, patients achieved reductions in mean resting and provoked (Valsalva) LVOT gradient by Week 4 which were sustained throughout the 30-week trial. At Week 30, the mean (SD) changes from baseline in resting and Valsalva LVOT gradients were -39 (29) mmHg and -49 (34) mmHg, respectively, for the CAMZYOS group and -6 (28) mmHg and -12 (31) mmHg, respectively, for the placebo group. The reductions in the Valsalva LVOT gradient were accompanied by decreases in LVEF, generally within the normal range. Eight weeks after discontinuation of CAMZYOS, mean LVEF and Valsalva LVOT gradients were similar to baseline. Echocardiographic measurements of the cardiac structure showed a mean (SD) reduction from baseline at Week 30 in left ventricular mass index (LVMI) in the mavacamten group (-7.4 [17.8] g/m2) versus an increase in LVMI in the placebo group (8.9 [15.3] g/m2). There was also a mean (SD) reduction from baseline in left atrial volume index (LAVI) in the mavacamten group(-7.5 [7.8] mL/m2) versus no change in the placebo group (-0.1 [8.7] mL/m2). The clinical significance of these findings is unknown. A reduction in a biomarker of cardiac wall stress, NT-proBNP, was observed by Week 4 and sustained through the end of treatment. At Week 30 compared with baseline, the reduction in NT-proBNP after mavacamten treatment was 80% greater than for placebo (proportion of geometric mean ratio between the two groups, 0.20 [95% CI: 0.17, 0.24]). The clinical significance of these findings is unknown. In healthy volunteers receiving multiple doses of mavacamten, a concentration-dependent increase in the QTc interval was observed at doses up to 25 mg once daily. No acute QTc changes have been observed at similar exposures during single-dose studies. The mechanism of the QT prolongation effect is not known. A meta-analysis across clinical studies in HCM patients does not suggest clinically relevant increases in the QTc interval in the therapeutic exposure range. In HCM, the QT interval may be intrinsically prolonged due to the underlying disease, in association with ventricular pacing, or in association with drugs with the potential for QT prolongation commonly used in the HCM population. The effect of coadministration of mavacamten with QT-prolonging drugs or in patients with potassium channel variants resulting in a long QT interval has not been characterized. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Myosin is a family of enzymes that can produce mechanical output by an ATP-mediated cyclic interaction with actin. When ATP is bound to the myosin head, it is hydrolyzed into ADP and organophosphate by myosin ATPase activity, and the energy produced from the reaction is stored in the myosin head. As the organophosphate dissociates from myosin, it shifts myosin into a strong binding state to actin, thus creating a myosin-actin complex otherwise known as "cross-bridging". Dissociation of the organophosphate also causes a conformation change in myosin that creates strain in the actin-myosin bridge that can only be released once the actin and myosin filaments slide past each other, thus shortening the sarcomere and create a muscle contraction. Once the sliding is completed, ADP is released to create further movement of the myosin head. Although this ADP release-induced movement is minor and unlikely to contribute to the sarcomere movement, researchers have hypothesized that this movement is likely essential in limiting the sliding velocity of actin. Finally, myosin then bind to a new ATP molecule to initiate the chemomechanical cycle again. Mavacamten reduces sarcomere hypercontractility by acting as an allosteric and reversible modulator of the beta-cardiac isoform of myosin to reduce its ATPase activity, thus reducing actin-myosin cross bridging. Specifically, mavacamten inhibits the phosphate release, the cycle's rate-limiting step, without affecting the ADP release rate in actin-bound myosin. Also, mavacamten inhibits binding of ADP-bound myosin to actin as well as ADP release to prime the myosin head to initiate turnover. Recently, it was also discovered when myosin is not in its active state to interact with actin, it exists in equilibrium between 2 energy sparing states: a disordered relaxed state, where interaction between actin and myosin by the thin filament regulatory proteins, and a super relaxed state, where significant myosin head-to-head interaction lengthen ATP turnover rate.. Mavacamten's binding to myosin can shift the equilibrium toward the super relaxed state, effectively exerting both a basal and actin-activated ATP inhibition. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Mavacamten has an estimated oral bioavailability of at least 85% and T max of 1 hour. Mavacamten exposures (AUC) increased up to 220% in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. The effect of severe (Child-Pugh C) hepatic impairment is unknown. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Through the use of a simple 4-species (mouse, rat, dog, and cynomolgus monkey) allometric scaling of unbound blood steady-state volume of distribution, the human volume of distribution of mavacamten is predicted to be 9.5 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of mavacamten is between 97 and 98%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Mavacamten is extensively metabolized, primarily through CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single 25 mg dose of radiolabeled mavacamten, 7% of the dose was recovered in feces (1% unchanged) and 85% in urine (3% unchanged). •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Mavacamten has a variable terminal t1/2 that depends on CYP2C19 metabolic status. Mavacamten's terminal half-life is 6-9 days in CYP2C19 normal metabolizers (NMs), which is prolonged in CYP2C19 poor metabolizers (PMs) to 23 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Mavacamten demonstrates a long terminal half-life and thus low clearance, with an estimated plasma clearance using human hepatocytes of less than 4.9 mL/min/kg. Assuming a one-compartment model, using simple allometric scaling of unbound blood clearance of mouse, rat, dog, and cynomolgus monkey, human plasma clearance of mavacamten is estimated to be 0.51 mL/min/kg. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Human experience of overdose with CAMZYOS is limited. CAMZYOS has been given as a single dose of up to 144 mg in patients with HCM. One subject administered a single dose of 144 mg experienced serious adverse events including vasovagal reaction, hypotension, and asystole, but the subject recovered. In healthy subjects, doses of up to 25 mg have been administered for up to 25 days, with 3 of 8 participants treated at the 25-mg dose level experiencing 20% or greater reductions in LVEF. An infant's death was reported after accidental ingestion of three 15-mg capsules. Systolic dysfunction is the most likely result of overdosage of CAMZYOS. Treatment of overdose with CAMZYOS consists of discontinuation of CAMZYOS treatment as well as medically supportive measures to maintain hemodynamic stability, including close monitoring of vital signs and LVEF and management of the clinical status of the patient. Overdose in humans can be life-threatening and result in asystole refractory to any medical intervention. Mavacamten was not genotoxic in a bacterial reverse mutation test (Ames test), a human in vitro lymphocyte clastogenicity assay, or a rat in vivo micronucleus assay. There was no evidence of carcinogenicity seen in a 6-month rasH2 transgenic mouse study at mavacamten doses of up to 2.0 mg/kg/day in males and 3.0 mg/kg/day in females, which resulted in exposures (AUC) that were 1.8- and 3-fold in males and females, respectively, compared to AUC exposures in humans at the MRHD. In reproductive toxicity studies, there was no evidence of the effects of mavacamten on mating and fertility in male or female rats at doses up to 1.2 mg/kg/day, or on the viability and fertility of offspring of dams dosed up to 1.5 mg/kg/day. Plasma exposure (AUC) of mavacamten at the highest dose tested was the same as in humans at the MRHD. The safety of mavacamten has been evaluated in rats and dogs at multiple dose levels (0.06 to 10 mg/kg/day) orally. Noted toxicities, including echocardiographic findings, reduction in systolic function, cardiac dilation, and death, as well as increased heart weights in rats, were consistent with mavacamten’s mechanism of action and primary pharmacological activity. Other findings included cardiac osseous metaplasia in rats and QTc prolongation in dogs. Plasma exposures (AUC) at the NOAEL in rats and dogs were 0.1 and 0.3 times, respectively, human exposure (AUC) at the MRHD. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Camzyos •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Mavacamten MYK-461 •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Mavacamten is a myosin inhibitor used to treat obstructive hypertrophic cardiomyopathy. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Measles virus vaccine live attenuated interact?

•Drug A: Abatacept •Drug B: Measles virus vaccine live attenuated •Severity: MODERATE •Description: The therapeutic efficacy of Measles virus vaccine live attenuated can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found

Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Question: Does Abatacept and Measles virus vaccine live attenuated interact? Information: •Drug A: Abatacept •Drug B: Measles virus vaccine live attenuated •Severity: MODERATE •Description: The therapeutic efficacy of Measles virus vaccine live attenuated can be decreased when used in combination with Abatacept. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Kidney and liver •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Brand Names (Drug A): Orencia •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Summary not found Output: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Does Abatacept and Mechlorethamine interact?

•Drug A: Abatacept •Drug B: Mechlorethamine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Mechlorethamine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the palliative treatment of Hodgkin's disease (Stages III and IV), lymphosarcoma, chronic myelocytic or chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides, and bronchogenic carcinoma. Also for the palliative treatment of metastatic carcinoma resulting in effusion. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Mechlorethamine also known as mustine, nitrogen mustard, and HN2, is the prototype anticancer chemotherapeutic drug. Successful clinical use of mechlorethamine gave birth to the field of anticancer chemotherapy. The drug is an analogue of mustard gas and was derived from toxic gas warfare research. Mechlorethamine is a nitrogen mustard alkylating agent. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. Mechlorethamine is cell cycle phase-nonspecific. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Partially absorbed following intracavitary administration, most likely due to rapid deactivation by body fluids. When it is topically administered, systemic exposure was undetectable. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Undergoes rapid chemical transformation and combines with water or reactive compounds of cells, so that the drug is no longer present in active form a few minutes after administration. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 15 minutes •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overexposure include severe leukopenia, anemia, thrombocytopenia, and a hemorrhagic diathesis with subsequent delayed bleeding may develop. Death may follow. The most common adverse reactions (≥5%) of the topical formulation are dermatitis, pruritus, bacterial skin infection, skin ulceration or blistering, and hyperpigmentation. The oral LD50 for a rat is 10 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Valchlor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlormethine Chlormethinum Clormetina Mechlorethamine Mustine Nitrogen mustard •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Mechlorethamine is an antineoplastic agent used to treat Hodgkin's disease, lymphosarcoma, and chronic myelocytic or lymphocytic leukemia.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Mechlorethamine interact? Information: •Drug A: Abatacept •Drug B: Mechlorethamine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Mechlorethamine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the palliative treatment of Hodgkin's disease (Stages III and IV), lymphosarcoma, chronic myelocytic or chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides, and bronchogenic carcinoma. Also for the palliative treatment of metastatic carcinoma resulting in effusion. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Mechlorethamine also known as mustine, nitrogen mustard, and HN2, is the prototype anticancer chemotherapeutic drug. Successful clinical use of mechlorethamine gave birth to the field of anticancer chemotherapy. The drug is an analogue of mustard gas and was derived from toxic gas warfare research. Mechlorethamine is a nitrogen mustard alkylating agent. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. Mechlorethamine is cell cycle phase-nonspecific. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Partially absorbed following intracavitary administration, most likely due to rapid deactivation by body fluids. When it is topically administered, systemic exposure was undetectable. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Undergoes rapid chemical transformation and combines with water or reactive compounds of cells, so that the drug is no longer present in active form a few minutes after administration. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 15 minutes •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Symptoms of overexposure include severe leukopenia, anemia, thrombocytopenia, and a hemorrhagic diathesis with subsequent delayed bleeding may develop. Death may follow. The most common adverse reactions (≥5%) of the topical formulation are dermatitis, pruritus, bacterial skin infection, skin ulceration or blistering, and hyperpigmentation. The oral LD50 for a rat is 10 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Valchlor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlormethine Chlormethinum Clormetina Mechlorethamine Mustine Nitrogen mustard •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Mechlorethamine is an antineoplastic agent used to treat Hodgkin's disease, lymphosarcoma, and chronic myelocytic or lymphocytic leukemia. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Meclizine interact?

•Drug A: Abatacept •Drug B: Meclizine •Severity: MODERATE •Description: The metabolism of Meclizine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for the symptomatic treatment of nausea, vomiting, and dizziness associated with motion sickness, and management of vertigo due to various causes, including radiation sickness, Meniere’s syndrome, labyrinthitis and other vestibular disturbances. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Meclizine works on the higher centres of the brain to reduce nausea, vomiting, or vertigo. It is effective against nausea and vomiting arising from many causes, including motion sickness and disorders affecting the vestibular system. The onset of action of meclizine is about 1 hour, with effects lasting between 8 to 24 hours. Meclizine is reported to cause drowsiness due to its anticholinergic actions. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Vomiting is a centrally regulated reflex mechanism that initiates from the vomiting center and the chemoreceptor trigger zone (CTZ) located in the medulla. Motion sickness is also regulated by CTZ. The blood-brain barrier near the CTZ is relatively permeable to circulating mediators and CTZ can transmit impulses to vomiting center located in the brainstem. Different receptors responding to different factors, including histamine, 5-HT, enkephalins, substance P, and dopamine, are expressed along the brainstem to activate respective pathways and contribute to the control of vomiting. Histamine H1 receptors are expressed on the vestibular nuclei and nucleus of the solitary tract (NTS) that are activated by motion sickness and stimuli from the pharynx and stomach. When activated, H1 receptor signaling from these nuclei is transmitted to the CTZ and vomiting centre. Through its antagonistic action on the H1 receptors, meclizine primarily works by inhibiting signaling pathway transduction through histaminergic neurotransmission from the vestibular nuclei and NTS to the CTZ and medullary vomiting center. Meclizine may also decrease the labyrinth excitability and vestibular stimulation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Most histamine H1 antagonists are reported to be readily absorbed following oral administration. Upon oral administration, the time to reach peak plasma concentrations (Cmax) of meclizine is about 3 hours post-dose, with the value ranging from 1.5 to 6 hours. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of meclizine in humans has not been fully studied. It is proposed that meclizine may be excreted into breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): There is limited data on the protein binding profile of meclizine. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): There is limited human data on meclizine metabolism. According to the findings of in vitro studies, meclizine may undergo aromatic hydroxylation or benzylic oxidation mediated by the hepatic CYP2D6 enzyme. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Meclizine is excreted in the urine as metabolites and in the feces as unchanged drug. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Meclizine has a plasma elimination half-life of about 5-6 hours in humans. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): There is limited data on the clearance of meclizine. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral and intraperitoneal LD 50 in mouse are 1600 mg/kg and 625 mg/kg, respectively. The lowest published toxic dose (TDLo) in rats via the oral route is 800 mg/kg. Symptoms of overdose mainly involve CNS depression with drowsiness, coma, and convulsions. Hypotension may also occur, particularly in the elderly. In children, anticholinergic effects and CNS stimulation, characterized by hallucinations, seizures, trouble sleeping, are more likely to occur. In case of overdose, symptomatic and supportive treatment is recommended. In case of recent ingestion, induction of emesis or gastric lavage should be initiated to limit further drug absorption. Although there is no known antidote to meclizine, physostigmine may be useful to counteract the CNS anticholinergic effects of meclizine. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Antivert, Bonine, Diphen, Dramamine, Travel-ease •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Meclizine is a histamine H1 antagonist used to treat nausea, vomiting, and dizziness associated with motion sickness.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Meclizine interact? Information: •Drug A: Abatacept •Drug B: Meclizine •Severity: MODERATE •Description: The metabolism of Meclizine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Indicated for the symptomatic treatment of nausea, vomiting, and dizziness associated with motion sickness, and management of vertigo due to various causes, including radiation sickness, Meniere’s syndrome, labyrinthitis and other vestibular disturbances. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Meclizine works on the higher centres of the brain to reduce nausea, vomiting, or vertigo. It is effective against nausea and vomiting arising from many causes, including motion sickness and disorders affecting the vestibular system. The onset of action of meclizine is about 1 hour, with effects lasting between 8 to 24 hours. Meclizine is reported to cause drowsiness due to its anticholinergic actions. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Vomiting is a centrally regulated reflex mechanism that initiates from the vomiting center and the chemoreceptor trigger zone (CTZ) located in the medulla. Motion sickness is also regulated by CTZ. The blood-brain barrier near the CTZ is relatively permeable to circulating mediators and CTZ can transmit impulses to vomiting center located in the brainstem. Different receptors responding to different factors, including histamine, 5-HT, enkephalins, substance P, and dopamine, are expressed along the brainstem to activate respective pathways and contribute to the control of vomiting. Histamine H1 receptors are expressed on the vestibular nuclei and nucleus of the solitary tract (NTS) that are activated by motion sickness and stimuli from the pharynx and stomach. When activated, H1 receptor signaling from these nuclei is transmitted to the CTZ and vomiting centre. Through its antagonistic action on the H1 receptors, meclizine primarily works by inhibiting signaling pathway transduction through histaminergic neurotransmission from the vestibular nuclei and NTS to the CTZ and medullary vomiting center. Meclizine may also decrease the labyrinth excitability and vestibular stimulation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Most histamine H1 antagonists are reported to be readily absorbed following oral administration. Upon oral administration, the time to reach peak plasma concentrations (Cmax) of meclizine is about 3 hours post-dose, with the value ranging from 1.5 to 6 hours. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of meclizine in humans has not been fully studied. It is proposed that meclizine may be excreted into breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): There is limited data on the protein binding profile of meclizine. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): There is limited human data on meclizine metabolism. According to the findings of in vitro studies, meclizine may undergo aromatic hydroxylation or benzylic oxidation mediated by the hepatic CYP2D6 enzyme. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Meclizine is excreted in the urine as metabolites and in the feces as unchanged drug. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Meclizine has a plasma elimination half-life of about 5-6 hours in humans. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): There is limited data on the clearance of meclizine. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral and intraperitoneal LD 50 in mouse are 1600 mg/kg and 625 mg/kg, respectively. The lowest published toxic dose (TDLo) in rats via the oral route is 800 mg/kg. Symptoms of overdose mainly involve CNS depression with drowsiness, coma, and convulsions. Hypotension may also occur, particularly in the elderly. In children, anticholinergic effects and CNS stimulation, characterized by hallucinations, seizures, trouble sleeping, are more likely to occur. In case of overdose, symptomatic and supportive treatment is recommended. In case of recent ingestion, induction of emesis or gastric lavage should be initiated to limit further drug absorption. Although there is no known antidote to meclizine, physostigmine may be useful to counteract the CNS anticholinergic effects of meclizine. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Antivert, Bonine, Diphen, Dramamine, Travel-ease •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Meclizine is a histamine H1 antagonist used to treat nausea, vomiting, and dizziness associated with motion sickness. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Mefenamic acid interact?

•Drug A: Abatacept •Drug B: Mefenamic acid •Severity: MODERATE •Description: The metabolism of Mefenamic acid can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of rheumatoid arthritis, osteoarthritis, dysmenorrhea, and mild to moderate pain, inflammation, and fever. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Mefenamic acid, an anthranilic acid derivative, is a member of the fenamate group of nonsteroidal anti-inflammatory drugs (NSAIDs). It exhibits anti-inflammatory, analgesic, and antipyretic activities. Similar to other NSAIDs, mefenamic acid inhibits prostaglandin synthetase. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Mefenamic acid binds the prostaglandin synthetase receptors COX-1 and COX-2, inhibiting the action of prostaglandin synthetase. As these receptors have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity, the symptoms of pain are temporarily reduced. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Mefenamic acid is rapidly absorbed after oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 1.06 L/kg [Normal Healthy Adults (18-45 yr)] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 90% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Mefenamic acid undergoes metabolism by CYP2C9 to 3-hydroxymethyl mefenamic acid, and further oxidation to a 3-carboxymefenamic acid may occur. The activity of these metabolites has not been studied. Mefenamic acid is also glucuronidated directly. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The fecal route of elimination accounts for up to 20% of the dose, mainly in the form of unconjugated 3-carboxymefenamic acid.3 The elimination half-life of mefenamic acid is approximately two hours. Mefenamic acid, its metabolites and conjugates are primarily excreted by the kidneys. Both renal and hepatic excretion are significant pathways of elimination. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 2 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Oral cl=21.23 L/hr [Healthy adults (18-45 yrs)] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral, rat LD 50: 740 mg/kg. Symptoms of overdose may include severe stomach pain, coffee ground-like vomit, dark stool, ringing in the ears, change in amount of urine, unusually fast or slow heartbeat, muscle weakness, slow or shallow breathing, confusion, severe headache or loss of consciousness. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Mefenamic, Ponstel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide méfénamique ácido mefenámico Acidum mefenamicum Mefenamic acid Mefenaminsäure •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Mefenamic acid is an NSAID used to treat mild to moderate pain for no more than a week, and primary dysmenorrhea.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Mefenamic acid interact? Information: •Drug A: Abatacept •Drug B: Mefenamic acid •Severity: MODERATE •Description: The metabolism of Mefenamic acid can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of rheumatoid arthritis, osteoarthritis, dysmenorrhea, and mild to moderate pain, inflammation, and fever. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Mefenamic acid, an anthranilic acid derivative, is a member of the fenamate group of nonsteroidal anti-inflammatory drugs (NSAIDs). It exhibits anti-inflammatory, analgesic, and antipyretic activities. Similar to other NSAIDs, mefenamic acid inhibits prostaglandin synthetase. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Mefenamic acid binds the prostaglandin synthetase receptors COX-1 and COX-2, inhibiting the action of prostaglandin synthetase. As these receptors have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity, the symptoms of pain are temporarily reduced. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Mefenamic acid is rapidly absorbed after oral administration. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): 1.06 L/kg [Normal Healthy Adults (18-45 yr)] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 90% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Mefenamic acid undergoes metabolism by CYP2C9 to 3-hydroxymethyl mefenamic acid, and further oxidation to a 3-carboxymefenamic acid may occur. The activity of these metabolites has not been studied. Mefenamic acid is also glucuronidated directly. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The fecal route of elimination accounts for up to 20% of the dose, mainly in the form of unconjugated 3-carboxymefenamic acid.3 The elimination half-life of mefenamic acid is approximately two hours. Mefenamic acid, its metabolites and conjugates are primarily excreted by the kidneys. Both renal and hepatic excretion are significant pathways of elimination. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 2 hours •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Oral cl=21.23 L/hr [Healthy adults (18-45 yrs)] •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Oral, rat LD 50: 740 mg/kg. Symptoms of overdose may include severe stomach pain, coffee ground-like vomit, dark stool, ringing in the ears, change in amount of urine, unusually fast or slow heartbeat, muscle weakness, slow or shallow breathing, confusion, severe headache or loss of consciousness. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Mefenamic, Ponstel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide méfénamique ácido mefenámico Acidum mefenamicum Mefenamic acid Mefenaminsäure •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Mefenamic acid is an NSAID used to treat mild to moderate pain for no more than a week, and primary dysmenorrhea. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Melatonin interact?

•Drug A: Abatacept •Drug B: Melatonin •Severity: MODERATE •Description: The metabolism of Melatonin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used orally for jet lag, insomnia, shift-work disorder, circadian rhythm disorders in the blind (evidence for efficacy), and benzodiazepine and nicotine withdrawal. Evidence indicates that melatonin is likely effective for treating circadian rhythm sleep disorders in blind children and adults. It has received FDA orphan drug status as an oral medication for this use. A number of studies have shown that melatonin may be effective for treating sleep-wake cycle disturbances in children and adolescents with mental retardation, autism, and other central nervous system disorders. It appears to decrease the time to fall asleep in children with developmental disabilities, such as cerebral palsy, autism, and mental retardation. It may also improve secondary insomnia associated with various sleep-wake cycle disturbances. Other possible uses for which there is some evidence for include: benzodiazepine withdrawal, cluster headache, delayed sleep phase syndrome (DSPS), primary insomnia, jet lag, nicotine withdrawal, preoperative anxiety and sedation, prostate cancer, solid tumors (when combined with IL-2 therapy in certain cancers), sunburn prevention (topical use), tardive dyskinesia, thrombocytopenia associated with cancer, chemotherapy and other disorders. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Melatonin is a hormone normally produced in the pineal gland and released into the blood. The essential amino acid L-tryptophan is a precursor in the synthesis of melatonin. It helps regulate sleep-wake cycles or the circadian rhythm. Production of melatonin is stimulated by darkness and inhibited by light. High levels of melatonin induce sleep and so consumption of the drug can be used to combat insomnia and jet lag. MT1 and MT2 receptors may be a target for the treatment of circadian and non circadian sleep disorders because of their differences in pharmacology and function within the SCN. SCN is responsible for maintaining the 24 hour cycle which regulates many different body functions ranging from sleep to immune functions •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Melatonin is a derivative of tryptophan. It binds to melatonin receptor type 1A, which then acts on adenylate cylcase and the inhibition of a cAMP signal transduction pathway. Melatonin not only inhibits adenylate cyclase, but it also activates phosphilpase C. This potentiates the release of arachidonate. By binding to melatonin receptors 1 and 2, the downstream signallling cascades have various effects in the body. The melatonin receptors are G protein-coupled receptors and are expressed in various tissues of the body. There are two subtypes of the receptor in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonists, on market or in clinical trials, all bind to and activate both receptor types.The binding of the agonists to the receptors has been investigated for over two decades or since 1986. It is somewhat known, but still not fully understood. When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes. MT1 receptors are expressed in many regions of the central nervous system (CNS): suprachiasmatic nucleus of the hypothalamus (SNC), hippocampus, substantia nigra, cerebellum, central dopaminergic pathways, ventral tegmental area and nucleus accumbens. MT1 is also expressed in the retina, ovary, testis, mammary gland, coronary circulation and aorta, gallbladder, liver, kidney, skin and the immune system. MT2 receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary and aortic tissue, myometrium and granulosa cells, immune cells, duodenum and adipocytes. The binding of melatonin to melatonin receptors activates a few signaling pathways. MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorilation of cAMP responsive element-binding protein (CREB binding protein) into P-CREB. MT1 receptors also activate phospholipase C (PLC), affect ion channels and regulate ion flux inside the cell. The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.[4] As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absorption and bioavailability of melatonin varies widely. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatically metabolized to at least 14 identified metabolites (identified in mouse urine): 6-hydroxymelatonin glucuronide, 6-hydroxymelatonin sulfate, N-acetylserotonin glucuronide, N-acetylserotonin sulfate, 6-hydroxymelatonin, 2-oxomelatonin, 3-hydroxymelatonin, melatonin glucuronide, cyclic melatonin, cyclic N-acetylserotonin glucuronide, cyclic 6-hydroxymelatonin, 5-hydroxyindole-3-acetaldehyde, di-hydroxymelatonin and its glucuronide conjugate. 6-Hydroxymelatonin glucuronide is the major metabolite found in mouse urine (65-88% of total melatonin metabolites in urine). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 35 to 50 minutes •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Generally well-tolerated when taken orally. The most common side effects, day-time drowsiness, headache and dizziness, appear to occur at the same frequency as with placebo. Other reported side effects include transient depressive symptoms, mild tremor, mild anxiety, abdominal cramps, irritability, reduced alertness, confusion, nausea, vomiting, and hypotension. Safety in Adults: Evidence indicates that it is likely safe to use in oral and parenteral forms for up to two months when used appropriately. Some evidence indicates that it can be safely used orally for up to 9 months in some patients. It is also likely safe to use topically when used appropriately. Safety in Children: Melatonin appeared to be used safely in small numbers of children enrolled in short-term clinical trials. However, concerns regarding safety in children have arisen based on their developmental state. Compared to adults over 20 years of age, people under 20 produce high levels of melatonin. Melatonin levels are inversely related to gonadal development and it is thought that exogenous administration of melatonin may adversely affect gonadal development. Safety during Pregnancy: High doses of melatonin administered orally or parenterally may inhibit ovulation. Not advised for use in individuals who are pregnant or trying to become pregnant. Safety during Lactation: Not recommended as safety has not be established. Oral, rat: LD 50 ≥3200 mg/kg •Brand Names (Drug A): Orencia •Brand Names (Drug B): Circadin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Melatonin Melatonina Mélatonine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Melatonin is an endogenous hormone produced by the pineal gland that regulates sleep-wake cycles and when provided exogenously has beneficial effects on sleep-onset latency; available as an over-the-counter supplement.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Melatonin interact? Information: •Drug A: Abatacept •Drug B: Melatonin •Severity: MODERATE •Description: The metabolism of Melatonin can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used orally for jet lag, insomnia, shift-work disorder, circadian rhythm disorders in the blind (evidence for efficacy), and benzodiazepine and nicotine withdrawal. Evidence indicates that melatonin is likely effective for treating circadian rhythm sleep disorders in blind children and adults. It has received FDA orphan drug status as an oral medication for this use. A number of studies have shown that melatonin may be effective for treating sleep-wake cycle disturbances in children and adolescents with mental retardation, autism, and other central nervous system disorders. It appears to decrease the time to fall asleep in children with developmental disabilities, such as cerebral palsy, autism, and mental retardation. It may also improve secondary insomnia associated with various sleep-wake cycle disturbances. Other possible uses for which there is some evidence for include: benzodiazepine withdrawal, cluster headache, delayed sleep phase syndrome (DSPS), primary insomnia, jet lag, nicotine withdrawal, preoperative anxiety and sedation, prostate cancer, solid tumors (when combined with IL-2 therapy in certain cancers), sunburn prevention (topical use), tardive dyskinesia, thrombocytopenia associated with cancer, chemotherapy and other disorders. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Melatonin is a hormone normally produced in the pineal gland and released into the blood. The essential amino acid L-tryptophan is a precursor in the synthesis of melatonin. It helps regulate sleep-wake cycles or the circadian rhythm. Production of melatonin is stimulated by darkness and inhibited by light. High levels of melatonin induce sleep and so consumption of the drug can be used to combat insomnia and jet lag. MT1 and MT2 receptors may be a target for the treatment of circadian and non circadian sleep disorders because of their differences in pharmacology and function within the SCN. SCN is responsible for maintaining the 24 hour cycle which regulates many different body functions ranging from sleep to immune functions •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Melatonin is a derivative of tryptophan. It binds to melatonin receptor type 1A, which then acts on adenylate cylcase and the inhibition of a cAMP signal transduction pathway. Melatonin not only inhibits adenylate cyclase, but it also activates phosphilpase C. This potentiates the release of arachidonate. By binding to melatonin receptors 1 and 2, the downstream signallling cascades have various effects in the body. The melatonin receptors are G protein-coupled receptors and are expressed in various tissues of the body. There are two subtypes of the receptor in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonists, on market or in clinical trials, all bind to and activate both receptor types.The binding of the agonists to the receptors has been investigated for over two decades or since 1986. It is somewhat known, but still not fully understood. When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes. MT1 receptors are expressed in many regions of the central nervous system (CNS): suprachiasmatic nucleus of the hypothalamus (SNC), hippocampus, substantia nigra, cerebellum, central dopaminergic pathways, ventral tegmental area and nucleus accumbens. MT1 is also expressed in the retina, ovary, testis, mammary gland, coronary circulation and aorta, gallbladder, liver, kidney, skin and the immune system. MT2 receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary and aortic tissue, myometrium and granulosa cells, immune cells, duodenum and adipocytes. The binding of melatonin to melatonin receptors activates a few signaling pathways. MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorilation of cAMP responsive element-binding protein (CREB binding protein) into P-CREB. MT1 receptors also activate phospholipase C (PLC), affect ion channels and regulate ion flux inside the cell. The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.[4] As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absorption and bioavailability of melatonin varies widely. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatically metabolized to at least 14 identified metabolites (identified in mouse urine): 6-hydroxymelatonin glucuronide, 6-hydroxymelatonin sulfate, N-acetylserotonin glucuronide, N-acetylserotonin sulfate, 6-hydroxymelatonin, 2-oxomelatonin, 3-hydroxymelatonin, melatonin glucuronide, cyclic melatonin, cyclic N-acetylserotonin glucuronide, cyclic 6-hydroxymelatonin, 5-hydroxyindole-3-acetaldehyde, di-hydroxymelatonin and its glucuronide conjugate. 6-Hydroxymelatonin glucuronide is the major metabolite found in mouse urine (65-88% of total melatonin metabolites in urine). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): 35 to 50 minutes •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Generally well-tolerated when taken orally. The most common side effects, day-time drowsiness, headache and dizziness, appear to occur at the same frequency as with placebo. Other reported side effects include transient depressive symptoms, mild tremor, mild anxiety, abdominal cramps, irritability, reduced alertness, confusion, nausea, vomiting, and hypotension. Safety in Adults: Evidence indicates that it is likely safe to use in oral and parenteral forms for up to two months when used appropriately. Some evidence indicates that it can be safely used orally for up to 9 months in some patients. It is also likely safe to use topically when used appropriately. Safety in Children: Melatonin appeared to be used safely in small numbers of children enrolled in short-term clinical trials. However, concerns regarding safety in children have arisen based on their developmental state. Compared to adults over 20 years of age, people under 20 produce high levels of melatonin. Melatonin levels are inversely related to gonadal development and it is thought that exogenous administration of melatonin may adversely affect gonadal development. Safety during Pregnancy: High doses of melatonin administered orally or parenterally may inhibit ovulation. Not advised for use in individuals who are pregnant or trying to become pregnant. Safety during Lactation: Not recommended as safety has not be established. Oral, rat: LD 50 ≥3200 mg/kg •Brand Names (Drug A): Orencia •Brand Names (Drug B): Circadin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Melatonin Melatonina Mélatonine •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Melatonin is an endogenous hormone produced by the pineal gland that regulates sleep-wake cycles and when provided exogenously has beneficial effects on sleep-onset latency; available as an over-the-counter supplement. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Meloxicam interact?

•Drug A: Abatacept •Drug B: Meloxicam •Severity: MODERATE •Description: The metabolism of Meloxicam can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Meloxicam is indicated for the symptomatic treatment of arthritis and osteoarthritis. In addition, it is indicated for the pauciarticular and polyarticular course of Juvenile Rheumatoid Arthritis (JRA) in patients aged 2 years old or above. Off-label uses include the treatment of dental or post-surgical pain. In addition to the above, meloxicam has also been studied in the treatment of neuropathic pain. Meloxicam, in combination with bupivacaine, is indicated for postsurgical analgesia in adult patients for up to 72 hours following soft tissue surgical procedures, foot and ankle procedures, and other orthopedic procedures in which direct exposure to articular cartilage is avoided. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Meloxicam is an anti-inflammatory, analgesic analgesic with antipyretic effects in fever. Prostaglandins are substances that contribute to inflammation. This drug also exerts preferential actions against COX-2, which may reduce the possible gastrointestinal effects of this drug. In humans, meloxicam has demonstrated the ability to decrease erythrocyte sedimentation rate(ESR) in patients with rheumatoid arthritis, and to decrease ESR, C-reactive protein (CRP), as well as aquaporin-1 expression. As with other NSAIDS, prolonged use of meloxicum can result in renal or cardiovascular impairment or thrombotic cardiovascular events. A note on gastrointestinal effects As meloxicam preferentially inhibits COX-2, it is thought to cause less gastrointestinal irritation compared to other NSAIDS. Despite this, it still carries a risk of gastric inflammation, bleeding and ulceration. In one study, patients on meloxicam suffered from gastrointestinal symptoms at a rate of 13% compared to 19% of those on diclofenac. GI events were found to be less severe in the meloxicam-treated patients. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Meloxicam inhibits prostaglandin synthetase (cylooxygenase 1 and 2) enzymes leading to a decreased synthesis of prostaglandins, which normally mediate painful inflammatory symptoms. As prostaglandins sensitize neuronal pain receptors, inhibition of their synthesis leads to analgesic and inflammatory effects. Meloxicam preferentially inhibits COX-2, but also exerts some activity against COX-1, causing gastrointestinal irritation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability oral capsules after a dose was 89% in one pharmacokinetic study. Cmax was reached 5–6 hours after administration of a single dose given after the first meal of the day. The Cmax doubled when the drug was administered in the fasting state. Despite this, meloxicam can be taken without regard to food, unlike many other NSAIDS. Meloxicam formulated for instillation with bupivacaine produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 1.8 mg of meloxicam produced a C max of 26 ± 14 ng/mL, a median T max of 18 h, and an AUC ∞ of 2079 ± 1631 ng*h/mL. For a 9 mg dose used in herniorrhaphy, the corresponding values were 225 ± 96 ng/mL, 54 h, and the AUC ∞ was not reported. Lastly, a 12 mg dose used in total knee arthroplasty produced values of 275 ± 134 ng/mL, 36 h, and 25,673 ± 17,666 ng*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of meloxicam is 10-15L. Because of its high binding to albumin, it is likely to be distributed in highly perfused tissues, such as the liver and kidney. Meloxicam concentrations in synovial fluid, measured after an oral dose, is estimated at 40% to 50% of the concentrations measured in the plasma. This drug is known to cross the placenta in humans. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Meloxicam is about 99.4% protein bound, primarily to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Meloxicam is almost completely metabolized. CYP2C9 is the main enzyme responsible for the metabolism of meloxicam with minor contributions from CYP3A4. Meloxicam has 4 major metabolites with no activity determined. About 60% of the ingested dose is metabolized to 5'-carboxy meloxicam from hepatic cytochrome enzyme oxidation of an intermediate metabolite, 5’-hydroxymethylmeloxicam. Two other metabolites are likely produced via peroxidation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Meloxicam is mainly eliminated through metabolism. Its metabolites are cleared through renal and fecal elimination. Less than <0.25% of a dose is eliminated in the urine as unchanged drug. About 1.6% of the parent drug is excreted in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life of meloxicam is approximately 20 hours, which is considerably longer than most other NSAIDS. It can therefore be dosed without the need for slow-release formulations. Meloxicam applied together with bupivacaine for postsurgical analgesia had a median half-life of 33-42 hours, depending on dose and application site. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): After an oral dose, the total clearance of meloxicam is 0.42–0.48 L/h. The FDA label indicates a plasma clearance from 7 to 9 mL/min. No dose changes are required in mild to moderate renal or hepatic impairment. The use of meloxicam in patients with severe renal or hepatic impairment has not been studied. FDA prescribing information advises against it. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD50 in rats is 98 mg/kg. Signs and symptoms of overdose with meloxicam may include shallow breathing, seizure, decreased urine output, gastrointestinal irritation, nausea, vomiting, gastrointestinal bleeding, and black tarry stools. In the case of an overdose, offer supportive treatment and attempt to remove gastrointestinal contents. Cholestyramine has been shown to enhance the elimination of meloxicam. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Anjeso, Mobic, Qmiiz, Vivlodex, Zynrelef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Meloxicam is an NSAID used to treat osteoarthritis in adults, rheumatoid arthritis in adults, and juvenile rheumatoid arthritis in pediatrics.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Meloxicam interact? Information: •Drug A: Abatacept •Drug B: Meloxicam •Severity: MODERATE •Description: The metabolism of Meloxicam can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Meloxicam is indicated for the symptomatic treatment of arthritis and osteoarthritis. In addition, it is indicated for the pauciarticular and polyarticular course of Juvenile Rheumatoid Arthritis (JRA) in patients aged 2 years old or above. Off-label uses include the treatment of dental or post-surgical pain. In addition to the above, meloxicam has also been studied in the treatment of neuropathic pain. Meloxicam, in combination with bupivacaine, is indicated for postsurgical analgesia in adult patients for up to 72 hours following soft tissue surgical procedures, foot and ankle procedures, and other orthopedic procedures in which direct exposure to articular cartilage is avoided. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Meloxicam is an anti-inflammatory, analgesic analgesic with antipyretic effects in fever. Prostaglandins are substances that contribute to inflammation. This drug also exerts preferential actions against COX-2, which may reduce the possible gastrointestinal effects of this drug. In humans, meloxicam has demonstrated the ability to decrease erythrocyte sedimentation rate(ESR) in patients with rheumatoid arthritis, and to decrease ESR, C-reactive protein (CRP), as well as aquaporin-1 expression. As with other NSAIDS, prolonged use of meloxicum can result in renal or cardiovascular impairment or thrombotic cardiovascular events. A note on gastrointestinal effects As meloxicam preferentially inhibits COX-2, it is thought to cause less gastrointestinal irritation compared to other NSAIDS. Despite this, it still carries a risk of gastric inflammation, bleeding and ulceration. In one study, patients on meloxicam suffered from gastrointestinal symptoms at a rate of 13% compared to 19% of those on diclofenac. GI events were found to be less severe in the meloxicam-treated patients. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Meloxicam inhibits prostaglandin synthetase (cylooxygenase 1 and 2) enzymes leading to a decreased synthesis of prostaglandins, which normally mediate painful inflammatory symptoms. As prostaglandins sensitize neuronal pain receptors, inhibition of their synthesis leads to analgesic and inflammatory effects. Meloxicam preferentially inhibits COX-2, but also exerts some activity against COX-1, causing gastrointestinal irritation. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absolute bioavailability oral capsules after a dose was 89% in one pharmacokinetic study. Cmax was reached 5–6 hours after administration of a single dose given after the first meal of the day. The Cmax doubled when the drug was administered in the fasting state. Despite this, meloxicam can be taken without regard to food, unlike many other NSAIDS. Meloxicam formulated for instillation with bupivacaine produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 1.8 mg of meloxicam produced a C max of 26 ± 14 ng/mL, a median T max of 18 h, and an AUC ∞ of 2079 ± 1631 ng*h/mL. For a 9 mg dose used in herniorrhaphy, the corresponding values were 225 ± 96 ng/mL, 54 h, and the AUC ∞ was not reported. Lastly, a 12 mg dose used in total knee arthroplasty produced values of 275 ± 134 ng/mL, 36 h, and 25,673 ± 17,666 ng*h/mL. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of meloxicam is 10-15L. Because of its high binding to albumin, it is likely to be distributed in highly perfused tissues, such as the liver and kidney. Meloxicam concentrations in synovial fluid, measured after an oral dose, is estimated at 40% to 50% of the concentrations measured in the plasma. This drug is known to cross the placenta in humans. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Meloxicam is about 99.4% protein bound, primarily to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Meloxicam is almost completely metabolized. CYP2C9 is the main enzyme responsible for the metabolism of meloxicam with minor contributions from CYP3A4. Meloxicam has 4 major metabolites with no activity determined. About 60% of the ingested dose is metabolized to 5'-carboxy meloxicam from hepatic cytochrome enzyme oxidation of an intermediate metabolite, 5’-hydroxymethylmeloxicam. Two other metabolites are likely produced via peroxidation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Meloxicam is mainly eliminated through metabolism. Its metabolites are cleared through renal and fecal elimination. Less than <0.25% of a dose is eliminated in the urine as unchanged drug. About 1.6% of the parent drug is excreted in the feces. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half-life of meloxicam is approximately 20 hours, which is considerably longer than most other NSAIDS. It can therefore be dosed without the need for slow-release formulations. Meloxicam applied together with bupivacaine for postsurgical analgesia had a median half-life of 33-42 hours, depending on dose and application site. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): After an oral dose, the total clearance of meloxicam is 0.42–0.48 L/h. The FDA label indicates a plasma clearance from 7 to 9 mL/min. No dose changes are required in mild to moderate renal or hepatic impairment. The use of meloxicam in patients with severe renal or hepatic impairment has not been studied. FDA prescribing information advises against it. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD50 in rats is 98 mg/kg. Signs and symptoms of overdose with meloxicam may include shallow breathing, seizure, decreased urine output, gastrointestinal irritation, nausea, vomiting, gastrointestinal bleeding, and black tarry stools. In the case of an overdose, offer supportive treatment and attempt to remove gastrointestinal contents. Cholestyramine has been shown to enhance the elimination of meloxicam. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Anjeso, Mobic, Qmiiz, Vivlodex, Zynrelef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Meloxicam is an NSAID used to treat osteoarthritis in adults, rheumatoid arthritis in adults, and juvenile rheumatoid arthritis in pediatrics. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Melphalan interact?

•Drug A: Abatacept •Drug B: Melphalan •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Melphalan is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Melphalan is indicated for use as a high-dose conditioning treatment prior to hematopoietic stem cell transplantation in patients with multiple myeloma. It is also indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Melphalan is a component of HEPZATO KIT, a liver-directed therapy indicated for the treatment of adults with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Melphalan possesses cytotoxic, immunosuppressive, and myeloablative activities. Melphalan produces chromosomal aberrations in vitro and in vivo; thus, it is considered to be potentially leukemogenic in humans. It also causes dose-limiting bone marrow suppression. The peak mean heart rate increased by 20 bpm from baseline following melphalan 100 mg/m for two consecutive days in multiple myeloma patients undergoing autologous stem cell transplantation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Melphalan is an alkylating agent of the bischloroethylamine type. It is believed to be taken up by tumour cells via a neutral amino acid active pathway shared by leucine. Melphalan binds at the N7 position of guanine and induces inter-strand cross-links in DNA, disrupting DNA synthesis or transcription. It can also cause DNA-protein cross-linking and induce lesions in RNA, proteins, and lipids. Melphalan is cytotoxic in resting and rapidly dividing tumour cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absorption of oral melphalan is highly variable concerning both the time to the first appearance of the drug in plasma (range: 0 to 6 hours) and peak plasma concentration (C max ). The average absolute bioavailability of melphalan ranges from 56% to 93%. High variability in bioavailability may be due to incomplete intestinal absorption, variable first-pass hepatic metabolism, or rapid hydrolysis. T max was one hour in patients who received single oral doses of 0.2 mg/kg to 0.25 mg/kg of melphalan. Oral administration of melphalan with a high-fat meal may reduce melphalan exposure (AUC) by 36% to 54%. Mean (± SD) C max and AUC 0-inf were 5.8 ± 1.5 mcg/mL and 451 ± 109 mcg x min/mL, respectively, following intravenous administration of 100 mg/m in multiple myeloma patients. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of melphalan ranges from approximately 35.5 to 185.7 L/m. Penetration into cerebrospinal fluid is low. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding of melphalan ranges from 50% to 90%. Serum albumin is the major binding protein, accounting for approximately 40% to 60% of the plasma protein binding, while α1-acid glycoprotein accounts for about 20% of the plasma protein binding. Approximately 30% of melphalan is covalently and irreversibly bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Melphalan primarily undergoes chemical hydrolysis to inactive metabolites, monohydroxymelphalan and dihydroxymelphalan. No other melphalan metabolites have been observed in humans. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): About 5.8% to 21.3% of melphalan is excreted in urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In patients given a single oral dose of 0.6 mg/kg of melphalan, the terminal elimination plasma half-life (± SD) was 1.5 ± 0.83 hours. Following intravenous administration, the terminal elimination half-life is approximately 75 minutes. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Average total body clearance (CL) ranges from approximately 250 to 325 mL/min/m. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral and intraperitoneal LD 50 in rats is 4484 µg/kg and 11200 µg/kg, respectively. The subcutaneous LD 50 in mice is 32 mg/kg. Overdoses resulting in death have been reported with melphalan. Overdoses, including intravenous doses up to 290 mg/m and oral doses up to 50 mg/day for 16 days, have been reported. Symptoms of overdose include severe nausea and vomiting, decreased consciousness, convulsions, muscular paralysis, cholinomimetic effects, mucositis, stomatitis, colitis, diarrhea, and hemorrhage of the gastrointestinal tract. Elevations in liver enzymes and veno-occlusive disease occur infrequently. Significant hyponatremia, caused by an associated inappropriate secretion of ADH syndrome, has been observed. Nephrotoxicity and adult respiratory distress syndrome have been reported rarely. The principal toxic effect is bone marrow suppression. Melphalan is not removed from plasma via hemodialysis, and overdose is typically managed by general supportive measures, with appropriate blood transfusions and antibiotics. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alkeran, Evomela, Hepzato •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): L-PAM L-Phenylalanine mustard L-Sarcolysine Melfalano Melphalan Melphalanum p-L-Sarcolysin Phenylalanine mustard Phenylalanine nitrogen mustard •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Melphalan is an alkylating agent used to treat multiple myeloma, ovarian carcinoma, uveal melanoma with unresectable hepatic metastases, and for high-dose conditioning before hematopoietic stem cell transplant in patients.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Melphalan interact? Information: •Drug A: Abatacept •Drug B: Melphalan •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Melphalan is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Melphalan is indicated for use as a high-dose conditioning treatment prior to hematopoietic stem cell transplantation in patients with multiple myeloma. It is also indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Melphalan is a component of HEPZATO KIT, a liver-directed therapy indicated for the treatment of adults with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Melphalan possesses cytotoxic, immunosuppressive, and myeloablative activities. Melphalan produces chromosomal aberrations in vitro and in vivo; thus, it is considered to be potentially leukemogenic in humans. It also causes dose-limiting bone marrow suppression. The peak mean heart rate increased by 20 bpm from baseline following melphalan 100 mg/m for two consecutive days in multiple myeloma patients undergoing autologous stem cell transplantation. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Melphalan is an alkylating agent of the bischloroethylamine type. It is believed to be taken up by tumour cells via a neutral amino acid active pathway shared by leucine. Melphalan binds at the N7 position of guanine and induces inter-strand cross-links in DNA, disrupting DNA synthesis or transcription. It can also cause DNA-protein cross-linking and induce lesions in RNA, proteins, and lipids. Melphalan is cytotoxic in resting and rapidly dividing tumour cells. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The absorption of oral melphalan is highly variable concerning both the time to the first appearance of the drug in plasma (range: 0 to 6 hours) and peak plasma concentration (C max ). The average absolute bioavailability of melphalan ranges from 56% to 93%. High variability in bioavailability may be due to incomplete intestinal absorption, variable first-pass hepatic metabolism, or rapid hydrolysis. T max was one hour in patients who received single oral doses of 0.2 mg/kg to 0.25 mg/kg of melphalan. Oral administration of melphalan with a high-fat meal may reduce melphalan exposure (AUC) by 36% to 54%. Mean (± SD) C max and AUC 0-inf were 5.8 ± 1.5 mcg/mL and 451 ± 109 mcg x min/mL, respectively, following intravenous administration of 100 mg/m in multiple myeloma patients. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of melphalan ranges from approximately 35.5 to 185.7 L/m. Penetration into cerebrospinal fluid is low. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding of melphalan ranges from 50% to 90%. Serum albumin is the major binding protein, accounting for approximately 40% to 60% of the plasma protein binding, while α1-acid glycoprotein accounts for about 20% of the plasma protein binding. Approximately 30% of melphalan is covalently and irreversibly bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Melphalan primarily undergoes chemical hydrolysis to inactive metabolites, monohydroxymelphalan and dihydroxymelphalan. No other melphalan metabolites have been observed in humans. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): About 5.8% to 21.3% of melphalan is excreted in urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): In patients given a single oral dose of 0.6 mg/kg of melphalan, the terminal elimination plasma half-life (± SD) was 1.5 ± 0.83 hours. Following intravenous administration, the terminal elimination half-life is approximately 75 minutes. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Average total body clearance (CL) ranges from approximately 250 to 325 mL/min/m. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral and intraperitoneal LD 50 in rats is 4484 µg/kg and 11200 µg/kg, respectively. The subcutaneous LD 50 in mice is 32 mg/kg. Overdoses resulting in death have been reported with melphalan. Overdoses, including intravenous doses up to 290 mg/m and oral doses up to 50 mg/day for 16 days, have been reported. Symptoms of overdose include severe nausea and vomiting, decreased consciousness, convulsions, muscular paralysis, cholinomimetic effects, mucositis, stomatitis, colitis, diarrhea, and hemorrhage of the gastrointestinal tract. Elevations in liver enzymes and veno-occlusive disease occur infrequently. Significant hyponatremia, caused by an associated inappropriate secretion of ADH syndrome, has been observed. Nephrotoxicity and adult respiratory distress syndrome have been reported rarely. The principal toxic effect is bone marrow suppression. Melphalan is not removed from plasma via hemodialysis, and overdose is typically managed by general supportive measures, with appropriate blood transfusions and antibiotics. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alkeran, Evomela, Hepzato •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): L-PAM L-Phenylalanine mustard L-Sarcolysine Melfalano Melphalan Melphalanum p-L-Sarcolysin Phenylalanine mustard Phenylalanine nitrogen mustard •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Melphalan is an alkylating agent used to treat multiple myeloma, ovarian carcinoma, uveal melanoma with unresectable hepatic metastases, and for high-dose conditioning before hematopoietic stem cell transplant in patients. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Meperidine interact?

•Drug A: Abatacept •Drug B: Meperidine •Severity: MODERATE •Description: The metabolism of Meperidine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used to control moderate to severe pain. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Meperidine is a synthetic opiate agonist belonging to the phenylpiperidine class. Meperidine may produce less smooth muscle spasm, constipation, and depression of the cough reflex than equivalent doses of morphine. The onset of action is lightly more rapid than with morphine, and the duration of action is slightly shorter. The chemical structure of meperidine is similar to local anesthetics. Meperidine is recommended for relief of moderate to severe acute pain and has the unique ability to interrupt postoperative shivering and shaking chills induced by amphotericin B. Meperidine has also been used for intravenous regional anesthesia, peripheral nerve blocks and intraarticular, epidural and spinal analgesia. Meperidine is considered a second-line agent for the treatment of acute pain. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Meperidine is primarily a kappa-opiate receptor agonist and also has local anesthetic effects. Meperidine has more affinity for the kappa-receptor than morphine. Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The oral bioavailability of meperidine in patients with normal hepatic function is 50-60% due to extensive first-pass metabolism. Bioavailability increases to 80-90% in patients with hepatic impairment (e.g. liver cirrhosis). Meperidine is less than half as effective when administered orally compared to parenteral administration. One study reported that 80-85% of the drug administered intramuscularly was absorbed within 6 hours of intragluteal injection in health adults; however, inter-individual variation and patient-specific variable appear to cause considerable variations in absorption upon IM injection. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Meperidine crosses the placenta and is distributed into breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 60-80% bound to plasma proteins, primarily albumin and α 1 -acid glycoprotein. The presence of cirrhosis or active viral hepatitis does not appear to affect the extent of protein binding. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Meperidine is metabolized in the liver by hydrolysis to meperidinic acid followed by partial conjugation with glucuronic acid. Meperidine also undergoes N-demethylation to normeperidine, which then undergoes hydrolysis and partial conjugation. Normeperidine is about half as potent as meperidine, but it has twice the CNS stimulation effects. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Excreted in the urine. The proportion of drug that is excreted unchanged or as metabolites is dependent on pH. When urine pH is uncontrolled, 5-30% of the meperidine dose is excreted as normeperidine and approximately 5% is excreted unchanged. Meperidine and normeperidine are found in acidic urine, while the free and conjugated forms of meperidinic and normperidinic acids are found in alkaline urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Initial distribution phase (t 1/2 α ) = 2-11 minutes; terminal elimination phase (t 1/2 β ) = 3-5 hours. In patients with hepatic dysfunction (e.g. liver cirrhosis or active viral hepatitis) the t 1/2 β is prolonged to 7-11 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Demerol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Meperidine is an opioid agonist with analgesic and sedative properties used to manage severe pain.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Meperidine interact? Information: •Drug A: Abatacept •Drug B: Meperidine •Severity: MODERATE •Description: The metabolism of Meperidine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Used to control moderate to severe pain. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Meperidine is a synthetic opiate agonist belonging to the phenylpiperidine class. Meperidine may produce less smooth muscle spasm, constipation, and depression of the cough reflex than equivalent doses of morphine. The onset of action is lightly more rapid than with morphine, and the duration of action is slightly shorter. The chemical structure of meperidine is similar to local anesthetics. Meperidine is recommended for relief of moderate to severe acute pain and has the unique ability to interrupt postoperative shivering and shaking chills induced by amphotericin B. Meperidine has also been used for intravenous regional anesthesia, peripheral nerve blocks and intraarticular, epidural and spinal analgesia. Meperidine is considered a second-line agent for the treatment of acute pain. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Meperidine is primarily a kappa-opiate receptor agonist and also has local anesthetic effects. Meperidine has more affinity for the kappa-receptor than morphine. Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): The oral bioavailability of meperidine in patients with normal hepatic function is 50-60% due to extensive first-pass metabolism. Bioavailability increases to 80-90% in patients with hepatic impairment (e.g. liver cirrhosis). Meperidine is less than half as effective when administered orally compared to parenteral administration. One study reported that 80-85% of the drug administered intramuscularly was absorbed within 6 hours of intragluteal injection in health adults; however, inter-individual variation and patient-specific variable appear to cause considerable variations in absorption upon IM injection. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Meperidine crosses the placenta and is distributed into breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 60-80% bound to plasma proteins, primarily albumin and α 1 -acid glycoprotein. The presence of cirrhosis or active viral hepatitis does not appear to affect the extent of protein binding. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Meperidine is metabolized in the liver by hydrolysis to meperidinic acid followed by partial conjugation with glucuronic acid. Meperidine also undergoes N-demethylation to normeperidine, which then undergoes hydrolysis and partial conjugation. Normeperidine is about half as potent as meperidine, but it has twice the CNS stimulation effects. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Excreted in the urine. The proportion of drug that is excreted unchanged or as metabolites is dependent on pH. When urine pH is uncontrolled, 5-30% of the meperidine dose is excreted as normeperidine and approximately 5% is excreted unchanged. Meperidine and normeperidine are found in acidic urine, while the free and conjugated forms of meperidinic and normperidinic acids are found in alkaline urine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Initial distribution phase (t 1/2 α ) = 2-11 minutes; terminal elimination phase (t 1/2 β ) = 3-5 hours. In patients with hepatic dysfunction (e.g. liver cirrhosis or active viral hepatitis) the t 1/2 β is prolonged to 7-11 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Demerol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Meperidine is an opioid agonist with analgesic and sedative properties used to manage severe pain. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Does Abatacept and Mepolizumab interact?

•Drug A: Abatacept •Drug B: Mepolizumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Mepolizumab. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Mepolizumab is an anti-IL-5 IgG1 kappa monoclonal antibody indicated as an add-on maintenance treatment in patients aged six years and older with severe eosinophilic asthma and as a treatment in adult patients for eosinophilic granulomatosis with polyangiitis (EGPA). Mepolizumab is also indicated for the treatment of hypereosinophilic syndrome (HES) in patients aged 12 and older in whom eosinophilia is present for at least six months without an identifiable non-hematologic secondary cause. Mepolizumab is additionally indicated as an add-on maintenance treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in patients ≥18 years old with inadequate response to nasal corticosteroids. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Mepolizumab is a monoclonal antibody that acts through interleukin-5 (IL-5) antagonism to reduce blood eosinophil levels, generally in the range of 60-90% of baseline depending on dose, which in turn offers therapeutic benefit in the specific conditions for which mepolizumab is indicated. Mepolizumab has a relatively long half-life of between 16 and 22 days, which allows for long-lasting therapeutic benefit and a four-week dosing schedule. Despite a good demonstrated safety profile, mepolizumab use does act to depress part of the immune system and may be associated with increased infections, such as with herpes zoster virus; pre-existing helminth infections should be treated before starting mepolizumab therapy. Inhaled and oral corticosteroids should not be discontinued after starting mepolizumab but may be tapered as appropriate. Mepolizumab should not be used to treat acute bronchospasms or status asthmatics. Finally, hypersensitivity reactions, including anaphylaxis, have been reported in patients; mepolizumab should be discontinued in patients with suspected or confirmed hypersensitivity. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Hypereosinophilia is typically considered as an absolute eosinophil count of 1500/mm or higher and is associated with aberrant immune responses in several conditions, including severe asthma, eosinophilic granulomatosis with polyangiitis, and the variable spectrum of hypereosinophilic syndrome (HES). Eosinophils are involved in the inflammatory response by secretion of molecules such as MBP, leukotrienes, matrix metalloproteinases, transforming growth factor-β, nitric oxide, and other reactive oxygen species. Interleukin-5 (IL-5) is the primary cytokine associated with the differentiation of bone marrow progenitor cells into mature inflammatory neutrophils and the subsequent migration, activation, and prolonged survival of activated neutrophils. In concert with other cells, including lymphocytes, neutrophils, mast cells, and macrophages, which themselves can secrete additional pro-inflammatory molecules, high concentrations of neutrophils are associated with tissue damage and fibrosis, leading to the symptoms of eosinophilic diseases. Typically, eosinophils arise from both CD34 and dual CD34, IL-5 receptor-positive (IL-5R ) progenitor cells, which is in part mediated by the cytokines IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Although there exists a population of eosinophils that are insensitive to IL-5 levels, the main population of inflammatory eosinophils proliferates and migrates into the tissue in response to IL-5. Mepolizumab is a fully-humanized monoclonal IgG1 kappa antibody that binds IL-5 with a dissociation constant of 100 pM, preventing IL-5 from binding to and subsequently activating IL-5R cells. This reduction lowers circulating blood eosinophil levels and therefore exerts a beneficial effect in eosinophilic disease; the exact mechanistic nature of mepolizumab action has not been definitively determined. Not all patients will benefit from mepolizumab treatment, such as those with milder asthma or those with a sub-type of HES that is independent of IL-5 signalling. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Mepolizumab is administered subcutaneously and has a bioavailability of approximately 80% based on a 100 mg dose given to both adult and adolescent subjects with asthma. With the recommended four-week dosing schedule, there is an approximately two-fold accumulation of mepolizumab at steady-state. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Mepolizumab has a population central volume of distribution of 3.6 L (for a 70 kg individual) in adult asthma patients. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): As a monoclonal antibody, mepolizumab is subject to proteolytic degradation at sites distributed throughout the body. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Mepolizumab has a mean terminal half-life of between 16 and 22 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Mepolizumab has an estimated apparent population systemic clearance of 0.28 L/day (for a 70-kg individual) in adult and adolescent subjects. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Toxicity information regarding mepolizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as newly established or worsening chronic infections, including those caused by helminths, and generalized immune depression. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Nucala •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Mepolizumab is a fully-humanized monoclonal IgG1 kappa anti-IL-5 antibody used in conjunction with other therapies to treat severe asthma, eosinophilic granulomatosis with polyangiitis, and hypereosinophilic syndrome.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Mepolizumab interact? Information: •Drug A: Abatacept •Drug B: Mepolizumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Mepolizumab. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Mepolizumab is an anti-IL-5 IgG1 kappa monoclonal antibody indicated as an add-on maintenance treatment in patients aged six years and older with severe eosinophilic asthma and as a treatment in adult patients for eosinophilic granulomatosis with polyangiitis (EGPA). Mepolizumab is also indicated for the treatment of hypereosinophilic syndrome (HES) in patients aged 12 and older in whom eosinophilia is present for at least six months without an identifiable non-hematologic secondary cause. Mepolizumab is additionally indicated as an add-on maintenance treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in patients ≥18 years old with inadequate response to nasal corticosteroids. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Mepolizumab is a monoclonal antibody that acts through interleukin-5 (IL-5) antagonism to reduce blood eosinophil levels, generally in the range of 60-90% of baseline depending on dose, which in turn offers therapeutic benefit in the specific conditions for which mepolizumab is indicated. Mepolizumab has a relatively long half-life of between 16 and 22 days, which allows for long-lasting therapeutic benefit and a four-week dosing schedule. Despite a good demonstrated safety profile, mepolizumab use does act to depress part of the immune system and may be associated with increased infections, such as with herpes zoster virus; pre-existing helminth infections should be treated before starting mepolizumab therapy. Inhaled and oral corticosteroids should not be discontinued after starting mepolizumab but may be tapered as appropriate. Mepolizumab should not be used to treat acute bronchospasms or status asthmatics. Finally, hypersensitivity reactions, including anaphylaxis, have been reported in patients; mepolizumab should be discontinued in patients with suspected or confirmed hypersensitivity. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Hypereosinophilia is typically considered as an absolute eosinophil count of 1500/mm or higher and is associated with aberrant immune responses in several conditions, including severe asthma, eosinophilic granulomatosis with polyangiitis, and the variable spectrum of hypereosinophilic syndrome (HES). Eosinophils are involved in the inflammatory response by secretion of molecules such as MBP, leukotrienes, matrix metalloproteinases, transforming growth factor-β, nitric oxide, and other reactive oxygen species. Interleukin-5 (IL-5) is the primary cytokine associated with the differentiation of bone marrow progenitor cells into mature inflammatory neutrophils and the subsequent migration, activation, and prolonged survival of activated neutrophils. In concert with other cells, including lymphocytes, neutrophils, mast cells, and macrophages, which themselves can secrete additional pro-inflammatory molecules, high concentrations of neutrophils are associated with tissue damage and fibrosis, leading to the symptoms of eosinophilic diseases. Typically, eosinophils arise from both CD34 and dual CD34, IL-5 receptor-positive (IL-5R ) progenitor cells, which is in part mediated by the cytokines IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Although there exists a population of eosinophils that are insensitive to IL-5 levels, the main population of inflammatory eosinophils proliferates and migrates into the tissue in response to IL-5. Mepolizumab is a fully-humanized monoclonal IgG1 kappa antibody that binds IL-5 with a dissociation constant of 100 pM, preventing IL-5 from binding to and subsequently activating IL-5R cells. This reduction lowers circulating blood eosinophil levels and therefore exerts a beneficial effect in eosinophilic disease; the exact mechanistic nature of mepolizumab action has not been definitively determined. Not all patients will benefit from mepolizumab treatment, such as those with milder asthma or those with a sub-type of HES that is independent of IL-5 signalling. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Mepolizumab is administered subcutaneously and has a bioavailability of approximately 80% based on a 100 mg dose given to both adult and adolescent subjects with asthma. With the recommended four-week dosing schedule, there is an approximately two-fold accumulation of mepolizumab at steady-state. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Mepolizumab has a population central volume of distribution of 3.6 L (for a 70 kg individual) in adult asthma patients. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): As a monoclonal antibody, mepolizumab is subject to proteolytic degradation at sites distributed throughout the body. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Mepolizumab has a mean terminal half-life of between 16 and 22 days. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Mepolizumab has an estimated apparent population systemic clearance of 0.28 L/day (for a 70-kg individual) in adult and adolescent subjects. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Toxicity information regarding mepolizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as newly established or worsening chronic infections, including those caused by helminths, and generalized immune depression. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Nucala •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Mepolizumab is a fully-humanized monoclonal IgG1 kappa anti-IL-5 antibody used in conjunction with other therapies to treat severe asthma, eosinophilic granulomatosis with polyangiitis, and hypereosinophilic syndrome. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Mercaptopurine interact?

•Drug A: Abatacept •Drug B: Mercaptopurine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Mercaptopurine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For remission induction and maintenance therapy of acute lymphatic leukemia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Mercaptopurine is one of a large series of purine analogues which interfere with nucleic acid biosynthesis and has been found active against human leukemias. It is an analogue of the purine bases adenine and hypoxanthine. It is not known exactly which of any one or more of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Mercaptopurine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to thioinosinic acid (TIMP). TIMP inhibits several reactions that involve inosinic acid (IMP), such as the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP). Upon methylation, TIMP forms 6-methylthioinosinate (MTIMP) which inhibits glutamine-5-phosphoribosylpyrophosphate amidotransferase in addition to TIMP. Glutamine-5-phosphoribosylpyrophosphate amidotransferase is the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. According to experimental findings using radiolabeled mercaptopurine, mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. In comparison, some mercaptopurine may be converted to nucleotide derivatives of 6-thioguanine (6-TG) via actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase that convert TIMP to thioguanylic acid (TGMP). •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Clinical studies have shown that the absorption of an oral dose of mercaptopurine in humans is incomplete and variable, averaging approximately 50% of the administered dose. The factors influencing absorption are unknown. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution exceeded that of the total body water. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding averages 19% over the concentration range 10 to 50 µg/mL (a concentration only achieved by intravenous administration of mercaptopurine at doses exceeding 5 to 10 mg/kg). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Degradation primarily by xanthine oxidase. The catabolism of mercaptopurine and its metabolites is complex. In humans, after oral administration of S-6-mercaptopurine, urine contains intact mercaptopurine, thiouric acid (formed by direct oxidation by xanthine oxidase, probably via 6-mercapto-8-hydroxypurine), and a number of 6-methylated thiopurines. The methylthiopurines yield appreciable amounts of inorganic sulfate. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Triphasic: 45 minutes, 2.5 hours, and 10 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Signs and symptoms of overdosage may be immediate such as anorexia, nausea, vomiting, and diarrhea; or delayed such as myelosuppression, liver dysfunction, and gastroenteritis. The oral LD 50 of mercaptopurine was determined to be 480 mg/kg in the mouse and 425 mg/kg in the rat. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Purixan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1,9-DIHYDRO-6H-PURINE-6-THIONE Mercaptopurina Mercaptopurine Mercaptopurinum Mercapurin •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Mercaptopurine is an antineoplastic agent used to treat acute lymphocytic leukemia.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Mercaptopurine interact? Information: •Drug A: Abatacept •Drug B: Mercaptopurine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Mercaptopurine is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For remission induction and maintenance therapy of acute lymphatic leukemia. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Mercaptopurine is one of a large series of purine analogues which interfere with nucleic acid biosynthesis and has been found active against human leukemias. It is an analogue of the purine bases adenine and hypoxanthine. It is not known exactly which of any one or more of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Mercaptopurine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to thioinosinic acid (TIMP). TIMP inhibits several reactions that involve inosinic acid (IMP), such as the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP). Upon methylation, TIMP forms 6-methylthioinosinate (MTIMP) which inhibits glutamine-5-phosphoribosylpyrophosphate amidotransferase in addition to TIMP. Glutamine-5-phosphoribosylpyrophosphate amidotransferase is the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. According to experimental findings using radiolabeled mercaptopurine, mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. In comparison, some mercaptopurine may be converted to nucleotide derivatives of 6-thioguanine (6-TG) via actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase that convert TIMP to thioguanylic acid (TGMP). •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Clinical studies have shown that the absorption of an oral dose of mercaptopurine in humans is incomplete and variable, averaging approximately 50% of the administered dose. The factors influencing absorption are unknown. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution exceeded that of the total body water. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding averages 19% over the concentration range 10 to 50 µg/mL (a concentration only achieved by intravenous administration of mercaptopurine at doses exceeding 5 to 10 mg/kg). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Degradation primarily by xanthine oxidase. The catabolism of mercaptopurine and its metabolites is complex. In humans, after oral administration of S-6-mercaptopurine, urine contains intact mercaptopurine, thiouric acid (formed by direct oxidation by xanthine oxidase, probably via 6-mercapto-8-hydroxypurine), and a number of 6-methylated thiopurines. The methylthiopurines yield appreciable amounts of inorganic sulfate. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Triphasic: 45 minutes, 2.5 hours, and 10 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Signs and symptoms of overdosage may be immediate such as anorexia, nausea, vomiting, and diarrhea; or delayed such as myelosuppression, liver dysfunction, and gastroenteritis. The oral LD 50 of mercaptopurine was determined to be 480 mg/kg in the mouse and 425 mg/kg in the rat. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Purixan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1,9-DIHYDRO-6H-PURINE-6-THIONE Mercaptopurina Mercaptopurine Mercaptopurinum Mercapurin •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Mercaptopurine is an antineoplastic agent used to treat acute lymphocytic leukemia. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Metamfetamine interact?

•Drug A: Abatacept •Drug B: Metamfetamine •Severity: MODERATE •Description: The metabolism of Metamfetamine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of Attention Deficit Disorder with Hyperactivity (ADHD) and exogenous obesity. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Methamphetamine is a potent central nervous system stimulant which affects neurochemical mechanisms responsible for regulating heart rate, body temperature, blood pressure, appetite, attention, mood and responses associated with alertness or alarm conditions. The acute effects of the drug closely resemble the physiological and psychological effects of an epinephrine-provoked fight-or-flight response, including increased heart rate and blood pressure, vasoconstriction (constriction of the arterial walls), bronchodilation, and hyperglycemia (increased blood sugar). Users experience an increase in focus, increased mental alertness, and the elimination of fatigue, as well as a decrease in appetite. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Methamphetamine enters the brain and triggers a cascading release of norepinephrine, dopamine and serotonin. To a lesser extent methamphetamine acts as a dopaminergic and adrenergic reuptake inhibitor and in high concentrations as a monamine oxidase inhibitor (MAOI). The mechanism of action involved in producing the beneficial behavioral changes seen in hyperkinetic children receiving methamphetamine is unknown. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Methamphetamine is rapidly absorbed from the gastrointestinal tract with peak methamphetamine concentrations occurring in 3.13 to 6.3 hours post ingestion. Moreover, when administered intranasally or as an inhalation, methamphetamine also demonstrates a high degree of absorption. It is distributed to most parts of the body. Because methamphetamine has a high lipophilicity it is distributed across the blood brain barrier and crosses the placenta. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. The primary site of metabolism is in the liver by aromatic hydroxylation, N-dealkylation and deamination. At least seven metabolites have been identified in the urine, with the main metabolites being amphetamine (active) and 4-hydroxymethamphetamine. Other minor metabolites include 4-hydroxyamphetamine, norephedrine, and 4-hydroxynorephedrine. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Excretion occurs primarily in the urine, the rate of which is dependent on urine pH. Between 30-54% of an oral dose is excreted in urine as unchanged methamphetamine and 10-23% as unchanged amphetamine. Following an intravenous dose, 45% is excreted as unchanged parent drug and 7% amphetamine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The biological half-life has been reported in the range of 4 to 5 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Manifestations of acute overdosage with methamphetamine include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia, and rhabdomyolysis. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning usually terminates in convulsions and coma. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Desoxyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): d-deoxyephedrine d-desoxyephedrine d-N-methylamphetamine d-phenylisopropylmethylamine Dextromethamphetamine Métamfétamine Metamfetamine Metamfetaminum Metanfetamina Methamphetamine Methamphetaminum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Metamfetamine is a sympathomimetic agent used in the treatment of attention deficit hyperactivity disorder (ADHD) and exogenous obesity.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Metamfetamine interact? Information: •Drug A: Abatacept •Drug B: Metamfetamine •Severity: MODERATE •Description: The metabolism of Metamfetamine can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): For the treatment of Attention Deficit Disorder with Hyperactivity (ADHD) and exogenous obesity. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Methamphetamine is a potent central nervous system stimulant which affects neurochemical mechanisms responsible for regulating heart rate, body temperature, blood pressure, appetite, attention, mood and responses associated with alertness or alarm conditions. The acute effects of the drug closely resemble the physiological and psychological effects of an epinephrine-provoked fight-or-flight response, including increased heart rate and blood pressure, vasoconstriction (constriction of the arterial walls), bronchodilation, and hyperglycemia (increased blood sugar). Users experience an increase in focus, increased mental alertness, and the elimination of fatigue, as well as a decrease in appetite. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Methamphetamine enters the brain and triggers a cascading release of norepinephrine, dopamine and serotonin. To a lesser extent methamphetamine acts as a dopaminergic and adrenergic reuptake inhibitor and in high concentrations as a monamine oxidase inhibitor (MAOI). The mechanism of action involved in producing the beneficial behavioral changes seen in hyperkinetic children receiving methamphetamine is unknown. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Methamphetamine is rapidly absorbed from the gastrointestinal tract with peak methamphetamine concentrations occurring in 3.13 to 6.3 hours post ingestion. Moreover, when administered intranasally or as an inhalation, methamphetamine also demonstrates a high degree of absorption. It is distributed to most parts of the body. Because methamphetamine has a high lipophilicity it is distributed across the blood brain barrier and crosses the placenta. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. The primary site of metabolism is in the liver by aromatic hydroxylation, N-dealkylation and deamination. At least seven metabolites have been identified in the urine, with the main metabolites being amphetamine (active) and 4-hydroxymethamphetamine. Other minor metabolites include 4-hydroxyamphetamine, norephedrine, and 4-hydroxynorephedrine. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Excretion occurs primarily in the urine, the rate of which is dependent on urine pH. Between 30-54% of an oral dose is excreted in urine as unchanged methamphetamine and 10-23% as unchanged amphetamine. Following an intravenous dose, 45% is excreted as unchanged parent drug and 7% amphetamine. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The biological half-life has been reported in the range of 4 to 5 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): Manifestations of acute overdosage with methamphetamine include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia, and rhabdomyolysis. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning usually terminates in convulsions and coma. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Desoxyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): d-deoxyephedrine d-desoxyephedrine d-N-methylamphetamine d-phenylisopropylmethylamine Dextromethamphetamine Métamfétamine Metamfetamine Metamfetaminum Metanfetamina Methamphetamine Methamphetaminum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Metamfetamine is a sympathomimetic agent used in the treatment of attention deficit hyperactivity disorder (ADHD) and exogenous obesity. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Methadone interact?

•Drug A: Abatacept •Drug B: Methadone •Severity: MODERATE •Description: The metabolism of Methadone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Methadone is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatment options are inadequate. It's recommended that use is reserved for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Methadone is also indicated for detoxification treatment of opioid addiction (heroin or other morphine-like drugs), and for maintenance substitution treatment for opioid dependence in adults in conjunction with appropriate social and medical services. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Overall, methadone's pharmacological actions result in analgesia, suppression of opioid withdrawal symptoms, sedation, miosis (through binding to receptors in the pupillary muscles), sweating, hypotension, bradycardia, nausea and vomiting (via binding within the chemoreceptor trigger zone), and constipation. Like many basic drugs, methadone also enters mast cells and releases histamine by a non-immunological mechanism leading to flushing, pruritus, and urticaria, which can commonly be misattributed to an allergic reaction. Compared to other opioids, methadone has fewer active metabolites and therefore a lower risk of neuropsychiatric toxicity. This means that higher doses needed to manage severe pain or addiction are less likely to result in delirium, hyperalgesia, or seizures. Similar to morphine, both methadone isomers are 5-HT(3) receptor antagonists, although l-methadone produces greater inhibition than d-methadone. Methadone's effects are reversible by naloxone with a pA2 value similar to its antagonism of morphine. Dependence and Tolerance As with other opioids, tolerance and physical dependence may develop upon repeated administration of methadone and there is a potential for development of psychological dependence. Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning. Cardiac Conduction Effects Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Methadone should be administered with particular caution to patients already at risk for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia). Careful monitoring is recommended when using methadone in patients with a history of cardiac conduction disease, those taking medications affecting cardiac conduction, and in other cases where history or physical exam suggest an increased risk of dysrhythmia. Respiratory Depression and Overdose Serious, life-threatening, or fatal respiratory depression may occur with use of methadone. Patients should be monitored for respiratory depression, especially during initiation of methadone or following a dose increase. Respiratory depression is of particular concern in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Methadone should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, and CNS depression or coma. In these patients, even usual therapeutic doses of methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative, non-opioid analgesics should be considered, and methadone should be employed only under careful medical supervision at the lowest effective dose. Infants exposed in-utero or through breast milk are at risk of life-threatening respiratory depression upon delivery or when nursed. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, in the short-term use setting. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. Head Injury and Increased Intracranial Pressure The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce effects which may obscure the clinical course of patients with head injuries. In such patients, methadone must be used with caution, and only if it is deemed essential. Incomplete Cross-tolerance between Methadone and other Opioids Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is of particular concern for patients tolerant to other µ-opioid agonists who are being converted to methadone, thus making the determination of dosing during opioid conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. A high degree of “opioid tolerance” does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Crosstolerance between morphine and methadone has been demonstrated, as steady-state plasma methadone concentrations required for effectiveness (C50%) were higher in abstinent rats previously dosed with morphine, as compared to controls. Misuse, Abuse, and Diversion of Opioids Methadone is a mu-agonist opioid with an abuse liability similar to morphine. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion. Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when dispensing Methadone in situations where the clinician is concerned about an increased risk of misuse, abuse, or diversion. Hypotensive Effect The administration of methadone may result in severe hypotension in patients whose ability to maintain normal blood pressure is compromised (e.g., severe volume depletion). Gastrointestinal Effects Methadone and other morphine-like opioids have been shown to decrease bowel motility and cause constipation. This primarily occurs through agonism of opioid receptors in the gut wall. Methadone may obscure the diagnosis or clinical course of patients with acute abdominal conditions. Sexual Function/Reproduction Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported. Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Methadone is a synthetic opioid analgesic with full agonist activity at the µ-opioid receptor. While agonism of the µ-opioid receptor is the primary mechanism of action for the treatment of pain, methadone also acts as an agonist of κ- and σ-opioid receptors within the central and peripheral nervous systems. Interestingly, methadone differs from morphine (which is considered the gold standard reference opioid) in its antagonism of the N-methyl-D-aspartate (NMDA) receptor and its strong inhibition of serotonin and norepinephrine uptake, which likely also contributes to its antinociceptive activity. Methadone is administered as a 50:50 racemic mixture of (R)- and (S)-stereoisomers, with (R)-methadone demonstrating ~10-fold higher affinity and potency for the µ-opioid receptor than the (S) stereoisomer. The analgesic activity of the racemate is almost entirely due to the (R)-isomer, while the (S)-isomer lacks significant respiratory depressant activity but does have antitussive effects. While methadone shares similar effects and risks of other opioids such as morphine, hydromorphone, oxycodone, and fentanyl it has a number of unique pharmacokinetic and pharmacodynamic properties that distinguish it from them and make it a useful agent for the treatment of opioid addiction. For example, methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Methadone is one of the more lipid-soluble opioids and is well absorbed from the gastrointestinal tract. Following oral administration of methadone, bioavailability ranges from 36-100%, with a marked interindividual variation. It can be detected in blood as soon as 15-45 minutes following administration with peak plasma concentrations achieved between 1 to 7.5 hours. A second peak is observed ~4 hours after administration and is likely due to enterohepatic circulation. Dose proportionality of methadone pharmacokinetics is not known. Following administration of daily oral doses ranging from 10 to 225 mg the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated. Slower absorption is observed in opioid users compared to healthy subjects, which may reflect the pharmacological effect of opioids in slowing gastric emptying and mobility. Due to the large inter-individual variation in methadone pharmacokinetics and pharmacodynamics, treatment should be individualized to each patient. There was an up to 17-fold interindividual variation found in methadone blood concentrations for a given dosage, likely due in part to individual variability in CYP enzyme function. There is also a large variability in pharmacokinetics between methadone's enantiomers, which further complicates pharmacokinetic interpretation and study. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Due to interindividual differences in pharmacokinetics, estimates of methadone's volume of distribution have ranged from 189-470 L with monographs listing it between 1.0-8.0L/kg. As this is higher than physiological volumes of total body water, methadone is highly distributed in the body including brain, gut, kidney, liver, muscle, and lung. A population pharmacokinetic study found that subject gender and weight explained ~33% of the variance in the apparent volume of distribution of methadone. Methadone is found to be secreted in saliva, sweat, breast milk, amniotic fluid and umbilical cord plasma. The concentration in cord blood is about half the maternal levels. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Methadone is highly bound to plasma proteins. While it primarily binds to α1-acid glycoprotein (85-90%), it also binds to albumin and other tissue and plasma proteins including lipoproteins. Methadone is unusual in the opioid class, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Methadone undergoes fairly extensive first-pass metabolism. Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9, CYP2C8, and CYP2D6, are responsible for conversion of methadone to EDDP (2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine) and other inactive metabolites, which are excreted mainly in the urine. Methadone first undergoes N-demethylation to form a highly unstable compound that spontaneously converts to EDDP through cyclization and dehydration. EDDP is then converted to 2-ethyl5-methyl-3,3-diphenyl-1-pyrroline (EDMP). Both EDDP and EDMP are inactive. The CYP isozymes also demonstrate different affinities for metabolizing the different methadone enantiomers: CYP2C19, CYP3A7, and CYP2C8 preferentially metabolize (R)-methadone while CYP2B6, CYP2D6, and CYP2C18 preferentially metabolize (S)-methadone. CYP3A4 does not have an enantiomer preference. Single nucleotide polymorphisms (SNPs) within the cytochrome P450 enzymes can impact methadone pharmacokinetics and contribute to the interindividual variation in response to methadone therapy. In particular, CYP2B6 polymorphisms have been shown to impact individual response to methadone as it is the predominant determinant involved in the N-demethylation of methadone, clearance, and the metabolic ratios of [methadone]/[EDDP]. The SNPs CYP2B6*6, *9, *11, CYP2C19*2, *3, CYP3A4*1B, and CYP3A5*3 result in increased methadone plasma concentrations, decreased N-demethylation, and decreased methadone clearance, while homozygous carriers of CYP2B6*6/*6 demonstrate diminished metabolism and clearance of methadone. See the pharmacogenomics section for further information. Pharmacogenomic effects on the CYP enzymes can be significant as the long half-life of methadone can result in some individuals having higher than normal therapeutic levels which puts them at risk of dose-related side effects. For example, elevated (R)-methadone levels can increase the risk of respiratory depression, while elevated (S)-methadone levels can increase the risk of severe cardiac arrhythmias due to prolonged QTc interval. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Due to interindividual differences in pharmacokinetics, estimates of methadone's half-life have ranged from 15–207 hours with official monographs listing it between 7-59 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Due to interindividual differences in pharmacokinetics, estimates of methadone's clearance have ranged from 5.9–13 L/h hours with approved monographs listing it between 1.4 to 126 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Diskets, Dolophine, Metadol, Metadol-D, Methadose •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Metadona Methadone Methadonum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Methadone is an opioid analgesic indicated for management of severe pain that is not responsive to alternative treatments. Also used to aid in detoxification and maintenance treatment of opioid addiction.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Methadone interact? Information: •Drug A: Abatacept •Drug B: Methadone •Severity: MODERATE •Description: The metabolism of Methadone can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Methadone is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatment options are inadequate. It's recommended that use is reserved for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Methadone is also indicated for detoxification treatment of opioid addiction (heroin or other morphine-like drugs), and for maintenance substitution treatment for opioid dependence in adults in conjunction with appropriate social and medical services. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Overall, methadone's pharmacological actions result in analgesia, suppression of opioid withdrawal symptoms, sedation, miosis (through binding to receptors in the pupillary muscles), sweating, hypotension, bradycardia, nausea and vomiting (via binding within the chemoreceptor trigger zone), and constipation. Like many basic drugs, methadone also enters mast cells and releases histamine by a non-immunological mechanism leading to flushing, pruritus, and urticaria, which can commonly be misattributed to an allergic reaction. Compared to other opioids, methadone has fewer active metabolites and therefore a lower risk of neuropsychiatric toxicity. This means that higher doses needed to manage severe pain or addiction are less likely to result in delirium, hyperalgesia, or seizures. Similar to morphine, both methadone isomers are 5-HT(3) receptor antagonists, although l-methadone produces greater inhibition than d-methadone. Methadone's effects are reversible by naloxone with a pA2 value similar to its antagonism of morphine. Dependence and Tolerance As with other opioids, tolerance and physical dependence may develop upon repeated administration of methadone and there is a potential for development of psychological dependence. Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning. Cardiac Conduction Effects Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Methadone should be administered with particular caution to patients already at risk for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia). Careful monitoring is recommended when using methadone in patients with a history of cardiac conduction disease, those taking medications affecting cardiac conduction, and in other cases where history or physical exam suggest an increased risk of dysrhythmia. Respiratory Depression and Overdose Serious, life-threatening, or fatal respiratory depression may occur with use of methadone. Patients should be monitored for respiratory depression, especially during initiation of methadone or following a dose increase. Respiratory depression is of particular concern in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Methadone should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, and CNS depression or coma. In these patients, even usual therapeutic doses of methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative, non-opioid analgesics should be considered, and methadone should be employed only under careful medical supervision at the lowest effective dose. Infants exposed in-utero or through breast milk are at risk of life-threatening respiratory depression upon delivery or when nursed. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, in the short-term use setting. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. Head Injury and Increased Intracranial Pressure The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce effects which may obscure the clinical course of patients with head injuries. In such patients, methadone must be used with caution, and only if it is deemed essential. Incomplete Cross-tolerance between Methadone and other Opioids Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is of particular concern for patients tolerant to other µ-opioid agonists who are being converted to methadone, thus making the determination of dosing during opioid conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. A high degree of “opioid tolerance” does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Crosstolerance between morphine and methadone has been demonstrated, as steady-state plasma methadone concentrations required for effectiveness (C50%) were higher in abstinent rats previously dosed with morphine, as compared to controls. Misuse, Abuse, and Diversion of Opioids Methadone is a mu-agonist opioid with an abuse liability similar to morphine. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion. Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when dispensing Methadone in situations where the clinician is concerned about an increased risk of misuse, abuse, or diversion. Hypotensive Effect The administration of methadone may result in severe hypotension in patients whose ability to maintain normal blood pressure is compromised (e.g., severe volume depletion). Gastrointestinal Effects Methadone and other morphine-like opioids have been shown to decrease bowel motility and cause constipation. This primarily occurs through agonism of opioid receptors in the gut wall. Methadone may obscure the diagnosis or clinical course of patients with acute abdominal conditions. Sexual Function/Reproduction Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported. Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Methadone is a synthetic opioid analgesic with full agonist activity at the µ-opioid receptor. While agonism of the µ-opioid receptor is the primary mechanism of action for the treatment of pain, methadone also acts as an agonist of κ- and σ-opioid receptors within the central and peripheral nervous systems. Interestingly, methadone differs from morphine (which is considered the gold standard reference opioid) in its antagonism of the N-methyl-D-aspartate (NMDA) receptor and its strong inhibition of serotonin and norepinephrine uptake, which likely also contributes to its antinociceptive activity. Methadone is administered as a 50:50 racemic mixture of (R)- and (S)-stereoisomers, with (R)-methadone demonstrating ~10-fold higher affinity and potency for the µ-opioid receptor than the (S) stereoisomer. The analgesic activity of the racemate is almost entirely due to the (R)-isomer, while the (S)-isomer lacks significant respiratory depressant activity but does have antitussive effects. While methadone shares similar effects and risks of other opioids such as morphine, hydromorphone, oxycodone, and fentanyl it has a number of unique pharmacokinetic and pharmacodynamic properties that distinguish it from them and make it a useful agent for the treatment of opioid addiction. For example, methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Methadone is one of the more lipid-soluble opioids and is well absorbed from the gastrointestinal tract. Following oral administration of methadone, bioavailability ranges from 36-100%, with a marked interindividual variation. It can be detected in blood as soon as 15-45 minutes following administration with peak plasma concentrations achieved between 1 to 7.5 hours. A second peak is observed ~4 hours after administration and is likely due to enterohepatic circulation. Dose proportionality of methadone pharmacokinetics is not known. Following administration of daily oral doses ranging from 10 to 225 mg the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated. Slower absorption is observed in opioid users compared to healthy subjects, which may reflect the pharmacological effect of opioids in slowing gastric emptying and mobility. Due to the large inter-individual variation in methadone pharmacokinetics and pharmacodynamics, treatment should be individualized to each patient. There was an up to 17-fold interindividual variation found in methadone blood concentrations for a given dosage, likely due in part to individual variability in CYP enzyme function. There is also a large variability in pharmacokinetics between methadone's enantiomers, which further complicates pharmacokinetic interpretation and study. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): Due to interindividual differences in pharmacokinetics, estimates of methadone's volume of distribution have ranged from 189-470 L with monographs listing it between 1.0-8.0L/kg. As this is higher than physiological volumes of total body water, methadone is highly distributed in the body including brain, gut, kidney, liver, muscle, and lung. A population pharmacokinetic study found that subject gender and weight explained ~33% of the variance in the apparent volume of distribution of methadone. Methadone is found to be secreted in saliva, sweat, breast milk, amniotic fluid and umbilical cord plasma. The concentration in cord blood is about half the maternal levels. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Methadone is highly bound to plasma proteins. While it primarily binds to α1-acid glycoprotein (85-90%), it also binds to albumin and other tissue and plasma proteins including lipoproteins. Methadone is unusual in the opioid class, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Methadone undergoes fairly extensive first-pass metabolism. Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9, CYP2C8, and CYP2D6, are responsible for conversion of methadone to EDDP (2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine) and other inactive metabolites, which are excreted mainly in the urine. Methadone first undergoes N-demethylation to form a highly unstable compound that spontaneously converts to EDDP through cyclization and dehydration. EDDP is then converted to 2-ethyl5-methyl-3,3-diphenyl-1-pyrroline (EDMP). Both EDDP and EDMP are inactive. The CYP isozymes also demonstrate different affinities for metabolizing the different methadone enantiomers: CYP2C19, CYP3A7, and CYP2C8 preferentially metabolize (R)-methadone while CYP2B6, CYP2D6, and CYP2C18 preferentially metabolize (S)-methadone. CYP3A4 does not have an enantiomer preference. Single nucleotide polymorphisms (SNPs) within the cytochrome P450 enzymes can impact methadone pharmacokinetics and contribute to the interindividual variation in response to methadone therapy. In particular, CYP2B6 polymorphisms have been shown to impact individual response to methadone as it is the predominant determinant involved in the N-demethylation of methadone, clearance, and the metabolic ratios of [methadone]/[EDDP]. The SNPs CYP2B6*6, *9, *11, CYP2C19*2, *3, CYP3A4*1B, and CYP3A5*3 result in increased methadone plasma concentrations, decreased N-demethylation, and decreased methadone clearance, while homozygous carriers of CYP2B6*6/*6 demonstrate diminished metabolism and clearance of methadone. See the pharmacogenomics section for further information. Pharmacogenomic effects on the CYP enzymes can be significant as the long half-life of methadone can result in some individuals having higher than normal therapeutic levels which puts them at risk of dose-related side effects. For example, elevated (R)-methadone levels can increase the risk of respiratory depression, while elevated (S)-methadone levels can increase the risk of severe cardiac arrhythmias due to prolonged QTc interval. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Due to interindividual differences in pharmacokinetics, estimates of methadone's half-life have ranged from 15–207 hours with official monographs listing it between 7-59 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Due to interindividual differences in pharmacokinetics, estimates of methadone's clearance have ranged from 5.9–13 L/h hours with approved monographs listing it between 1.4 to 126 L/h. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Diskets, Dolophine, Metadol, Metadol-D, Methadose •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Metadona Methadone Methadonum •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Methadone is an opioid analgesic indicated for management of severe pain that is not responsive to alternative treatments. Also used to aid in detoxification and maintenance treatment of opioid addiction. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Does Abatacept and Methimazole interact?

•Drug A: Abatacept •Drug B: Methimazole •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Methimazole is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): In the United States, methimazole is indicated for the treatment of hyperthyroidism in patients with Graves' disease or toxic multinodular goiter for whom thyroidectomy or radioactive iodine therapy are not appropriate treatment options. Methimazole is also indicated for the amelioration of hyperthyroid symptoms in preparation for thyroidectomy or radioactive iodine therapy. In Canada, methimazole carries the above indications and is also indicated for the medical treatment of hyperthyroidism regardless of other available treatment options. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Methimazole inhibits the synthesis of thyroid hormones resulting in an alleviation of hyperthyroidism. Onset of action occurs within 12 to 18 hours, and its duration of action is 36 to 72 hours, likely due to concentration of methimazole and some metabolites within the thyroid gland after administration. The most serious potential side effect of methimazole therapy is agranulocytosis, and patients should be instructed to monitor for, and report, any signs or symptoms of agranulocytosis such as fever or sore throat. Other cytopenias may also occur during methimazole therapy. There also exists the potential for severe hepatic toxicity with the use of methimazole, and monitoring for signs and symptoms of hepatic dysfunction, such as jaundice, anorexia, pruritus, and elevation in liver transaminases, is prudent in patients using this therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Methimazole's primary mechanism of action appears to be interference in an early step in thyroid hormone synthesis involving thyroid peroxidase (TPO), however the exact method through which methimazole inhibits this step is unclear. TPO, along with hydrogen peroxide, normally catalyzes the conversion of iodide to iodine and then further catalyzes the incorporation of this iodine onto the 3 and/or 5 positions of the phenol rings of tyrosine residues in thyroglobulin. These thyroglobulin molecules then degrade within thyroid follicular cells to form either thyroxine (T 4 ) or tri-iodothyronine (T 3 ), which are the main hormones produced by the thyroid gland. Methimazole may directly inhibit TPO, but has been shown in vivo to instead act as a competitive substrate for TPO, thus becoming iodinated itself and interfering with the iodination of thyroglobulin. Another proposed theory is that methimazole’s sulfur moiety may interact directly with the iron atom at the centre of TPO’s heme molecule, thus inhibiting its ability to iodinate tyrosine residues. Other proposed mechanisms with weaker evidence include methimazole binding directly to thyroglobulin or direct inhibition of thyroglobulin itself. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption of methimazole after oral administration is rapid and extensive, with an absolute bioavailability of approximately 0.93 and a T max ranging from 0.25 to 4.0 hours. C max is slightly, but not significantly, higher in hyperthyroid patients, and both C max and AUC are significantly affected by the oral dose administered. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of methimazole has been reported as roughly 20 L. Following oral administration, methimazole is highly concentrated in the thyroid gland - intrathyroidal methimazole levels are approximately 2 to 5 times higher than peak plasma levels, and remain high for 20 hours after ingestion. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Methimazole exhibits little-to-no protein binding, existing primarily as free drug in the serum. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Methimazole is rapidly and extensively metabolized by the liver, mainly via the CYP450 and FMO enzyme systems. Several metabolites have been identified, though the specific enzyme isoforms responsible for their formation are not entirely clear. One of the first methimazole metabolites identified, 3-methyl-2-thiohydantoin, may contribute to antithyroid activity - its antithyroid activity has been demonstrated in rats and may explain the prolonged duration of iodination inhibition following administration despite methimazole's relatively short half-life. A number of metabolites have been investigated as being the culprits behind methimazole-induced hepatotoxicity. Both glyoxal and N-methylthiourea have established cytotoxicity and are known metabolic products of methimazole's dihydrodiol intermediate. Sulfenic and sulfinic acid derivatives of methimazole are thought to be the ultimate toxicants responsible for hepatotoxicity, though their origin is unclear - they may arise from direct oxidation of methimazole via FMO, or from oxidation of N-methylthiourea further downstream in the metabolic process. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Urinary excretion of unchanged methimazole has been reported to be between 7% and 12%. Elimination via feces appears to be limited, with a cumulative fecal excretion of 3% after administration of methimazole. Enterohepatic circulation also appears to play a role in the elimination of methimazole and its metabolites, as significant amounts of these substances are found in the bile post-administration. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Following a single intravenous bolus injection of 10mg of methimazole, the t 1/2 of the distribution phase was 0.17 hours and the t 1/2 of the elimination phase was 5.3 hours. Methimazole's primary active metabolite, 3-methyl-2-thiohydantoin, has a half-life approximately 3 times longer than its parent drug. Renal impairment does not appear to alter the half-life of methimazole, but patients with hepatic impairment showed an increase in half-life roughly proportional to the severity of their impairment - moderate insufficiency resulted in a elimination t 1/2 of 7.1 hours, while severe insufficiency resulted in an elimination t 1/2 of 22.1 hours. There does not appear to be any significant differences in half-life based on thyroid status (i.e. no difference between euthyroid and hyperthyroid patients). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Following a single intravenous bolus injection of 10mg of methimazole, clearance was found to be 5.70 L/h. Renal impairment does not appear to alter clearance of methimazole, but patients with hepatic impairment showed a reduction in clearance roughly proportional to the severity of their impairment - moderate insufficiency resulted in a clearance of 3.49 L/h, while severe insufficiency resulted in a clearance of 0.83 L/h. There does not appear to be any significant differences in clearance based on thyroid status (i.e. no difference between euthyroid and hyperthyroid patients). •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 of methimazole in rats is 2250 mg/kg. Signs and symptoms of methimazole overdose may include gastrointestinal distress, headache, fever, joint pain, pruritus, and edema. More serious adverse effects, such as aplastic anemia or agranulocytosis, may manifest within hours to days. Hepatitis, nephrotic syndrome, exfoliative dermatitis, and CNS effects such as neuropathy or CNS depression/stimulation are also potential, albeit less frequent, results of overdose. Management of overdose involves supportive treatment as dictated by the patient's status. This may involve monitoring of the patient's vital signs, blood gases, serum electrolytes, or bone marrow function as indicated. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tapazole •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Methimazole Thiamazol Thiamazole Thiamazolum Tiamazol •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Methimazole is a thionamide antithyroid agent that inhibits the actions of thyroid peroxidase, leading to a reduction in thyroid hormone synthesis and amelioration of hyperthyroidism.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Abatacept and Methimazole interact? Information: •Drug A: Abatacept •Drug B: Methimazole •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Methimazole is combined with Abatacept. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): In the United States, methimazole is indicated for the treatment of hyperthyroidism in patients with Graves' disease or toxic multinodular goiter for whom thyroidectomy or radioactive iodine therapy are not appropriate treatment options. Methimazole is also indicated for the amelioration of hyperthyroid symptoms in preparation for thyroidectomy or radioactive iodine therapy. In Canada, methimazole carries the above indications and is also indicated for the medical treatment of hyperthyroidism regardless of other available treatment options. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Methimazole inhibits the synthesis of thyroid hormones resulting in an alleviation of hyperthyroidism. Onset of action occurs within 12 to 18 hours, and its duration of action is 36 to 72 hours, likely due to concentration of methimazole and some metabolites within the thyroid gland after administration. The most serious potential side effect of methimazole therapy is agranulocytosis, and patients should be instructed to monitor for, and report, any signs or symptoms of agranulocytosis such as fever or sore throat. Other cytopenias may also occur during methimazole therapy. There also exists the potential for severe hepatic toxicity with the use of methimazole, and monitoring for signs and symptoms of hepatic dysfunction, such as jaundice, anorexia, pruritus, and elevation in liver transaminases, is prudent in patients using this therapy. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Methimazole's primary mechanism of action appears to be interference in an early step in thyroid hormone synthesis involving thyroid peroxidase (TPO), however the exact method through which methimazole inhibits this step is unclear. TPO, along with hydrogen peroxide, normally catalyzes the conversion of iodide to iodine and then further catalyzes the incorporation of this iodine onto the 3 and/or 5 positions of the phenol rings of tyrosine residues in thyroglobulin. These thyroglobulin molecules then degrade within thyroid follicular cells to form either thyroxine (T 4 ) or tri-iodothyronine (T 3 ), which are the main hormones produced by the thyroid gland. Methimazole may directly inhibit TPO, but has been shown in vivo to instead act as a competitive substrate for TPO, thus becoming iodinated itself and interfering with the iodination of thyroglobulin. Another proposed theory is that methimazole’s sulfur moiety may interact directly with the iron atom at the centre of TPO’s heme molecule, thus inhibiting its ability to iodinate tyrosine residues. Other proposed mechanisms with weaker evidence include methimazole binding directly to thyroglobulin or direct inhibition of thyroglobulin itself. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Absorption of methimazole after oral administration is rapid and extensive, with an absolute bioavailability of approximately 0.93 and a T max ranging from 0.25 to 4.0 hours. C max is slightly, but not significantly, higher in hyperthyroid patients, and both C max and AUC are significantly affected by the oral dose administered. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The apparent volume of distribution of methimazole has been reported as roughly 20 L. Following oral administration, methimazole is highly concentrated in the thyroid gland - intrathyroidal methimazole levels are approximately 2 to 5 times higher than peak plasma levels, and remain high for 20 hours after ingestion. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Methimazole exhibits little-to-no protein binding, existing primarily as free drug in the serum. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Methimazole is rapidly and extensively metabolized by the liver, mainly via the CYP450 and FMO enzyme systems. Several metabolites have been identified, though the specific enzyme isoforms responsible for their formation are not entirely clear. One of the first methimazole metabolites identified, 3-methyl-2-thiohydantoin, may contribute to antithyroid activity - its antithyroid activity has been demonstrated in rats and may explain the prolonged duration of iodination inhibition following administration despite methimazole's relatively short half-life. A number of metabolites have been investigated as being the culprits behind methimazole-induced hepatotoxicity. Both glyoxal and N-methylthiourea have established cytotoxicity and are known metabolic products of methimazole's dihydrodiol intermediate. Sulfenic and sulfinic acid derivatives of methimazole are thought to be the ultimate toxicants responsible for hepatotoxicity, though their origin is unclear - they may arise from direct oxidation of methimazole via FMO, or from oxidation of N-methylthiourea further downstream in the metabolic process. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Urinary excretion of unchanged methimazole has been reported to be between 7% and 12%. Elimination via feces appears to be limited, with a cumulative fecal excretion of 3% after administration of methimazole. Enterohepatic circulation also appears to play a role in the elimination of methimazole and its metabolites, as significant amounts of these substances are found in the bile post-administration. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): Following a single intravenous bolus injection of 10mg of methimazole, the t 1/2 of the distribution phase was 0.17 hours and the t 1/2 of the elimination phase was 5.3 hours. Methimazole's primary active metabolite, 3-methyl-2-thiohydantoin, has a half-life approximately 3 times longer than its parent drug. Renal impairment does not appear to alter the half-life of methimazole, but patients with hepatic impairment showed an increase in half-life roughly proportional to the severity of their impairment - moderate insufficiency resulted in a elimination t 1/2 of 7.1 hours, while severe insufficiency resulted in an elimination t 1/2 of 22.1 hours. There does not appear to be any significant differences in half-life based on thyroid status (i.e. no difference between euthyroid and hyperthyroid patients). •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Following a single intravenous bolus injection of 10mg of methimazole, clearance was found to be 5.70 L/h. Renal impairment does not appear to alter clearance of methimazole, but patients with hepatic impairment showed a reduction in clearance roughly proportional to the severity of their impairment - moderate insufficiency resulted in a clearance of 3.49 L/h, while severe insufficiency resulted in a clearance of 0.83 L/h. There does not appear to be any significant differences in clearance based on thyroid status (i.e. no difference between euthyroid and hyperthyroid patients). •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 of methimazole in rats is 2250 mg/kg. Signs and symptoms of methimazole overdose may include gastrointestinal distress, headache, fever, joint pain, pruritus, and edema. More serious adverse effects, such as aplastic anemia or agranulocytosis, may manifest within hours to days. Hepatitis, nephrotic syndrome, exfoliative dermatitis, and CNS effects such as neuropathy or CNS depression/stimulation are also potential, albeit less frequent, results of overdose. Management of overdose involves supportive treatment as dictated by the patient's status. This may involve monitoring of the patient's vital signs, blood gases, serum electrolytes, or bone marrow function as indicated. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tapazole •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Methimazole Thiamazol Thiamazole Thiamazolum Tiamazol •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Methimazole is a thionamide antithyroid agent that inhibits the actions of thyroid peroxidase, leading to a reduction in thyroid hormone synthesis and amelioration of hyperthyroidism. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Abatacept and Methotrexate interact?

•Drug A: Abatacept •Drug B: Methotrexate •Severity: MAJOR •Description: The metabolism of Methotrexate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Methotrexate oral solution is indicated for pediatric acute lymphoblastic leukemia and pediatric polyarticular juvenile idiopathic arthritis. Methotrexate injections for subcutaneous use are indicated for severe active rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and severe, recalcitrant, disabling psoriasis. It has also been approved by the EMA for the treatment of adult patients requiring systemic therapy for moderate-to-severe plaque psoriasis. Other formulations are indicated to treat gestational choriocarcinoma, chorioadenoma destruens, hydatiform mole, breast cancer, epidermoid cancer of the head and neck, advanced mycosis fungoides, lung cancer, and advanced non-Hodgkin's lymphoma. It is also used in the maintenance of acute lymphocytic leukemia. Methotrexate is also given before treatment with leucovorin to prolong relapse-free survival following surgical removal of a tumour in non-metastatic osteosarcoma. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Methotrexate inhibits enzymes responsible for nucleotide synthesis which prevents cell division and leads to anti-inflammatory actions. It has a long duration of action and is generally given to patients once weekly. Methotrexate has a narrow therapeutic index. Do not take methotrexate daily. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Methotrexate enters tissues and is converted to a methotrexate polyglutamate by folylpolyglutamate. Methotrexate's mechanism of action is due to its inhibition of enzymes responsible for nucleotide synthesis including dihydrofolate reductase, thymidylate synthase, aminoimidazole caboxamide ribonucleotide transformylase (AICART), and amido phosphoribosyltransferase. Inhibtion of nucleotide synthesis prevents cell division. In rheumatoid arthritis, methotrexate polyglutamates inhibit AICART more than methotrexate. This inhibition leads to accumulation of AICART ribonucleotide, which inhibits adenosine deaminase, leading to an accumulation of adenosine triphosphate and adenosine in the extracellular space, stimulating adenosine receptors, leading to anti-inflammatory action. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Methotrexate has a bioavailability of 64-90%, though this decreases at oral doses above 25mg due to saturation of the carrier mediated transport of methotrexate.. Methotrexate has a T max of 1 to 2 hours. oral doses of 10-15µg reach serum levels of 0.01-0.1µM. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of methotrexate at steady state is approximately 1L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Methotrexate is 46.5-54% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Methotrexate is metabolized by folylpolyglutamate synthase to methotrexate polyglutamate in the liver as well as in tissues. Gamma-glutamyl hydrolase hydrolyzes the glutamyl chains of methotrexate polyglutamates converting them back to methotrexate. A small amount of methotrexate is also converted to 7-hydroxymethotrexate. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Methotrexate is >80% excreted as the unchanged drug and approximately 3% as the 7-hydroxylated metabolite. Methotrexate is primarily excreted in the urine with 8.7-26% of an intravenous dose appearing in the bile. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half life of low dose methotrexate is 3 to 10 hours in adults. The half life for high dose methotrexate is 8 to 15 hours. Pediatric patients taking methotrexate for acute lymphoblastic anemia experience a terminal half life of 0.7 to 5.8 hours. Pediatric patients taking methotrexate for juvenile idiopathic arthritis experience a half life of 0.9 to 2.3 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Methotrexate clearance varies widely between patients and decreases with increasing doses. Currently, predicting clearance of methotrexate is difficult and exceedingly high serum levels of methotrexate can still occur when all precautions are taken. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in rats is 135mg/kg and in mice is 146mg/kg. Symptoms of overdose include hematologic and gastrointestinal reactions like leukopenia, thombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, and gastrointestinal bleeding. In the event of an overdose, patients should be treated with glucarpidase and not be given leucovorin for 2 hours before or after glucarpidase. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Metoject, Nordimet, Otrexup, Rasuvo, Reditrex, Trexall, Xatmep •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amethopterin Methotrexat Méthotrexate Methotrexate Methotrexatum Metotrexato •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Methotrexate is an antineoplastic agent used the treatment of a wide variety of cancers as well as severe psoriasis, severe rheumatoid arthritis, and juvenile rheumatoid arthritis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Methotrexate interact? Information: •Drug A: Abatacept •Drug B: Methotrexate •Severity: MAJOR •Description: The metabolism of Methotrexate can be increased when combined with Abatacept. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Abatacept is indicated in adult patients for the treatment of moderately-to-severely active rheumatoid arthritis and in patients ≥2 years of age for the treatment of active psoriatic arthritis. In patients two years of age and older, abatacept is also indicated for the treatment of moderately-to-severely active juvenile idiopathic arthritis. Abatacept is also indicated for the prophylaxis of acute graft-versus-host disease, in combination with methotrexate and a calcineurin inhibitor such as tacrolimus, in patients two years of age and older who are undergoing hematopoietic stem cell transplantation from a matched or 1 allele-mismatched unrelated donor. •Indication (Drug B): Methotrexate oral solution is indicated for pediatric acute lymphoblastic leukemia and pediatric polyarticular juvenile idiopathic arthritis. Methotrexate injections for subcutaneous use are indicated for severe active rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and severe, recalcitrant, disabling psoriasis. It has also been approved by the EMA for the treatment of adult patients requiring systemic therapy for moderate-to-severe plaque psoriasis. Other formulations are indicated to treat gestational choriocarcinoma, chorioadenoma destruens, hydatiform mole, breast cancer, epidermoid cancer of the head and neck, advanced mycosis fungoides, lung cancer, and advanced non-Hodgkin's lymphoma. It is also used in the maintenance of acute lymphocytic leukemia. Methotrexate is also given before treatment with leucovorin to prolong relapse-free survival following surgical removal of a tumour in non-metastatic osteosarcoma. •Pharmacodynamics (Drug A): Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G 1 (IgG 1. The Fc portion of the drug consists of the hinge region, the C H 2 domain, and the C H 3 domain of IgG 1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy. •Pharmacodynamics (Drug B): Methotrexate inhibits enzymes responsible for nucleotide synthesis which prevents cell division and leads to anti-inflammatory actions. It has a long duration of action and is generally given to patients once weekly. Methotrexate has a narrow therapeutic index. Do not take methotrexate daily. •Mechanism of action (Drug A): Abatacept is a selective costimulation modulator - like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. •Mechanism of action (Drug B): Methotrexate enters tissues and is converted to a methotrexate polyglutamate by folylpolyglutamate. Methotrexate's mechanism of action is due to its inhibition of enzymes responsible for nucleotide synthesis including dihydrofolate reductase, thymidylate synthase, aminoimidazole caboxamide ribonucleotide transformylase (AICART), and amido phosphoribosyltransferase. Inhibtion of nucleotide synthesis prevents cell division. In rheumatoid arthritis, methotrexate polyglutamates inhibit AICART more than methotrexate. This inhibition leads to accumulation of AICART ribonucleotide, which inhibits adenosine deaminase, leading to an accumulation of adenosine triphosphate and adenosine in the extracellular space, stimulating adenosine receptors, leading to anti-inflammatory action. •Absorption (Drug A): When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. •Absorption (Drug B): Methotrexate has a bioavailability of 64-90%, though this decreases at oral doses above 25mg due to saturation of the carrier mediated transport of methotrexate.. Methotrexate has a T max of 1 to 2 hours. oral doses of 10-15µg reach serum levels of 0.01-0.1µM. •Volume of distribution (Drug A): 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration] •Volume of distribution (Drug B): The volume of distribution of methotrexate at steady state is approximately 1L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Methotrexate is 46.5-54% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Methotrexate is metabolized by folylpolyglutamate synthase to methotrexate polyglutamate in the liver as well as in tissues. Gamma-glutamyl hydrolase hydrolyzes the glutamyl chains of methotrexate polyglutamates converting them back to methotrexate. A small amount of methotrexate is also converted to 7-hydroxymethotrexate. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Methotrexate is >80% excreted as the unchanged drug and approximately 3% as the 7-hydroxylated metabolite. Methotrexate is primarily excreted in the urine with 8.7-26% of an intravenous dose appearing in the bile. •Half-life (Drug A): 16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients. •Half-life (Drug B): The half life of low dose methotrexate is 3 to 10 hours in adults. The half life for high dose methotrexate is 8 to 15 hours. Pediatric patients taking methotrexate for acute lymphoblastic anemia experience a terminal half life of 0.7 to 5.8 hours. Pediatric patients taking methotrexate for juvenile idiopathic arthritis experience a half life of 0.9 to 2.3 hours. •Clearance (Drug A): 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight. •Clearance (Drug B): Methotrexate clearance varies widely between patients and decreases with increasing doses. Currently, predicting clearance of methotrexate is difficult and exceedingly high serum levels of methotrexate can still occur when all precautions are taken. •Toxicity (Drug A): Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic effect. •Toxicity (Drug B): The oral LD 50 in rats is 135mg/kg and in mice is 146mg/kg. Symptoms of overdose include hematologic and gastrointestinal reactions like leukopenia, thombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, and gastrointestinal bleeding. In the event of an overdose, patients should be treated with glucarpidase and not be given leucovorin for 2 hours before or after glucarpidase. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Metoject, Nordimet, Otrexup, Rasuvo, Reditrex, Trexall, Xatmep •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amethopterin Methotrexat Méthotrexate Methotrexate Methotrexatum Metotrexato •Summary (Drug A): Abatacept is a disease-modifying antirheumatic drug (DMARD) used in the management of rheumatic conditions, such as rheumatoid or psoriatic arthritis, and for the prophylaxis of acute graft-versus-host disease. •Summary (Drug B): Methotrexate is an antineoplastic agent used the treatment of a wide variety of cancers as well as severe psoriasis, severe rheumatoid arthritis, and juvenile rheumatoid arthritis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.