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Does Abatacept and Aldesleukin interact?

•Drug A: Abatacept •Drug B: Aldesleukin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Aldesleukin 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 adults with metastatic renal cell carcinoma. •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 to treat renal cell carcinoma, Aldesleukin induces the enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines, the enhancement of lymphocyte cytotoxicity, the induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and the induction of interferon-gamma production. IL-2 is normally produced by the body, secreted by T cells, and stimulates growth and differentiation of T cell response. It can be used in immunotherapy to treat cancer. It enhances the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor. •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): Aldesleukin binds to the IL-2 receptor which leads to heterodimerization of the cytoplasmic domains of the IL-2R beta and gamma(c) chains, activation of the tyrosine kinase Jak3, and phosphorylation of tyrosine residues on the IL-2R beta chain. These events led to the creation of an activated receptor complex, to which various cytoplasmic signaling molecules are recruited and become substrates for regulatory enzymes (especially tyrosine kinases) that are associated with the receptor. These events stimulate growth and differentiation of T 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): 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): 0.18 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): The pharmacokinetic profile of Proleukin is characterized by high plasma concentrations following a short IV infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. Following the initial rapid organ distribution, the primary route of clearance of circulating proleukin is the kidney. Greater than 80% of the amount of Proleukin distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules. •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 min-85 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): 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): Proleukin •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): Aldesleukin is a recombinant analog of interleukin-2 used to induce an adaptive immune response in the treatment of renal cell carcinoma.

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 Aldesleukin interact? Information: •Drug A: Abatacept •Drug B: Aldesleukin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Aldesleukin 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 adults with metastatic renal cell carcinoma. •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 to treat renal cell carcinoma, Aldesleukin induces the enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines, the enhancement of lymphocyte cytotoxicity, the induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and the induction of interferon-gamma production. IL-2 is normally produced by the body, secreted by T cells, and stimulates growth and differentiation of T cell response. It can be used in immunotherapy to treat cancer. It enhances the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor. •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): Aldesleukin binds to the IL-2 receptor which leads to heterodimerization of the cytoplasmic domains of the IL-2R beta and gamma(c) chains, activation of the tyrosine kinase Jak3, and phosphorylation of tyrosine residues on the IL-2R beta chain. These events led to the creation of an activated receptor complex, to which various cytoplasmic signaling molecules are recruited and become substrates for regulatory enzymes (especially tyrosine kinases) that are associated with the receptor. These events stimulate growth and differentiation of T 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): 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): 0.18 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): The pharmacokinetic profile of Proleukin is characterized by high plasma concentrations following a short IV infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. Following the initial rapid organ distribution, the primary route of clearance of circulating proleukin is the kidney. Greater than 80% of the amount of Proleukin distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules. •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 min-85 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): 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): Proleukin •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): Aldesleukin is a recombinant analog of interleukin-2 used to induce an adaptive immune response in the treatment of renal cell carcinoma. 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 Alectinib interact?

•Drug A: Abatacept •Drug B: Alectinib •Severity: MAJOR •Description: The metabolism of Alectinib 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): Alectinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. •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): Alectinib is a second generation oral drug that selectively inhibits the activity of anaplastic lymphoma kinase (ALK) tyrosine kinase. It is specifically used in the treatment of non-small cell lung cancer (NSCLC) expressing the ALK-EML4 (echinoderm microtubule-associated protein-like 4) fusion protein that causes proliferation of NSCLC cells. Inhibition of ALK prevents phosphorylation and subsequent downstream activation of STAT3 and AKT resulting in reduced tumour cell viability. Both alectinib and its major active metabolite M4 demonstrate similar in vivo and in vitro activity against multiple mutant forms of ALK. •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): Alectinib reached maximal concentrations at 4 hours following administration of 600 mg twice daily under fed conditions in patients with ALK-positive NSCLC. The absolute bioavailability was 37% in the fed state. A high-fat, high-calorie meal increased the combined exposure of alectinib and its major metabolite M4 by 3.1-fold following oral administration of a single 600 mg 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): 4016 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Alectinib and its major metabolite M4 are >99% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Alectinib is metabolized by CYP3A4 to its major active metabolite M4. M4 is then further metabolized by CYP3A4. Both alectinib and M4 demonstrate similar in vivo and in vitro activity. In vitro studies suggest that alectinib is not a substrate for P-gp while M4 is. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): When radioactively labeled, 98% of radioactivity was found in feces with 84% of that amount excreted as unchanged alectinib and 6% as M4. Less than 0.5% was found to be recovered 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): The mean elimination half life is 33 hr for alectinib and 31 hr for M4. •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 is 81.9L/hr for alectinib and 217 L/hr for M4. •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 (>5%) associated with alectinib use were fatigue, constipation, edema, and myalgia. Less common effects associated with use were hepatotoxicity, interstitial lung disease (ILD)/pneumonitis, bradycardia, severe myalgia and creatine phosphokinase (CPK) elevation, and embryo-fetal toxicity. Females of reproductive potential are advised to use effective contraception during treatment with alectinib and for 1 week following the final dose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alecensa, Alecensaro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alectinib •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): Alectinib is a kinase inhibitor used to treat anaplastic lymphoma kinase positive metastatic non small cell lung 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 CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Alectinib interact? Information: •Drug A: Abatacept •Drug B: Alectinib •Severity: MAJOR •Description: The metabolism of Alectinib 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): Alectinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. •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): Alectinib is a second generation oral drug that selectively inhibits the activity of anaplastic lymphoma kinase (ALK) tyrosine kinase. It is specifically used in the treatment of non-small cell lung cancer (NSCLC) expressing the ALK-EML4 (echinoderm microtubule-associated protein-like 4) fusion protein that causes proliferation of NSCLC cells. Inhibition of ALK prevents phosphorylation and subsequent downstream activation of STAT3 and AKT resulting in reduced tumour cell viability. Both alectinib and its major active metabolite M4 demonstrate similar in vivo and in vitro activity against multiple mutant forms of ALK. •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): Alectinib reached maximal concentrations at 4 hours following administration of 600 mg twice daily under fed conditions in patients with ALK-positive NSCLC. The absolute bioavailability was 37% in the fed state. A high-fat, high-calorie meal increased the combined exposure of alectinib and its major metabolite M4 by 3.1-fold following oral administration of a single 600 mg 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): 4016 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Alectinib and its major metabolite M4 are >99% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Alectinib is metabolized by CYP3A4 to its major active metabolite M4. M4 is then further metabolized by CYP3A4. Both alectinib and M4 demonstrate similar in vivo and in vitro activity. In vitro studies suggest that alectinib is not a substrate for P-gp while M4 is. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): When radioactively labeled, 98% of radioactivity was found in feces with 84% of that amount excreted as unchanged alectinib and 6% as M4. Less than 0.5% was found to be recovered 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): The mean elimination half life is 33 hr for alectinib and 31 hr for M4. •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 is 81.9L/hr for alectinib and 217 L/hr for M4. •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 (>5%) associated with alectinib use were fatigue, constipation, edema, and myalgia. Less common effects associated with use were hepatotoxicity, interstitial lung disease (ILD)/pneumonitis, bradycardia, severe myalgia and creatine phosphokinase (CPK) elevation, and embryo-fetal toxicity. Females of reproductive potential are advised to use effective contraception during treatment with alectinib and for 1 week following the final dose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alecensa, Alecensaro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alectinib •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): Alectinib is a kinase inhibitor used to treat anaplastic lymphoma kinase positive metastatic non small cell lung 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 CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Alemtuzumab interact?

•Drug A: Abatacept •Drug B: Alemtuzumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Alemtuzumab 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): LEMTRADA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, the use of LEMTRADA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS. LEMTRADA contains the same active ingredient (alemtuzumab) found in CAMPATH, and CAMPATH is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), although generally administered at higher and more frequent doses (e.g., 30 mg) than recommended in the treatment of MS. •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): Alemtuzumab depletes circulating T and B lymphocytes after each treatment course. In clinical trials, the lowest cell counts occurred 1 month after a course of treatment at the time of the first post-treatment blood count. Lymphocyte counts then increased over time: B cell counts usually recovered within 6 months; T cell counts increased more slowly and usually remained below baseline 12 months after treatment. Approximately 60% of patients had total lymphocyte counts below the lower limit of normal 6 months after each treatment course and 20% had counts below the lower limit of normal after 12 months. Reconstitution of the lymphocyte population varies for the different lymphocyte subtypes. At Month 1 in clinical trials, the mean CD4+ lymphocyte count was 40 cells per microliter, and, at Month 12, 270 cells per microliter. At 30 months, approximately half of patients had CD4+ lymphocyte counts that remained below the lower limit of normal. •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 alemtuzumab exerts its therapeutic effects in multiple sclerosis is unknown but is presumed to involve binding to CD52, a cell surface antigen present on T and B lymphocytes, and on natural killer cells, monocytes, and macrophages. Following cell surface binding to T and B lymphocytes, alemtuzumab results in antibody-dependent cellular cytolysis and complement-mediated lysis. Research suggests that alemtuzumab can also exert immunomodulatory effects through the depletion and repopulation of lymphocytes, including alterations in the number, proportions, and properties of some lymphocyte subsets posttreatment, increasing representation of regulatory T cell subsets, and increasing representation of memory T- and B-lymphocytes. The reduction in the level of circulating B and T cells by alemtuzumab and subsequent repopulation may reduce the potential for relapse, which ultimately delays disease progression. •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): Serum concentrations increased with each consecutive dose within a treatment course, with the highest observed concentrations occurring following the last infusion of a treatment course. The mean maximum concentration was 3014 ng/mL on Day 5 of the first treatment course, and 2276 ng/mL on Day 3 of the second treatment course. •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): Alemtuzumab is largely confined to the blood and interstitial space with a central volume of distribution of 14.1 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): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Alemtuzumab is a large-molecule monoclonal antibody and as such, it is cleared primarily through target-mediated clearance and through simple non-target specific IgG clearance mechanisms. Alemtuzumab is not excreted renally or eliminated via cytochrome P450 (CYP450) isoenzymes. Alemtuzumab is most likely removed by opsonization via the reticuloendothelial system when bound to B or T lymphocytes. •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 was approximately 2 weeks and was comparable between courses. The serum concentrations were generally undetectable (<60 ng/mL) within approximately 30 days following each treatment course. •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 alemtuzumab ranged from 0.012 – 0.096 l/h depending on the study, dose group, and anti-alemtuzumab antibody status. The inter-subject variability for clearance was large (58 %). Higher clearance values were observed in cycle 1 compared to cycle 2, with the decrease in clearance from cycle 1 to cycle 2 being less than 20%. •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): LEMTRADA induces persistent thyroid disorders [see Warnings and Precautions (5.8)]. Untreated hypothyroidism in pregnant women increases the risk of miscarriage and may have effects on the fetus including mental retardation and dwarfism. In mothers with Graves’ disease, maternal thyroid stimulating hormone receptor antibodies can be transferred to a developing fetus and can cause neonatal Graves’ disease. In a patient who developed Graves’ disease after treatment with alemtuzumab, placental transfer of anti-thyrotropin receptor antibodies resulted in neonatal Graves’ disease with thyroid storm in her infant who was born 1 year after alemtuzumab dosing. When LEMTRADA was administered to pregnant huCD52 transgenic mice during organogenesis (gestation days [GD] 6-10 or GD 11-15) at doses of 3 or 10 mg/kg IV, no teratogenic effects were observed. However, there was an increase in embryo lethality (increased postimplantation loss and the number of dams with all fetuses dead or resorbed) in pregnant animals dosed during GD 11-15. In a separate study in pregnant huCD52 transgenic mice, administration of LEMTRADA during organogenesis (GD 6-10 or GD 11-15) at doses of 3 or 10 mg/kg IV, decreases in B- and T-lymphocyte populations were observed in the offspring at both doses tested. In pregnant huCD52 transgenic mice administered LEMTRADA at doses of 3 or 10 mg/kg/day IV throughout gestation and lactation, there was an increase in pup deaths during the lactation period at 10 mg/kg. Decreases in T- and B-lymphocyte populations and in antibody response were observed in offspring at both doses tested. Before initiation of LEMTRADA treatment, women of childbearing potential should be counseled on the potential for serious risk to the fetus. To avoid in-utero exposure to LEMTRADA, women of childbearing potential should use effective contraceptive measures when receiving a course of treatment with LEMTRADA and for 4 months following that course of treatment. In huCD52 transgenic mice, administration of LEMTRADA prior to and during the mating period resulted in adverse effects on sperm parameters in males and a reduced number of corpora lutea and implantations in females. Two MS patients experienced serious reactions (headache, rash, and either hypotension or sinus tachycardia) after a single accidental infusion of up to 60 mg of LEMTRADA. Doses of LEMTRADA greater than those recommended may increase the intensity and/or duration of infusion reactions or their immune effects. There is no known antidote for alemtuzumab overdosage. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Campath, Lemtrada, MabCampath •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): Alemtuzumab is a monoclonal anti-CD52 antibody used in the treatment of B-cell chronic lymphocytic leukemia and relapsing forms of multiple sclerosis.

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 Alemtuzumab interact? Information: •Drug A: Abatacept •Drug B: Alemtuzumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Alemtuzumab 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): LEMTRADA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, the use of LEMTRADA should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS. LEMTRADA contains the same active ingredient (alemtuzumab) found in CAMPATH, and CAMPATH is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), although generally administered at higher and more frequent doses (e.g., 30 mg) than recommended in the treatment of MS. •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): Alemtuzumab depletes circulating T and B lymphocytes after each treatment course. In clinical trials, the lowest cell counts occurred 1 month after a course of treatment at the time of the first post-treatment blood count. Lymphocyte counts then increased over time: B cell counts usually recovered within 6 months; T cell counts increased more slowly and usually remained below baseline 12 months after treatment. Approximately 60% of patients had total lymphocyte counts below the lower limit of normal 6 months after each treatment course and 20% had counts below the lower limit of normal after 12 months. Reconstitution of the lymphocyte population varies for the different lymphocyte subtypes. At Month 1 in clinical trials, the mean CD4+ lymphocyte count was 40 cells per microliter, and, at Month 12, 270 cells per microliter. At 30 months, approximately half of patients had CD4+ lymphocyte counts that remained below the lower limit of normal. •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 alemtuzumab exerts its therapeutic effects in multiple sclerosis is unknown but is presumed to involve binding to CD52, a cell surface antigen present on T and B lymphocytes, and on natural killer cells, monocytes, and macrophages. Following cell surface binding to T and B lymphocytes, alemtuzumab results in antibody-dependent cellular cytolysis and complement-mediated lysis. Research suggests that alemtuzumab can also exert immunomodulatory effects through the depletion and repopulation of lymphocytes, including alterations in the number, proportions, and properties of some lymphocyte subsets posttreatment, increasing representation of regulatory T cell subsets, and increasing representation of memory T- and B-lymphocytes. The reduction in the level of circulating B and T cells by alemtuzumab and subsequent repopulation may reduce the potential for relapse, which ultimately delays disease progression. •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): Serum concentrations increased with each consecutive dose within a treatment course, with the highest observed concentrations occurring following the last infusion of a treatment course. The mean maximum concentration was 3014 ng/mL on Day 5 of the first treatment course, and 2276 ng/mL on Day 3 of the second treatment course. •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): Alemtuzumab is largely confined to the blood and interstitial space with a central volume of distribution of 14.1 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): No metabolism available •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Alemtuzumab is a large-molecule monoclonal antibody and as such, it is cleared primarily through target-mediated clearance and through simple non-target specific IgG clearance mechanisms. Alemtuzumab is not excreted renally or eliminated via cytochrome P450 (CYP450) isoenzymes. Alemtuzumab is most likely removed by opsonization via the reticuloendothelial system when bound to B or T lymphocytes. •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 was approximately 2 weeks and was comparable between courses. The serum concentrations were generally undetectable (<60 ng/mL) within approximately 30 days following each treatment course. •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 alemtuzumab ranged from 0.012 – 0.096 l/h depending on the study, dose group, and anti-alemtuzumab antibody status. The inter-subject variability for clearance was large (58 %). Higher clearance values were observed in cycle 1 compared to cycle 2, with the decrease in clearance from cycle 1 to cycle 2 being less than 20%. •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): LEMTRADA induces persistent thyroid disorders [see Warnings and Precautions (5.8)]. Untreated hypothyroidism in pregnant women increases the risk of miscarriage and may have effects on the fetus including mental retardation and dwarfism. In mothers with Graves’ disease, maternal thyroid stimulating hormone receptor antibodies can be transferred to a developing fetus and can cause neonatal Graves’ disease. In a patient who developed Graves’ disease after treatment with alemtuzumab, placental transfer of anti-thyrotropin receptor antibodies resulted in neonatal Graves’ disease with thyroid storm in her infant who was born 1 year after alemtuzumab dosing. When LEMTRADA was administered to pregnant huCD52 transgenic mice during organogenesis (gestation days [GD] 6-10 or GD 11-15) at doses of 3 or 10 mg/kg IV, no teratogenic effects were observed. However, there was an increase in embryo lethality (increased postimplantation loss and the number of dams with all fetuses dead or resorbed) in pregnant animals dosed during GD 11-15. In a separate study in pregnant huCD52 transgenic mice, administration of LEMTRADA during organogenesis (GD 6-10 or GD 11-15) at doses of 3 or 10 mg/kg IV, decreases in B- and T-lymphocyte populations were observed in the offspring at both doses tested. In pregnant huCD52 transgenic mice administered LEMTRADA at doses of 3 or 10 mg/kg/day IV throughout gestation and lactation, there was an increase in pup deaths during the lactation period at 10 mg/kg. Decreases in T- and B-lymphocyte populations and in antibody response were observed in offspring at both doses tested. Before initiation of LEMTRADA treatment, women of childbearing potential should be counseled on the potential for serious risk to the fetus. To avoid in-utero exposure to LEMTRADA, women of childbearing potential should use effective contraceptive measures when receiving a course of treatment with LEMTRADA and for 4 months following that course of treatment. In huCD52 transgenic mice, administration of LEMTRADA prior to and during the mating period resulted in adverse effects on sperm parameters in males and a reduced number of corpora lutea and implantations in females. Two MS patients experienced serious reactions (headache, rash, and either hypotension or sinus tachycardia) after a single accidental infusion of up to 60 mg of LEMTRADA. Doses of LEMTRADA greater than those recommended may increase the intensity and/or duration of infusion reactions or their immune effects. There is no known antidote for alemtuzumab overdosage. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Campath, Lemtrada, MabCampath •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): Alemtuzumab is a monoclonal anti-CD52 antibody used in the treatment of B-cell chronic lymphocytic leukemia and relapsing forms of multiple sclerosis. 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 Alfentanil interact?

•Drug A: Abatacept •Drug B: Alfentanil •Severity: MODERATE •Description: The metabolism of Alfentanil 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 management of postoperative pain and the 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): Alfentanil is a synthetic opioid analgesic. Alfentanil interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, alfentanil exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. Alfentanil may increase the patient's tolerance for pain and decrease the perception of suffering, although the presence of the pain itself may still be recognized. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Alfentanil depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. •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): 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. Alfentanil's analgesic activity is, most likely, due to its conversion to morphine. 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): For intravenous injection or infusion only. •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): 0.4 to 1 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 92% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The liver is the major site of biotransformation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Only 1.0% of the dose is excreted as unchanged drug; urinary excretion is the major route of elimination of 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): 90-111 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): 5 mL/kg/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 overexposure include characteristic rigidity of the skeletal muscles, cardiac and respiratory depression, and narrowing of the pupils. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alfenta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alfentanil Alfentanilo Alfentanilum Alfentanyl •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): Alfentanil is an opioid agonist used to induce and maintain anesthesia, as well as an analgesic.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Alfentanil interact? Information: •Drug A: Abatacept •Drug B: Alfentanil •Severity: MODERATE •Description: The metabolism of Alfentanil 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 management of postoperative pain and the 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): Alfentanil is a synthetic opioid analgesic. Alfentanil interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, alfentanil exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. Alfentanil may increase the patient's tolerance for pain and decrease the perception of suffering, although the presence of the pain itself may still be recognized. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Alfentanil depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. •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): 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. Alfentanil's analgesic activity is, most likely, due to its conversion to morphine. 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): For intravenous injection or infusion only. •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): 0.4 to 1 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 92% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The liver is the major site of biotransformation. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Only 1.0% of the dose is excreted as unchanged drug; urinary excretion is the major route of elimination of 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): 90-111 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): 5 mL/kg/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 overexposure include characteristic rigidity of the skeletal muscles, cardiac and respiratory depression, and narrowing of the pupils. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alfenta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alfentanil Alfentanilo Alfentanilum Alfentanyl •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): Alfentanil is an opioid agonist used to induce and maintain anesthesia, as well as an analgesic. 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 Allogeneic processed thymus tissue interact?

•Drug A: Abatacept •Drug B: Allogeneic processed thymus tissue •Severity: MINOR •Description: The therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Abatacept. •Extended Description: Allogeneic processed thymus tissue for immune reconstitution therapy aims to restore the immune function of patients with severe immunodeficiency caused by congenital athymia. The concomitant use of immunosuppressive agents may interfere with the therapeutic efficacy of immune reconstitution therapy. •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

Allogeneic processed thymus tissue for immune reconstitution therapy aims to restore the immune function of patients with severe immunodeficiency caused by congenital athymia. The concomitant use of immunosuppressive agents may interfere with the therapeutic efficacy of immune reconstitution therapy. The severity of the interaction is minor.

Question: Does Abatacept and Allogeneic processed thymus tissue interact? Information: •Drug A: Abatacept •Drug B: Allogeneic processed thymus tissue •Severity: MINOR •Description: The therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Abatacept. •Extended Description: Allogeneic processed thymus tissue for immune reconstitution therapy aims to restore the immune function of patients with severe immunodeficiency caused by congenital athymia. The concomitant use of immunosuppressive agents may interfere with the therapeutic efficacy of immune reconstitution therapy. •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: Allogeneic processed thymus tissue for immune reconstitution therapy aims to restore the immune function of patients with severe immunodeficiency caused by congenital athymia. The concomitant use of immunosuppressive agents may interfere with the therapeutic efficacy of immune reconstitution therapy. The severity of the interaction is minor.

Does Abatacept and Almotriptan interact?

•Drug A: Abatacept •Drug B: Almotriptan •Severity: MODERATE •Description: The metabolism of Almotriptan 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 acute migraine headache 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): Almotriptan is a selective 5-hydroxytryptamine receptor subtype agonist indicated for the acute treatment of migraine attacks with or without aura in adults. Almotriptan is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. Almotriptan is an agonist for a vascular 5-hydroxytryptamine receptor subtype (probably a member of the 5-HT 1D family) having only a weak affinity for 5-HT 1A, 5-HT 5A, and 5-HT 7 receptors and no significant affinity or pharmacological activity at 5-HT 2, 5-HT 3 or 5-HT 4 receptor subtypes or at alpha1-, alpha2-, or beta-adrenergic, dopamine1,; dopamine2; muscarinic, or benzodiazepine receptors. This action in humans correlates with the relief of migraine headache. In addition to causing vasoconstriction, experimental data from animal studies show that Almotriptan also activates 5-HT 1 receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels, which may also contribute to the antimigrainous effect of Almotriptan in humans. •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): Almotriptan binds with high affinity to human 5-HT 1B and 5-HT 1D receptors leading to cranial blood vessel constriction. •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): 180 to 200 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 35% •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): Almotriptan is eliminated primarily by renal excretion (about 75% of the oral dose), with approximately 40% of an administered dose excreted unchanged in urine. Approximately 13% of the administered dose is excreted via feces, both unchanged and metabolized. •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): 3-4 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): 57 L/h [healthy] 34.2 L/h [moderate renal impairment (creatinine clearance between 31 and 71 mL/min)] 9.8 L/h [severe renal impairment (creatinine clearance between 10 and 30 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): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Axert •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Almotriptan •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): Almotriptan is a 5-HT1B/1D receptor agonist used to treat migraines.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Almotriptan interact? Information: •Drug A: Abatacept •Drug B: Almotriptan •Severity: MODERATE •Description: The metabolism of Almotriptan 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 acute migraine headache 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): Almotriptan is a selective 5-hydroxytryptamine receptor subtype agonist indicated for the acute treatment of migraine attacks with or without aura in adults. Almotriptan is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. Almotriptan is an agonist for a vascular 5-hydroxytryptamine receptor subtype (probably a member of the 5-HT 1D family) having only a weak affinity for 5-HT 1A, 5-HT 5A, and 5-HT 7 receptors and no significant affinity or pharmacological activity at 5-HT 2, 5-HT 3 or 5-HT 4 receptor subtypes or at alpha1-, alpha2-, or beta-adrenergic, dopamine1,; dopamine2; muscarinic, or benzodiazepine receptors. This action in humans correlates with the relief of migraine headache. In addition to causing vasoconstriction, experimental data from animal studies show that Almotriptan also activates 5-HT 1 receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels, which may also contribute to the antimigrainous effect of Almotriptan in humans. •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): Almotriptan binds with high affinity to human 5-HT 1B and 5-HT 1D receptors leading to cranial blood vessel constriction. •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): 180 to 200 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 35% •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): Almotriptan is eliminated primarily by renal excretion (about 75% of the oral dose), with approximately 40% of an administered dose excreted unchanged in urine. Approximately 13% of the administered dose is excreted via feces, both unchanged and metabolized. •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): 3-4 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): 57 L/h [healthy] 34.2 L/h [moderate renal impairment (creatinine clearance between 31 and 71 mL/min)] 9.8 L/h [severe renal impairment (creatinine clearance between 10 and 30 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): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Axert •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Almotriptan •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): Almotriptan is a 5-HT1B/1D receptor agonist used to treat migraines. 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 Alogliptin interact?

•Drug A: Abatacept •Drug B: Alogliptin •Severity: MODERATE •Description: The metabolism of Alogliptin 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 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): Peak inhibition of DPP-4 occurs within 2-3 hours after a single-dose administration to healthy subjects. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Alogliptin also demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an 8-hour period following a standardized meal. Alogliptin does not affect the QTc 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): Alogliptin inhibits dipeptidyl peptidase 4 (DPP-4), which normally degrades the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide 1 ( GLP-1). The inhibition of DPP-4 increases the amount of active plasma incretins which helps with glycemic control. GIP and GLP-1 stimulate glucose dependent secretion of insulin in pancreatic beta cells. GLP-1 has the additional effects of suppressing glucose dependent glucagon secretion, inducing satiety, reducing food intake, and reducing gastric emptying. •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 pharmacokinetics of NESINA was also shown to be similar in healthy subjects and in patients with type 2 diabetes. When single, oral doses up to 800 mg in healthy subjects and type 2 diabetes patients are given, the peak plasma alogliptin concentration (median Tmax) occurred 1 to 2 hours after dosing. Accumulation of aloglipin is minimal. The absolute bioavailability of NESINA is approximately 100%. Food does not affect the absorption of alogliptin. •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 a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Alogliptin is 20% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Alogliptin does not undergo extensive metabolism. Two minor metabolites that were detected are N-demethylated alogliptin (<1% of parent compound) and N-acetylated alogliptin (<6% of parent compound). The N-demethylated metabolite is active and an inhibitor of DPP-4. The N-acetylated metabolite is inactive. Cytochrome enzymes that are involved with the metabolism of alogliptin are CYP2D6 and CYP3A4 but the extent to which this occurs is minimal. Approximately 10-20% of the dose is hepatically metabolized by cytochrome enzymes. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Renal excretion (76%) and feces (13%). 60% to 71% of the dose is excreted as unchanged drug 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): Terminal half-life = 21 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): Renal clearance = 9.6 L/h (this value indicates some active renal tubular secretion); Systemic clearance = 14.0 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): Common adverse reactions (reported in ≥4% of patients treated with alogliptin 25 mg and more frequently than in patients who received placebo) are: nasopharyngitis, headache, and upper respiratory tract infection. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Incresync, Kazano, Nesina, Oseni •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): Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor 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 CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Alogliptin interact? Information: •Drug A: Abatacept •Drug B: Alogliptin •Severity: MODERATE •Description: The metabolism of Alogliptin 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 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): Peak inhibition of DPP-4 occurs within 2-3 hours after a single-dose administration to healthy subjects. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Alogliptin also demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an 8-hour period following a standardized meal. Alogliptin does not affect the QTc 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): Alogliptin inhibits dipeptidyl peptidase 4 (DPP-4), which normally degrades the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide 1 ( GLP-1). The inhibition of DPP-4 increases the amount of active plasma incretins which helps with glycemic control. GIP and GLP-1 stimulate glucose dependent secretion of insulin in pancreatic beta cells. GLP-1 has the additional effects of suppressing glucose dependent glucagon secretion, inducing satiety, reducing food intake, and reducing gastric emptying. •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 pharmacokinetics of NESINA was also shown to be similar in healthy subjects and in patients with type 2 diabetes. When single, oral doses up to 800 mg in healthy subjects and type 2 diabetes patients are given, the peak plasma alogliptin concentration (median Tmax) occurred 1 to 2 hours after dosing. Accumulation of aloglipin is minimal. The absolute bioavailability of NESINA is approximately 100%. Food does not affect the absorption of alogliptin. •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 a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Alogliptin is 20% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Alogliptin does not undergo extensive metabolism. Two minor metabolites that were detected are N-demethylated alogliptin (<1% of parent compound) and N-acetylated alogliptin (<6% of parent compound). The N-demethylated metabolite is active and an inhibitor of DPP-4. The N-acetylated metabolite is inactive. Cytochrome enzymes that are involved with the metabolism of alogliptin are CYP2D6 and CYP3A4 but the extent to which this occurs is minimal. Approximately 10-20% of the dose is hepatically metabolized by cytochrome enzymes. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Renal excretion (76%) and feces (13%). 60% to 71% of the dose is excreted as unchanged drug 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): Terminal half-life = 21 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): Renal clearance = 9.6 L/h (this value indicates some active renal tubular secretion); Systemic clearance = 14.0 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): Common adverse reactions (reported in ≥4% of patients treated with alogliptin 25 mg and more frequently than in patients who received placebo) are: nasopharyngitis, headache, and upper respiratory tract infection. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Incresync, Kazano, Nesina, Oseni •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): Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor 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 CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Alosetron interact?

•Drug A: Abatacept •Drug B: Alosetron •Severity: MODERATE •Description: The metabolism of Alosetron 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): Only for the treatment of symptoms of severe diarrhea-predominant irritable bowel syndrome (IBS) in women with chronic symptoms (generally lasting greater than 6 months) who does not present with anatomic or biochemical GI abnormalities and have not responded to conventional 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): Alosetron is a potent and selective antagonist of the serotonin 5-HT 3 receptor type. Activation of these receptors and the resulting neuronal depolarization affects the regulation of visceral pain, colonic transit, and GI secretions processes that are related to IBS. By blocking these receptors, alosetron is able to effectively control IBS. •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): Alosetron is a potent and selective 5-HT 3 receptor antagonist. 5-HT 3 receptors are nonselective cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit and gastrointestinal secretions, processes that relate to the pathophysiology of irritable bowel syndrome (IBS). 5-HT 3 receptor antagonists such as alosetron inhibit activation of non-selective cation channels which results in the modulation of serotonin-sensitive GI motor and sensory processes. •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): 50-60 % •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): 65 to 95 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 82% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic, via microsomal cytochrome P450 (CYP) •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Renal elimination of unchanged alosetron accounts for only 6% of the dose. Alosetron is extensively metabolized 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): 1.5 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): 600 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): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Lotronex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alosetron •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): Alosetron is a 5-HT3 antagonist used to treat diarrhea-predominant IBS.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Alosetron interact? Information: •Drug A: Abatacept •Drug B: Alosetron •Severity: MODERATE •Description: The metabolism of Alosetron 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): Only for the treatment of symptoms of severe diarrhea-predominant irritable bowel syndrome (IBS) in women with chronic symptoms (generally lasting greater than 6 months) who does not present with anatomic or biochemical GI abnormalities and have not responded to conventional 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): Alosetron is a potent and selective antagonist of the serotonin 5-HT 3 receptor type. Activation of these receptors and the resulting neuronal depolarization affects the regulation of visceral pain, colonic transit, and GI secretions processes that are related to IBS. By blocking these receptors, alosetron is able to effectively control IBS. •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): Alosetron is a potent and selective 5-HT 3 receptor antagonist. 5-HT 3 receptors are nonselective cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit and gastrointestinal secretions, processes that relate to the pathophysiology of irritable bowel syndrome (IBS). 5-HT 3 receptor antagonists such as alosetron inhibit activation of non-selective cation channels which results in the modulation of serotonin-sensitive GI motor and sensory processes. •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): 50-60 % •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): 65 to 95 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 82% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic, via microsomal cytochrome P450 (CYP) •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Renal elimination of unchanged alosetron accounts for only 6% of the dose. Alosetron is extensively metabolized 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): 1.5 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): 600 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): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Lotronex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alosetron •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): Alosetron is a 5-HT3 antagonist used to treat diarrhea-predominant IBS. 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 Alpelisib interact?

•Drug A: Abatacept •Drug B: Alpelisib •Severity: MAJOR •Description: The metabolism of Alpelisib 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): Alpelisib is indicated in combination with fulvestrant to treat postmenopausal women, and men, with advanced or metastatic breast cancer. This cancer must be hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and PIK3CA­ mutated. The cancer must be detected by an FDA-approved test following progression on or after an endocrine-based regimen. Alpelisib is also used to treat adult and pediatric patients two years of age and older with severe manifestations of PIK3CA-Related Overgrowth Spectrum (PROS) who require systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). •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): Alpelisib does not prolong the QTcF interval. Patients taking alpelisib experience a dose dependent benefit from treatment with a 51% advantage of a 200mg daily dose over a 100mg dose and a 22% advantage of 300mg once daily over 150mg twice daily. This suggests patients requiring a lower dose may benefit from twice daily dosing. •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): Phosphatidylinositol-3-kinase-α (PI3Kα) is responsible for cell proliferation in response to growth factor-tyrosine kinase pathway activation. In some cancers PI3Kα's p110α catalytic subunit is mutated making it hyperactive. Alpelisib inhibits (PI3K), with the highest specificity for PI3Kα. •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): Alpelisib reached a peak concentration in plasma of 1320±912ng/mL after 2 hours. Alpelisib has an AUC last of 11,100±3760h ng/mL and an AUC INF of 11,100±3770h ng/mL. A large, high fat meal increases the AUC by 73% and C max by 84% while a small, low fat meal increases the AUC by 77% and C max by 145%. •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 114L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Alpelisib is 89% protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Alpelisib is metabolized by hydrolysis reactions to form the primary metabolite. It is also metabolized by CYP3A4. The full metabolism of Alpelisib has yet to be determined but a series of reactions have been proposed. The main metabolic reaction is the substitution of an amine group on alpelisib for a hydroxyl group to form a metabolite known as M4 or BZG791. Alpelisib can also be glucuronidated to form the M1 and M12 metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 36% of an oral dose is eliminated as unchanged drug in the feces and 32% as the primary metabolite BZG791 in the feces. About 2% of an oral dose is eliminated in the urine as unchanged drug and 7.1% as the primary metabolite BZG791. In total 81% of an oral dose is eliminated in the feces and 14% 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 mean half life of alprelisib is 8 to 9 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 apparent oral clearance was 39.0L/h. The predicted clearance is 9.2L/hr under fed conditions. •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 hyperglycemia, nausea, asthenia, and rash. There is no antidote for an overdose of alpelisib so patients should be treated symptomatically. Data regarding an LD 50 is not readily available. In clinical trials, patients were given doses of up to 450mg once daily. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Piqray 300 Mg Daily Dose, Vijoice 50 Mg 28 Day •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 with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Alpelisib interact? Information: •Drug A: Abatacept •Drug B: Alpelisib •Severity: MAJOR •Description: The metabolism of Alpelisib 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): Alpelisib is indicated in combination with fulvestrant to treat postmenopausal women, and men, with advanced or metastatic breast cancer. This cancer must be hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and PIK3CA­ mutated. The cancer must be detected by an FDA-approved test following progression on or after an endocrine-based regimen. Alpelisib is also used to treat adult and pediatric patients two years of age and older with severe manifestations of PIK3CA-Related Overgrowth Spectrum (PROS) who require systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). •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): Alpelisib does not prolong the QTcF interval. Patients taking alpelisib experience a dose dependent benefit from treatment with a 51% advantage of a 200mg daily dose over a 100mg dose and a 22% advantage of 300mg once daily over 150mg twice daily. This suggests patients requiring a lower dose may benefit from twice daily dosing. •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): Phosphatidylinositol-3-kinase-α (PI3Kα) is responsible for cell proliferation in response to growth factor-tyrosine kinase pathway activation. In some cancers PI3Kα's p110α catalytic subunit is mutated making it hyperactive. Alpelisib inhibits (PI3K), with the highest specificity for PI3Kα. •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): Alpelisib reached a peak concentration in plasma of 1320±912ng/mL after 2 hours. Alpelisib has an AUC last of 11,100±3760h ng/mL and an AUC INF of 11,100±3770h ng/mL. A large, high fat meal increases the AUC by 73% and C max by 84% while a small, low fat meal increases the AUC by 77% and C max by 145%. •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 114L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Alpelisib is 89% protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Alpelisib is metabolized by hydrolysis reactions to form the primary metabolite. It is also metabolized by CYP3A4. The full metabolism of Alpelisib has yet to be determined but a series of reactions have been proposed. The main metabolic reaction is the substitution of an amine group on alpelisib for a hydroxyl group to form a metabolite known as M4 or BZG791. Alpelisib can also be glucuronidated to form the M1 and M12 metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 36% of an oral dose is eliminated as unchanged drug in the feces and 32% as the primary metabolite BZG791 in the feces. About 2% of an oral dose is eliminated in the urine as unchanged drug and 7.1% as the primary metabolite BZG791. In total 81% of an oral dose is eliminated in the feces and 14% 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 mean half life of alprelisib is 8 to 9 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 apparent oral clearance was 39.0L/h. The predicted clearance is 9.2L/hr under fed conditions. •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 hyperglycemia, nausea, asthenia, and rash. There is no antidote for an overdose of alpelisib so patients should be treated symptomatically. Data regarding an LD 50 is not readily available. In clinical trials, patients were given doses of up to 450mg once daily. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Piqray 300 Mg Daily Dose, Vijoice 50 Mg 28 Day •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 with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Alprazolam interact?

•Drug A: Abatacept •Drug B: Alprazolam •Severity: MODERATE •Description: The metabolism of Alprazolam 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): Alprazolam is indicated for the acute treatment of generalized anxiety disorder in adults. Alprazolam is also indicated, either as a standard or extended-release formulation, for the treatment of panic disorder with or without agoraphobia in adults. Alprazolam may also be prescribed off-label for insomnia, premenstrual syndrome, and depression. •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): Alprazolam is a benzodiazepine that binds γ-aminobutyric acid (GABA) type-A receptors (GABA A Rs) to enhance their inhibitory effect on neurotransmission, specifically in the brain. Concomitant use with opioids may result in profound sedation, respiratory depression, coma, and death; patients taking benzodiazepines and opioids concurrently may require lower doses of one or both medications, depending on their clinical situation. Patients with pre-existing impaired respiratory function are at increased risk of adverse effects including death during treatment with benzodiazepines. In addition, due to its CNS depressant effects, patients taking alprazolam should avoid operating heavy machinery or driving and should avoid other CNS depressants such as alcohol. As with other benzodiazepines, alprazolam carries a risk of abuse, misuse, and addiction, which is higher in predisposed individuals and may require strict monitoring. Cessation of therapy may result in acute or protracted withdrawal symptoms, which may be life-threatening; the patient dose should be gradually tapered whenever discontinuation or reduced dosage are necessary. Newborns born to mothers using alprazolam later in pregnancy may suffer from sedation and withdrawal symptoms. As CYP3A is required for the initial step in alprazolam metabolism, alprazolam is contraindicated in patients taking strong CYP3A inhibitors, such as ketoconazole and itraconazole; milder CYP3A inhibitors still necessitate alprazolam dosage adjustments. Lastly, benzodiazepines may have negative effects, such as panic disorders, increased suicide incidence, and episodes of mania/hypomania, in patients suffering from depression. •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): Neurotransmission relies on excitatory and inhibitory signalling. γ-aminobutyric acid (GABA) type-A receptors (GABA A Rs) are members of the pentameric ligand-gated ion channel (PLGIC) superfamily located synaptically and perisynaptically to mediate phasic inhibition and extrasynaptically to mediate tonic inhibition. GABA A Rs comprise a variety of subunits from a homologous family whose members are named based on sequence identity as one of α1-6, β1-3, γ1-3, δ, ε, θ, π, and ρ1-3. Each subunit possesses an extracellular (ECD), transmembrane (TMD), and intracellular (ICD) domain; inter-subunit interfaces are the primary points of neurotransmitter and modulator binding, described by coordination of the principal (+) and complementary (-) sites in each subunit. Binding of GABA to GABA A Rs induces pore opening, rapid flow of chloride ions, and synaptic hyperpolarization, which in turn manifests as an inhibitory signal. The most prevalent GABA A Rs in vivo are the α1β2γ2 receptors, which contain both GABA (β+/α-) and benzodiazepine (BZD, α+/γ-) binding sites in the intersubunit interfaces of the relevant subunits. In general, any receptors containing an α x /γ z interface, where x = 1-3,5 and z = 1-3, have potential high-affinity BZD binding sites, although small sequence differences between subunits may alter binding affinity to individual molecules. The α4 and α6 subunits, in which an otherwise conserved histidine is replaced by arginine, do not bind traditional BZD ligands such as diazepam and hence are considered "diazepam-insensitive". GABA binding results in a series of conformational changes in the ECDs of GABA A R β subunits, "locking" each to its neighbouring α- interface. The binding of alprazolam in the high-affinity BZD site stabilizes the α+/γ- interface and facilitates the conformational changes that lead to pore opening, hence functioning as a positive allosteric modulator. The exact manner in which GABA A R allosteric modulation mediates the therapeutic and unwanted effects of benzodiazepines remains unclear. Earlier studies suggested that the primary factor was the α subunit composition, with α1-containing receptors mediating the sedative effects, α2/3-containing receptors the anxiolytic effects, and α5-containing receptors the memory effects of benzodiazepines. More recent studies suggest a more complex set of factors including subunit composition, physiological location, neuronal circuit, and nerve cell type. To further complicate matters, there may be up to five distinct BZD binding sites on GABA A Rs, with site 1 corresponding to the classical high-affinity α+/γ- interface. The effects of binding at sites 2-4 are not fully understood and likely impart greater complexity to benzodiazepine pharmacological 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): Alprazolam administered orally is rapidly absorbed in the gastrointestinal tract, reaching C max in about 1.8 (1-2) hours. Absorption is high, resulting in an oral bioavailability of 84-91%. A 1 mg oral dose results in a C max of 12-22 μg/L. The extended-release formulation of alprazolam (XANAX XR) has similar absorption, bioavailability, and pharmacokinetics as the standard release, with the exception that the T max is ~10 hours compared to 1-2 hours. Temporal dosing alters these parameters, with C max increasing by 30% and T max decreasing by one hour when dosed at night as opposed to in the morning. Food has an effect on alprazolam absorption; a high-fat meal up to two hours before dosing increases the C max by ~25% and either a reduction (food consumed immediately prior to dosing) or increase (food consumed after dosing) of ~1/3 in T max. Neither the AUC nor half-life are appreciably affected by eating. •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): Alprazolam has a volume of distribution following oral administration of 0.8-1.3L/kg. Alprazolam crosses the blood-brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Alprazolam is ~80% protein-bound in serum. The majority of this protein binding is to serum albumin. Alprazolam is also bound to alpha1-acid glycoprotein with low frequency. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Alprazolam is metabolized to less effective metabolites by various CYPs including CYP3A4, CYP3A5, CYP3A7, and CYP2C9. The majority of alprazolam metabolism is mediated by hydroxylation via CYP3As. 4-hydroxyalprazolam has 20% the binding affinity of the parent drug, alpha-hydroxyalprazolam has 66% the affinity, and the benzophenone metabolite has <1% the affinity. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Alprazolam is mainly eliminated in the urine. A large portion of the dose is eliminated as unmetabolized alprazolam. <10% of the dose is eliminated as alpha-hydroxy-alprazolam and 4-hydroxy-alprazolam. •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): Alprazolam has a mean plasma elimination half-life of 11.2 hours in healthy patients (range 6.3-26.9 hours). The mean half-life is 16.3 hours (range 9.0-26.9 hours) in the elderly, 21.8 hours (range 9.9-40.4 hours) in obese patients, and 19.7 hours (range 5.8-65.3 hours) in patients with alcoholic liver disease. The half-life is 25% higher in Asian patients compared to Caucasians. Other studies have shown the half-life to be 9-16h. The extended-release formulation has a half-life of 10.7-15.8 hours in healthy adult 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): A 0.8 mg oral dose of alprazolam had a clearance of 0.90 ± 0.21 mL/min/kg, which increased to 2.13 ± 0.54 mL/min/kg when coadministered with the strong CYP3A4 inducer carbamazepine. Other studies have demonstrated a clearance of 0.70-1.5mL/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): Alprazolam overdose can present as sleepiness, confusion, poor coordination, slow reflexes, coma, and death. Taking alprazolam with alcohol lowers the threshold for overdose. Patients should have their respiration, pulse, and blood pressure monitored. Patients can be treated by gastric lavage and intravenous fluids.. If hypotension occurs, patients may be treated with vasopressors. In known, or suspected overdoses, patients can be given the benzodiazepine receptor antagonist flumazenil in addition to other methods of management. Oral LD50 in rats is 331-2171mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Niravam, Xanax •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alprazolam •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): Alprazolam is a triazolobenzodiazepine with intermediate onset commonly used to treat panic disorders and generalized anxiety in addition to 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 CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Alprazolam interact? Information: •Drug A: Abatacept •Drug B: Alprazolam •Severity: MODERATE •Description: The metabolism of Alprazolam 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): Alprazolam is indicated for the acute treatment of generalized anxiety disorder in adults. Alprazolam is also indicated, either as a standard or extended-release formulation, for the treatment of panic disorder with or without agoraphobia in adults. Alprazolam may also be prescribed off-label for insomnia, premenstrual syndrome, and depression. •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): Alprazolam is a benzodiazepine that binds γ-aminobutyric acid (GABA) type-A receptors (GABA A Rs) to enhance their inhibitory effect on neurotransmission, specifically in the brain. Concomitant use with opioids may result in profound sedation, respiratory depression, coma, and death; patients taking benzodiazepines and opioids concurrently may require lower doses of one or both medications, depending on their clinical situation. Patients with pre-existing impaired respiratory function are at increased risk of adverse effects including death during treatment with benzodiazepines. In addition, due to its CNS depressant effects, patients taking alprazolam should avoid operating heavy machinery or driving and should avoid other CNS depressants such as alcohol. As with other benzodiazepines, alprazolam carries a risk of abuse, misuse, and addiction, which is higher in predisposed individuals and may require strict monitoring. Cessation of therapy may result in acute or protracted withdrawal symptoms, which may be life-threatening; the patient dose should be gradually tapered whenever discontinuation or reduced dosage are necessary. Newborns born to mothers using alprazolam later in pregnancy may suffer from sedation and withdrawal symptoms. As CYP3A is required for the initial step in alprazolam metabolism, alprazolam is contraindicated in patients taking strong CYP3A inhibitors, such as ketoconazole and itraconazole; milder CYP3A inhibitors still necessitate alprazolam dosage adjustments. Lastly, benzodiazepines may have negative effects, such as panic disorders, increased suicide incidence, and episodes of mania/hypomania, in patients suffering from depression. •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): Neurotransmission relies on excitatory and inhibitory signalling. γ-aminobutyric acid (GABA) type-A receptors (GABA A Rs) are members of the pentameric ligand-gated ion channel (PLGIC) superfamily located synaptically and perisynaptically to mediate phasic inhibition and extrasynaptically to mediate tonic inhibition. GABA A Rs comprise a variety of subunits from a homologous family whose members are named based on sequence identity as one of α1-6, β1-3, γ1-3, δ, ε, θ, π, and ρ1-3. Each subunit possesses an extracellular (ECD), transmembrane (TMD), and intracellular (ICD) domain; inter-subunit interfaces are the primary points of neurotransmitter and modulator binding, described by coordination of the principal (+) and complementary (-) sites in each subunit. Binding of GABA to GABA A Rs induces pore opening, rapid flow of chloride ions, and synaptic hyperpolarization, which in turn manifests as an inhibitory signal. The most prevalent GABA A Rs in vivo are the α1β2γ2 receptors, which contain both GABA (β+/α-) and benzodiazepine (BZD, α+/γ-) binding sites in the intersubunit interfaces of the relevant subunits. In general, any receptors containing an α x /γ z interface, where x = 1-3,5 and z = 1-3, have potential high-affinity BZD binding sites, although small sequence differences between subunits may alter binding affinity to individual molecules. The α4 and α6 subunits, in which an otherwise conserved histidine is replaced by arginine, do not bind traditional BZD ligands such as diazepam and hence are considered "diazepam-insensitive". GABA binding results in a series of conformational changes in the ECDs of GABA A R β subunits, "locking" each to its neighbouring α- interface. The binding of alprazolam in the high-affinity BZD site stabilizes the α+/γ- interface and facilitates the conformational changes that lead to pore opening, hence functioning as a positive allosteric modulator. The exact manner in which GABA A R allosteric modulation mediates the therapeutic and unwanted effects of benzodiazepines remains unclear. Earlier studies suggested that the primary factor was the α subunit composition, with α1-containing receptors mediating the sedative effects, α2/3-containing receptors the anxiolytic effects, and α5-containing receptors the memory effects of benzodiazepines. More recent studies suggest a more complex set of factors including subunit composition, physiological location, neuronal circuit, and nerve cell type. To further complicate matters, there may be up to five distinct BZD binding sites on GABA A Rs, with site 1 corresponding to the classical high-affinity α+/γ- interface. The effects of binding at sites 2-4 are not fully understood and likely impart greater complexity to benzodiazepine pharmacological 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): Alprazolam administered orally is rapidly absorbed in the gastrointestinal tract, reaching C max in about 1.8 (1-2) hours. Absorption is high, resulting in an oral bioavailability of 84-91%. A 1 mg oral dose results in a C max of 12-22 μg/L. The extended-release formulation of alprazolam (XANAX XR) has similar absorption, bioavailability, and pharmacokinetics as the standard release, with the exception that the T max is ~10 hours compared to 1-2 hours. Temporal dosing alters these parameters, with C max increasing by 30% and T max decreasing by one hour when dosed at night as opposed to in the morning. Food has an effect on alprazolam absorption; a high-fat meal up to two hours before dosing increases the C max by ~25% and either a reduction (food consumed immediately prior to dosing) or increase (food consumed after dosing) of ~1/3 in T max. Neither the AUC nor half-life are appreciably affected by eating. •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): Alprazolam has a volume of distribution following oral administration of 0.8-1.3L/kg. Alprazolam crosses the blood-brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Alprazolam is ~80% protein-bound in serum. The majority of this protein binding is to serum albumin. Alprazolam is also bound to alpha1-acid glycoprotein with low frequency. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Alprazolam is metabolized to less effective metabolites by various CYPs including CYP3A4, CYP3A5, CYP3A7, and CYP2C9. The majority of alprazolam metabolism is mediated by hydroxylation via CYP3As. 4-hydroxyalprazolam has 20% the binding affinity of the parent drug, alpha-hydroxyalprazolam has 66% the affinity, and the benzophenone metabolite has <1% the affinity. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Alprazolam is mainly eliminated in the urine. A large portion of the dose is eliminated as unmetabolized alprazolam. <10% of the dose is eliminated as alpha-hydroxy-alprazolam and 4-hydroxy-alprazolam. •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): Alprazolam has a mean plasma elimination half-life of 11.2 hours in healthy patients (range 6.3-26.9 hours). The mean half-life is 16.3 hours (range 9.0-26.9 hours) in the elderly, 21.8 hours (range 9.9-40.4 hours) in obese patients, and 19.7 hours (range 5.8-65.3 hours) in patients with alcoholic liver disease. The half-life is 25% higher in Asian patients compared to Caucasians. Other studies have shown the half-life to be 9-16h. The extended-release formulation has a half-life of 10.7-15.8 hours in healthy adult 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): A 0.8 mg oral dose of alprazolam had a clearance of 0.90 ± 0.21 mL/min/kg, which increased to 2.13 ± 0.54 mL/min/kg when coadministered with the strong CYP3A4 inducer carbamazepine. Other studies have demonstrated a clearance of 0.70-1.5mL/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): Alprazolam overdose can present as sleepiness, confusion, poor coordination, slow reflexes, coma, and death. Taking alprazolam with alcohol lowers the threshold for overdose. Patients should have their respiration, pulse, and blood pressure monitored. Patients can be treated by gastric lavage and intravenous fluids.. If hypotension occurs, patients may be treated with vasopressors. In known, or suspected overdoses, patients can be given the benzodiazepine receptor antagonist flumazenil in addition to other methods of management. Oral LD50 in rats is 331-2171mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Niravam, Xanax •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alprazolam •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): Alprazolam is a triazolobenzodiazepine with intermediate onset commonly used to treat panic disorders and generalized anxiety in addition to 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 CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Ambrisentan interact?

•Drug A: Abatacept •Drug B: Ambrisentan •Severity: MODERATE •Description: The metabolism of Ambrisentan 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): Ambrisentan is indicated for treatment of idiopathic (‘primary’) pulmonary arterial hypertension (IPAH) and pulmonary arterial hypertension (PAH) associated with connective tissue disease in patients with WHO functional class II or III symptoms. In the United States of America, ambrisentan is also indicated in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. •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): Ambrisentan 10 mg daily had no significant effect on the QTc interval, whereas a 40 mg daily dose of ambrisentan increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. Significant QTc prolongation is not expected in patients taking ambrisentan without concomitant metabolic inhibitors. Plasma concentrations of B-type natriuretic peptide (BNP) in patients who received ambrisentan for 12 weeks were significantly decreased. Two Phase III placebo-controlled studies demonstrated a decrease in BNP plasma concentrations by 29% in the 2.5 mg group, 30% in the 5 mg group, and 45% in the 10 mg group (p < 0.001 for each dose group) and an increase by 11% in the placebo group. •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): Endothelin-1 (ET-1) is an endogenous peptide that acts on the endothelin type A (ETA) and endothelin type B (ETB) receptors in vascular smooth muscle and endothelium. ETA-mediated actions include vasoconstriction and cell proliferation, whereas ETB predominantly mediates vasodilation, anti-proliferation, and ET-1 clearance. In patients with pulmonary arterial hypertension, ET-1 levels are increased and correlate with increased right arterial pressure and severity of disease. Ambrisentan is one of several newly developed vasodilator drugs that selectively target the endothelin type A (ETA) receptor, inhibiting its action and preventing vasoconstriction. Selective inhibition of the ETA receptor prevents phospholipase C-mediated vasoconstriction and protein kinase C-mediated cell proliferation. Endothelin type B (ETB) receptor function is not significantly inhibited, and nitric oxide and prostacyclin production, cyclic GMP- and cyclic AMP-mediated vasodilation, and endothelin-1 (ET-1) clearance is preserved. •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): Ambrisentan is rapidly absorbed with peak plasma concentrations occuring around 2 hours after oral administration. Cmax and AUC increase proportionally with dose across the therapeutic dosing range. Absolute oral bioavailability of ambrisentan is unknown. Absorption is not affected 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): Ambrisentan has a low distribution into red blow cells, with a mean blood:plasma ratio of 0.57 and 0.61 in males and females, respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Ambrisentan is 99% plasma protein bound, primarily to albumin (96.5%) and to a lesser degree alpha1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ambrisentan is a metabolized primarily by uridine 5’-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S,1A3S to form ambrisentan glucuronide. Ambrisentan is also metabolized to a lesser extent by CYP3A4, CYP3A5 and CYP2C19 to form 4- hydroxymethyl ambrisentan which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Ambrisentan is primarily cleared by non-renal pathways. Along with its metabolites, ambrisentan is primarily found in the feces following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan. •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): Ambrisentan has a terminal half-life of 15 hours. It is thought that steady state is achieved after around 4 days of repeat-dosing. •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 oral clearance of ambrisentan was found to be 38 mL/min in healthy subjects and 19 mL/min in patients with pulmonary artery hypertension. •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): Ambrisentan is teratogenic and has a high risk of embryo-fetal toxicity. LD50 was found to be greater than or equal to 3160 mg/kg when studied in rats. There was no evidence of carcinogenic potential in 2 year oral daily dosing studies in rats and mice. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Letairis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ambrisentan •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): Ambrisentan is a selective type A endothelin receptor antagonist used to treat primary pulmonary arterial hypertension and pulmonary arterial hypertension based on diagnostic classifications.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Ambrisentan interact? Information: •Drug A: Abatacept •Drug B: Ambrisentan •Severity: MODERATE •Description: The metabolism of Ambrisentan 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): Ambrisentan is indicated for treatment of idiopathic (‘primary’) pulmonary arterial hypertension (IPAH) and pulmonary arterial hypertension (PAH) associated with connective tissue disease in patients with WHO functional class II or III symptoms. In the United States of America, ambrisentan is also indicated in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. •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): Ambrisentan 10 mg daily had no significant effect on the QTc interval, whereas a 40 mg daily dose of ambrisentan increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. Significant QTc prolongation is not expected in patients taking ambrisentan without concomitant metabolic inhibitors. Plasma concentrations of B-type natriuretic peptide (BNP) in patients who received ambrisentan for 12 weeks were significantly decreased. Two Phase III placebo-controlled studies demonstrated a decrease in BNP plasma concentrations by 29% in the 2.5 mg group, 30% in the 5 mg group, and 45% in the 10 mg group (p < 0.001 for each dose group) and an increase by 11% in the placebo group. •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): Endothelin-1 (ET-1) is an endogenous peptide that acts on the endothelin type A (ETA) and endothelin type B (ETB) receptors in vascular smooth muscle and endothelium. ETA-mediated actions include vasoconstriction and cell proliferation, whereas ETB predominantly mediates vasodilation, anti-proliferation, and ET-1 clearance. In patients with pulmonary arterial hypertension, ET-1 levels are increased and correlate with increased right arterial pressure and severity of disease. Ambrisentan is one of several newly developed vasodilator drugs that selectively target the endothelin type A (ETA) receptor, inhibiting its action and preventing vasoconstriction. Selective inhibition of the ETA receptor prevents phospholipase C-mediated vasoconstriction and protein kinase C-mediated cell proliferation. Endothelin type B (ETB) receptor function is not significantly inhibited, and nitric oxide and prostacyclin production, cyclic GMP- and cyclic AMP-mediated vasodilation, and endothelin-1 (ET-1) clearance is preserved. •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): Ambrisentan is rapidly absorbed with peak plasma concentrations occuring around 2 hours after oral administration. Cmax and AUC increase proportionally with dose across the therapeutic dosing range. Absolute oral bioavailability of ambrisentan is unknown. Absorption is not affected 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): Ambrisentan has a low distribution into red blow cells, with a mean blood:plasma ratio of 0.57 and 0.61 in males and females, respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Ambrisentan is 99% plasma protein bound, primarily to albumin (96.5%) and to a lesser degree alpha1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ambrisentan is a metabolized primarily by uridine 5’-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S,1A3S to form ambrisentan glucuronide. Ambrisentan is also metabolized to a lesser extent by CYP3A4, CYP3A5 and CYP2C19 to form 4- hydroxymethyl ambrisentan which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Ambrisentan is primarily cleared by non-renal pathways. Along with its metabolites, ambrisentan is primarily found in the feces following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan. •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): Ambrisentan has a terminal half-life of 15 hours. It is thought that steady state is achieved after around 4 days of repeat-dosing. •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 oral clearance of ambrisentan was found to be 38 mL/min in healthy subjects and 19 mL/min in patients with pulmonary artery hypertension. •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): Ambrisentan is teratogenic and has a high risk of embryo-fetal toxicity. LD50 was found to be greater than or equal to 3160 mg/kg when studied in rats. There was no evidence of carcinogenic potential in 2 year oral daily dosing studies in rats and mice. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Letairis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ambrisentan •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): Ambrisentan is a selective type A endothelin receptor antagonist used to treat primary pulmonary arterial hypertension and pulmonary arterial hypertension based on diagnostic classifications. 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 Aminophylline interact?

•Drug A: Abatacept •Drug B: Aminophylline •Severity: MAJOR •Description: The metabolism of Aminophylline 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 treatment of bronchospasm due to asthma, emphysema and chronic bronchitis. •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): Aminophylline is the ethylenediamine salt of theophylline. Theophylline stimulates the CNS, skeletal muscles, and cardiac muscle. It relaxes certain smooth muscles in the bronchi, produces diuresis, and causes an increase in gastric secretion. •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): Aminophylline is the ethylenediamine salt of theophylline. After ingestion, theophylline is released from aminophylline, and theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin. •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): 0.3 to 0.7 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 60% •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): 7-9 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): 0.29 mL/kg/min [postnatal age 3-15 days] 0.64 mL/kg/min [postnatal age 25-57 days] 1.7 mL/kg/min [ 1-4 years] 1.6 mL/kg/min [4-12 years] 0.9 mL/kg/min [13-15 years] 1.4 mL/kg/min [16-17 years] 0.65 mL/kg/min [Adults (16-60 years), non-smoking asthmatics] 0.41 mL/kg/min [Elderly (>60 years). liver, and renal function] 0.33 mL/kg/min [Acute pulmonary edema] 0.54 mL/kg/min [COPD->60 years, stable non-smoker >1 year] 0.48 mL/kg/min [COPD with cor pulmonale] 1.25 mL/kg/min [Cystic fibrosis (14-28 years)] 0.31 mL/kg/min [Liver disease -cholestasis] 0.35 mL/kg/min [cirrhosis] 0.65 mL/kg/min [acute hepatitis] 0.47 mL/kg/min [Sepsis with multi-organ failure] 0.38 mL/kg/min [hypothyroid] 0.8 mL/kg/min [hyperthyroid] •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): Aminofilina Aminophyllin Aminophylline Aminophyllinum •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): Aminophylline is a bronchodilator consisting of theophylline that is used for the treatment of bronchospasm due to asthma, emphysema and chronic bronchitis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Aminophylline interact? Information: •Drug A: Abatacept •Drug B: Aminophylline •Severity: MAJOR •Description: The metabolism of Aminophylline 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 treatment of bronchospasm due to asthma, emphysema and chronic bronchitis. •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): Aminophylline is the ethylenediamine salt of theophylline. Theophylline stimulates the CNS, skeletal muscles, and cardiac muscle. It relaxes certain smooth muscles in the bronchi, produces diuresis, and causes an increase in gastric secretion. •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): Aminophylline is the ethylenediamine salt of theophylline. After ingestion, theophylline is released from aminophylline, and theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin. •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): 0.3 to 0.7 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 60% •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): 7-9 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): 0.29 mL/kg/min [postnatal age 3-15 days] 0.64 mL/kg/min [postnatal age 25-57 days] 1.7 mL/kg/min [ 1-4 years] 1.6 mL/kg/min [4-12 years] 0.9 mL/kg/min [13-15 years] 1.4 mL/kg/min [16-17 years] 0.65 mL/kg/min [Adults (16-60 years), non-smoking asthmatics] 0.41 mL/kg/min [Elderly (>60 years). liver, and renal function] 0.33 mL/kg/min [Acute pulmonary edema] 0.54 mL/kg/min [COPD->60 years, stable non-smoker >1 year] 0.48 mL/kg/min [COPD with cor pulmonale] 1.25 mL/kg/min [Cystic fibrosis (14-28 years)] 0.31 mL/kg/min [Liver disease -cholestasis] 0.35 mL/kg/min [cirrhosis] 0.65 mL/kg/min [acute hepatitis] 0.47 mL/kg/min [Sepsis with multi-organ failure] 0.38 mL/kg/min [hypothyroid] 0.8 mL/kg/min [hyperthyroid] •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): Aminofilina Aminophyllin Aminophylline Aminophyllinum •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): Aminophylline is a bronchodilator consisting of theophylline that is used for the treatment of bronchospasm due to asthma, emphysema and chronic bronchitis. 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 Amiodarone interact?

•Drug A: Abatacept •Drug B: Amiodarone •Severity: MAJOR •Description: The metabolism of Amiodarone 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 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): The FDA approved indications for amiodarone are recurrent ventricular fibrillation (VF) and recurrent hemodynamically unstable ventricular tachycardia (VT). The FDA emphasizes that this drug should only be given in these conditions when they are clinically documented and have not responded to normal therapeutic doses of other antiarrhythmic agents, or when other drugs are not tolerated by the patient. Off-label indications include atrial fibrillation and supraventricular tachycardia. •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): After intravenous administration, amiodarone acts to relax smooth muscles that line vascular walls, decreases peripheral vascular resistance (afterload), and increases the cardiac index by a small amount. Administration by this route also decreases cardiac conduction, preventing and treating arrhythmias. When it is given orally, however, amiodarone does not lead to significant changes in the left ventricular ejection fraction. Similar to other anti-arrhythmic agents, controlled clinical trials do not confirm that oral amiodarone increases survival. Amiodarone prolongs the QRS duration and QT interval. In addition, a decreased SA (sinoatrial) node automaticity occurs with a decrease in AV node conduction velocity. Ectopic pacemaker automaticity is also inhibited. Thyrotoxicosis or hypothyroidism may also result from the administration of amiodarone, which contains high levels of iodine, and interferes with normal thyroid 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): Amiodarone is considered a class III anti-arrhythmic drug. It blocks potassium currents that cause repolarization of the heart muscle during the third phase of the cardiac action potential. As a result amiodarone increases the duration of the action potential as well as the effective refractory period for cardiac cells (myocytes). Therefore, cardiac muscle cell excitability is reduced, preventing and treating abnormal heart rhythms. Unique from other members of the class III anti-arrhythmic drug class, amiodarone also interferes with the functioning of beta-adrenergic receptors, sodium channels, and calcium channels channels. These actions, at times, can lead to undesirable effects, such as hypotension, bradycardia, and Torsades de pointes (TdP). In addition to the above, amiodarone may increase activity of peroxisome proliferator-activated receptors, leading to steatogenic changes in the liver or other organs. Finally, amiodarone has been found to bind to the thyroid receptor due to its iodine content, potentially leading to amiodarone induced hypothyroidism or thyrotoxicosis. •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 Cmax of amiodarone in the plasma is achieved about 3 to 7 hours after administration. The general time to onset of action of amiodarone after one dose given by the intravenous route is between 1 and 30 minutes, with therapeutic effects lasting from 1-3 hours. Steady-state concentrations of amiodarone in the plasma ranges between 0.4 to 11.99 μg/ml; it is advisable that steady-state levels are generally maintained between 1.0 and 2.5 μg/ml in patients with arrhythmias. Interestingly, its onset of action may sometimes begin after 2 to 3 days, but frequently takes 1 to 3 weeks, despite the administration of higher loading doses. The bioavailability of amiodarone varies in clinical studies, averaging between 35 and 65%. Effect of food In healthy subjects who were given a single 600-mg dose immediately after consuming a meal high in fat, the AUC of amiodarone increased by 2.3 and the Cmax by 3.8 times. Food also enhances absorption, reducing the Tmax by about 37%. •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 a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients. Prescribing information mentions that the volume of distribution of amiodarone varies greatly, with a mean distribution of approximately 60 L/kg. It accumulates throughout the body, especially in adipose tissue and highly vascular organs including the lung, liver, and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), is found in even higher proportions in the same tissues as amiodarone. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of amiodarone is about 96%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): This drug is metabolized to the main metabolite desethylamiodarone (DEA) by the CYP3A4 and CYP2C8 enzymes. The CYP3A4 enzyme is found in the liver and intestines. A hydroxyl metabolite of DEA has been identified in mammals, but its clinical significance is unknown. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion. A small amount of desethylamiodarone (DEA) is found 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 amiodarone varies according to the patient, but is long nonetheless, and ranges from about 9-100 days. The half-life duration varies according to different sources. According to the prescribing information for amiodarone, the average apparent plasma terminal elimination half-life of amiodarone is of 58 days (ranging from 15 to 142 days). The terminal half-life range was between 14 to 75 days for the active metabolite, (DEA). The plasma half-life of amiodarone after one dose ranges from 3.2 to 79.7 hours, according to one source. •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 amiodarone after intravenous administration in patients with ventricular fibrillation and ventricular tachycardia ranged from 220 to 440 ml/hr/kg in one clinically study. Another study determined that the total body clearance of amiodarone varies from 0.10 to 0.77 L/min after one intravenous dose. Renal impairment does not appear to affect the clearance of amiodarone, but hepatic impairment may reduce clearance. Patients with liver cirrhosis exhibited significantly lower Cmax and mean amiodarone concentration for DEA, but not for amiodarone. Severe left ventricular dysfunction prolongs the half-life of DEA. A note on monitoring No guidelines have been developed for adjusting the dose of amiodarone in renal, hepatic, or cardiac abnormalities. In patients on chronic amiodarone treatment, close clinical monitoring is advisable, especially for elderly patients and those with severe left ventricular dysfunction. •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 LD50 of oral amiodarone in mice and rats exceeds 3,000 mg/kg. An overdose with amiodarone can have a fatal outcome due to its potential to cause arrhythmia. Signs or symptoms of an overdose may include, hypotension, shock, bradycardia, AV block, and liver toxicity. In cases of an overdose, initiate supportive treatment and, if needed, use fluids, vasopressors, or positive inotropic agents. Temporary pacing may be required for heart block. Ensure to monitor liver function regularly. Amiodarone and its main metabolite, DEA, are not removable by dialysis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Nexterone, Pacerone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amiodarona Amiodarone Amiodaronum •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): Amiodarone is a class III antiarrhythmic indicated for the treatment of recurrent hemodynamically unstable ventricular tachycardia and recurrent ventricular fibrillation.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Amiodarone interact? Information: •Drug A: Abatacept •Drug B: Amiodarone •Severity: MAJOR •Description: The metabolism of Amiodarone 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 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): The FDA approved indications for amiodarone are recurrent ventricular fibrillation (VF) and recurrent hemodynamically unstable ventricular tachycardia (VT). The FDA emphasizes that this drug should only be given in these conditions when they are clinically documented and have not responded to normal therapeutic doses of other antiarrhythmic agents, or when other drugs are not tolerated by the patient. Off-label indications include atrial fibrillation and supraventricular tachycardia. •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): After intravenous administration, amiodarone acts to relax smooth muscles that line vascular walls, decreases peripheral vascular resistance (afterload), and increases the cardiac index by a small amount. Administration by this route also decreases cardiac conduction, preventing and treating arrhythmias. When it is given orally, however, amiodarone does not lead to significant changes in the left ventricular ejection fraction. Similar to other anti-arrhythmic agents, controlled clinical trials do not confirm that oral amiodarone increases survival. Amiodarone prolongs the QRS duration and QT interval. In addition, a decreased SA (sinoatrial) node automaticity occurs with a decrease in AV node conduction velocity. Ectopic pacemaker automaticity is also inhibited. Thyrotoxicosis or hypothyroidism may also result from the administration of amiodarone, which contains high levels of iodine, and interferes with normal thyroid 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): Amiodarone is considered a class III anti-arrhythmic drug. It blocks potassium currents that cause repolarization of the heart muscle during the third phase of the cardiac action potential. As a result amiodarone increases the duration of the action potential as well as the effective refractory period for cardiac cells (myocytes). Therefore, cardiac muscle cell excitability is reduced, preventing and treating abnormal heart rhythms. Unique from other members of the class III anti-arrhythmic drug class, amiodarone also interferes with the functioning of beta-adrenergic receptors, sodium channels, and calcium channels channels. These actions, at times, can lead to undesirable effects, such as hypotension, bradycardia, and Torsades de pointes (TdP). In addition to the above, amiodarone may increase activity of peroxisome proliferator-activated receptors, leading to steatogenic changes in the liver or other organs. Finally, amiodarone has been found to bind to the thyroid receptor due to its iodine content, potentially leading to amiodarone induced hypothyroidism or thyrotoxicosis. •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 Cmax of amiodarone in the plasma is achieved about 3 to 7 hours after administration. The general time to onset of action of amiodarone after one dose given by the intravenous route is between 1 and 30 minutes, with therapeutic effects lasting from 1-3 hours. Steady-state concentrations of amiodarone in the plasma ranges between 0.4 to 11.99 μg/ml; it is advisable that steady-state levels are generally maintained between 1.0 and 2.5 μg/ml in patients with arrhythmias. Interestingly, its onset of action may sometimes begin after 2 to 3 days, but frequently takes 1 to 3 weeks, despite the administration of higher loading doses. The bioavailability of amiodarone varies in clinical studies, averaging between 35 and 65%. Effect of food In healthy subjects who were given a single 600-mg dose immediately after consuming a meal high in fat, the AUC of amiodarone increased by 2.3 and the Cmax by 3.8 times. Food also enhances absorption, reducing the Tmax by about 37%. •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 a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients. Prescribing information mentions that the volume of distribution of amiodarone varies greatly, with a mean distribution of approximately 60 L/kg. It accumulates throughout the body, especially in adipose tissue and highly vascular organs including the lung, liver, and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), is found in even higher proportions in the same tissues as amiodarone. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of amiodarone is about 96%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): This drug is metabolized to the main metabolite desethylamiodarone (DEA) by the CYP3A4 and CYP2C8 enzymes. The CYP3A4 enzyme is found in the liver and intestines. A hydroxyl metabolite of DEA has been identified in mammals, but its clinical significance is unknown. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion. A small amount of desethylamiodarone (DEA) is found 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 amiodarone varies according to the patient, but is long nonetheless, and ranges from about 9-100 days. The half-life duration varies according to different sources. According to the prescribing information for amiodarone, the average apparent plasma terminal elimination half-life of amiodarone is of 58 days (ranging from 15 to 142 days). The terminal half-life range was between 14 to 75 days for the active metabolite, (DEA). The plasma half-life of amiodarone after one dose ranges from 3.2 to 79.7 hours, according to one source. •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 amiodarone after intravenous administration in patients with ventricular fibrillation and ventricular tachycardia ranged from 220 to 440 ml/hr/kg in one clinically study. Another study determined that the total body clearance of amiodarone varies from 0.10 to 0.77 L/min after one intravenous dose. Renal impairment does not appear to affect the clearance of amiodarone, but hepatic impairment may reduce clearance. Patients with liver cirrhosis exhibited significantly lower Cmax and mean amiodarone concentration for DEA, but not for amiodarone. Severe left ventricular dysfunction prolongs the half-life of DEA. A note on monitoring No guidelines have been developed for adjusting the dose of amiodarone in renal, hepatic, or cardiac abnormalities. In patients on chronic amiodarone treatment, close clinical monitoring is advisable, especially for elderly patients and those with severe left ventricular dysfunction. •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 LD50 of oral amiodarone in mice and rats exceeds 3,000 mg/kg. An overdose with amiodarone can have a fatal outcome due to its potential to cause arrhythmia. Signs or symptoms of an overdose may include, hypotension, shock, bradycardia, AV block, and liver toxicity. In cases of an overdose, initiate supportive treatment and, if needed, use fluids, vasopressors, or positive inotropic agents. Temporary pacing may be required for heart block. Ensure to monitor liver function regularly. Amiodarone and its main metabolite, DEA, are not removable by dialysis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Nexterone, Pacerone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amiodarona Amiodarone Amiodaronum •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): Amiodarone is a class III antiarrhythmic indicated for the treatment of recurrent hemodynamically unstable ventricular tachycardia and recurrent ventricular fibrillation. 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 with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Amitriptyline interact?

•Drug A: Abatacept •Drug B: Amitriptyline •Severity: MAJOR •Description: The metabolism of Amitriptyline 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 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): This drug in indicated for the following conditions: Major depressive disorder in adults Management of neuropathic pain in adults Prophylactic treatment of chronic tension-type headache (CTTH) in adults Prophylactic treatment of migraine in adults Treatment of nocturnal enuresis in children aged 6 years and above when organic pathology, including spina bifida and related disorders, have been excluded and no response has been achieved to all other non-drug and drug treatments, including antispasmodics and vasopressin-related products. This product should only be prescribed by a healthcare professional with expertise in the management of persistent enuresis Off-label uses: irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation, fibromyalgia, and insomnia •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): Effects in pain and depression Amitriptyline is a tricyclic antidepressant and an analgesic. It has anticholinergic and sedative properties. Clinical studies have shown that oral amitriptyline achieves, at a minimum, good to moderate response in up to 2/3 of patients diagnosed with post-herpetic neuralgia and 3/4 of patients diagnosed with diabetic neuropathic pain, and neurogenic pain syndromes that are frequently unresponsive to narcotic analgesics. Amitriptyline has also shown efficacy in diverse groups of patients with chronic non-malignant pain. There have also been some studies showing efficacy in managing fibromyalgia (an off-label use of this drug),. Cardiovascular and Anticholinergic Effects Amitriptyline has strong anticholinergic properties and may cause ECG changes and quinidine-like effects on the heart. Amitriptyline may inhibit ion channels, which are necessary for cardiac repolarization (hERG channels), in the upper micromolar range of therapeutic plasma concentrations. Therefore, amitriptyline may increase the risk for cardiac arrhythmia. Orthostatic hypotension and tachycardia can be a problem in elderly patients receiving this drug at normal doses for depression. There is evidence in the literature that these effects may occur, rarely, at the lower dosages utilized in the treatment of pain. As with any other tricyclic antidepressant agent, increased glucose levels can occur with amitriptyline. Effects on seizure threshold This drug also decreases the convulsive threshold and causes alterations in EEG and sleep patterns. •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 this drug is not fully elucidated. It is suggested that amitriptyline inhibits the membrane pump mechanism responsible for the re-uptake of transmitter amines, such as norepinephrine and serotonin, thereby increasing their concentration at the synaptic clefts of the brain,. These amines are important in regulating mood. The monoamine hypothesis in depression, one of the oldest hypotheses, postulates that deficiencies of serotonin (5-HT) and/or norepinephrine (NE) neurotransmission in the brain lead to depressive effects. This drug counteracts these mechanisms, and this may be the mechanism of amitriptyline in improving depressive symptoms. Whether its analgesic effects are related to its mood-altering activities or attributable to a different, less obvious pharmacological action (or a combination of both) 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): Rapidly absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations are reached 2-12 hours after oral or intramuscular administration. Steady-state plasma concentrations vary greatly and this variation may be due to genetic differences. •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 (Vd)β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg). It is found widely distributed throughout the body. Amitriptyline and the main metabolite nortriptyline pass across the placental barrier and small amounts are present in breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Very highly protein bound (95%) in plasma and tissues. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro, the metabolism of amitriptyline occurs mainly by demethylation (CYP2C19, CYP3A4) as well as hydroxylation (CYP2D6) followed by conjugation with glucuronic acid. Other isozymes involved in amitriptyline metabolism are CYP1A2 and CYP2C9. The metabolism of this drug is subject to genetic polymorphisms. The main active metabolite is the secondary amine, nortriptyline. Nortriptyline is a stronger inhibitor of noradrenaline than of serotonin uptake, while amitriptyline inhibits the uptake of noradrenaline and serotonin with equal efficacy. Other metabolites such as cis- and trans-10-hydroxyamitriptyline and cis- and trans-10-hydroxynortriptyline have the same pharmacologic profile as nortriptyline but are significantly weaker. Demethylnortriptyline and amitriptyline N oxide are only present in plasma in negligible amounts; the latter is mostly inactive. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Amitriptyline and its metabolites are mainly excreted in the urine. Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with approximately 2% of unchanged drug appearing in the urine. 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours. Small amounts are excreted in feces via biliary 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 elimination half-life (t1⁄2 β) amitriptyline after peroral administration is about 25 hours (24.65 ± 6.31 hours; range 16.49-40.36 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 systemic clearance (Cls) is 39.24 ± 10.18 L/h (range: 24.53-53.73 L/h). No clear effect of older age on the pharmacokinetics of amitriptyline has been determined, although it is possible that clearance may be decreased. •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 Data: Oral TDLO (child): 4167 μg/kg; Oral TDLO (man): 714 μg/kg/1D (intermittent); Oral TDLO (woman): 10 mg/kg. Ingestion of 750 mg or more by an adult may result in severe toxicity. The effects in overdose are further increased by simultaneous ingestion of alcohol and another psychotropic agent. Symptoms of overdose include abnormally low blood pressure, confusion, convulsions, dilated pupils and other eye problems, disturbed concentration, drowsiness, hallucinations, impaired heart function, rapid or irregular heartbeat, reduced body temperature, stupor, and unresponsiveness or coma, among others,. Use in pregnancy For amitriptyline, only limited clinical data are available regarding its use in pregnancy. Amitriptyline is not recommended during pregnancy unless clearly required and only after careful consideration of both risks and benefits. Use in breastfeeding Amitriptyline and its metabolites are excreted into breast milk (corresponding to 0.6 % - 1 % of the maternal dose). A risk to the suckling child must be considered. A decision should be made as to whether it is appropriate to discontinue breastfeeding or to discontinue/abstain from the therapy of this medicinal product, considering the benefit of breastfeeding for the child and the benefit of therapy for the woman. Effects on fertility Animal studies have shown reproductive toxicity. No data on the effects of amitriptyline on human fertility are available. Mutagenesis and carcinogenesis The genotoxic potential of amitriptyline has been investigated in various in vitro and in vivo studies. Although these investigations showed some contradictory results, a potential of amitriptyline to lead to chromosome abnormalities cannot be excluded. Long-term carcinogenicity studies have not been performed to this date. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Elavil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amitriptilina Amitriptylin Amitriptyline Amitriptylinum •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): Amitriptyline is a tricyclic antidepressant indicated in the treatment of depressive illness, either endogenous or psychotic, and to relieve depression associated anxiety.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Amitriptyline interact? Information: •Drug A: Abatacept •Drug B: Amitriptyline •Severity: MAJOR •Description: The metabolism of Amitriptyline 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 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): This drug in indicated for the following conditions: Major depressive disorder in adults Management of neuropathic pain in adults Prophylactic treatment of chronic tension-type headache (CTTH) in adults Prophylactic treatment of migraine in adults Treatment of nocturnal enuresis in children aged 6 years and above when organic pathology, including spina bifida and related disorders, have been excluded and no response has been achieved to all other non-drug and drug treatments, including antispasmodics and vasopressin-related products. This product should only be prescribed by a healthcare professional with expertise in the management of persistent enuresis Off-label uses: irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation, fibromyalgia, and insomnia •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): Effects in pain and depression Amitriptyline is a tricyclic antidepressant and an analgesic. It has anticholinergic and sedative properties. Clinical studies have shown that oral amitriptyline achieves, at a minimum, good to moderate response in up to 2/3 of patients diagnosed with post-herpetic neuralgia and 3/4 of patients diagnosed with diabetic neuropathic pain, and neurogenic pain syndromes that are frequently unresponsive to narcotic analgesics. Amitriptyline has also shown efficacy in diverse groups of patients with chronic non-malignant pain. There have also been some studies showing efficacy in managing fibromyalgia (an off-label use of this drug),. Cardiovascular and Anticholinergic Effects Amitriptyline has strong anticholinergic properties and may cause ECG changes and quinidine-like effects on the heart. Amitriptyline may inhibit ion channels, which are necessary for cardiac repolarization (hERG channels), in the upper micromolar range of therapeutic plasma concentrations. Therefore, amitriptyline may increase the risk for cardiac arrhythmia. Orthostatic hypotension and tachycardia can be a problem in elderly patients receiving this drug at normal doses for depression. There is evidence in the literature that these effects may occur, rarely, at the lower dosages utilized in the treatment of pain. As with any other tricyclic antidepressant agent, increased glucose levels can occur with amitriptyline. Effects on seizure threshold This drug also decreases the convulsive threshold and causes alterations in EEG and sleep patterns. •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 this drug is not fully elucidated. It is suggested that amitriptyline inhibits the membrane pump mechanism responsible for the re-uptake of transmitter amines, such as norepinephrine and serotonin, thereby increasing their concentration at the synaptic clefts of the brain,. These amines are important in regulating mood. The monoamine hypothesis in depression, one of the oldest hypotheses, postulates that deficiencies of serotonin (5-HT) and/or norepinephrine (NE) neurotransmission in the brain lead to depressive effects. This drug counteracts these mechanisms, and this may be the mechanism of amitriptyline in improving depressive symptoms. Whether its analgesic effects are related to its mood-altering activities or attributable to a different, less obvious pharmacological action (or a combination of both) 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): Rapidly absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations are reached 2-12 hours after oral or intramuscular administration. Steady-state plasma concentrations vary greatly and this variation may be due to genetic differences. •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 (Vd)β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg). It is found widely distributed throughout the body. Amitriptyline and the main metabolite nortriptyline pass across the placental barrier and small amounts are present in breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Very highly protein bound (95%) in plasma and tissues. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro, the metabolism of amitriptyline occurs mainly by demethylation (CYP2C19, CYP3A4) as well as hydroxylation (CYP2D6) followed by conjugation with glucuronic acid. Other isozymes involved in amitriptyline metabolism are CYP1A2 and CYP2C9. The metabolism of this drug is subject to genetic polymorphisms. The main active metabolite is the secondary amine, nortriptyline. Nortriptyline is a stronger inhibitor of noradrenaline than of serotonin uptake, while amitriptyline inhibits the uptake of noradrenaline and serotonin with equal efficacy. Other metabolites such as cis- and trans-10-hydroxyamitriptyline and cis- and trans-10-hydroxynortriptyline have the same pharmacologic profile as nortriptyline but are significantly weaker. Demethylnortriptyline and amitriptyline N oxide are only present in plasma in negligible amounts; the latter is mostly inactive. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Amitriptyline and its metabolites are mainly excreted in the urine. Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with approximately 2% of unchanged drug appearing in the urine. 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours. Small amounts are excreted in feces via biliary 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 elimination half-life (t1⁄2 β) amitriptyline after peroral administration is about 25 hours (24.65 ± 6.31 hours; range 16.49-40.36 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 systemic clearance (Cls) is 39.24 ± 10.18 L/h (range: 24.53-53.73 L/h). No clear effect of older age on the pharmacokinetics of amitriptyline has been determined, although it is possible that clearance may be decreased. •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 Data: Oral TDLO (child): 4167 μg/kg; Oral TDLO (man): 714 μg/kg/1D (intermittent); Oral TDLO (woman): 10 mg/kg. Ingestion of 750 mg or more by an adult may result in severe toxicity. The effects in overdose are further increased by simultaneous ingestion of alcohol and another psychotropic agent. Symptoms of overdose include abnormally low blood pressure, confusion, convulsions, dilated pupils and other eye problems, disturbed concentration, drowsiness, hallucinations, impaired heart function, rapid or irregular heartbeat, reduced body temperature, stupor, and unresponsiveness or coma, among others,. Use in pregnancy For amitriptyline, only limited clinical data are available regarding its use in pregnancy. Amitriptyline is not recommended during pregnancy unless clearly required and only after careful consideration of both risks and benefits. Use in breastfeeding Amitriptyline and its metabolites are excreted into breast milk (corresponding to 0.6 % - 1 % of the maternal dose). A risk to the suckling child must be considered. A decision should be made as to whether it is appropriate to discontinue breastfeeding or to discontinue/abstain from the therapy of this medicinal product, considering the benefit of breastfeeding for the child and the benefit of therapy for the woman. Effects on fertility Animal studies have shown reproductive toxicity. No data on the effects of amitriptyline on human fertility are available. Mutagenesis and carcinogenesis The genotoxic potential of amitriptyline has been investigated in various in vitro and in vivo studies. Although these investigations showed some contradictory results, a potential of amitriptyline to lead to chromosome abnormalities cannot be excluded. Long-term carcinogenicity studies have not been performed to this date. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Elavil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amitriptilina Amitriptylin Amitriptyline Amitriptylinum •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): Amitriptyline is a tricyclic antidepressant indicated in the treatment of depressive illness, either endogenous or psychotic, and to relieve depression associated anxiety. 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 with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Amodiaquine interact?

•Drug A: Abatacept •Drug B: Amodiaquine •Severity: MODERATE •Description: The metabolism of Amodiaquine 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): For treatment of acute malarial attacks in non-immune subjects. •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): Amodiaquine, a 4-aminoquinoline similar to chloroquine in structure and activity, has been used as both an antimalarial and an anti-inflammatory agent for more than 40 years. Amodiaquine is at least as effective as chloroquine, and is effective against some chloroquine-resistant strains, although resistance to amodiaquine has been reported. The mode of action of amodiaquine has not yet been determined. 4-Aminoquinolines depress cardiac muscle, impair cardiac conductivity, and produce vasodilatation with resultant hypotension. They depress respiration and cause diplopia, dizziness and nausea. •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 plasmodicidal action of amodiaquine is not completely certain. Like other quinoline derivatives, it is thought to inhibit heme polymerase activity. This results in accumulation of free heme, which is toxic to the parasites. The drug binds the free heme preventing the parasite from converting it to a form less toxic. This drug-heme complex is toxic and disrupts membrane function. •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 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): 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 biotransformation to desethylamodiaquine (the principal biologically active metabolite) is the predominant route of amodiaquine clearance with such a considerable first pass effect that very little orally administered amodiaquine escapes untransformed into the systemic circulation. •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): 5.2 ± 1.7 (range 0.4 to 5.5) 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): LD 50 (mouse, intraperitoneal) 225 mg/kg, LD 50 (mouse, oral) 550 mg/kg. Symptoms of overdose include headache, drowsiness, visual disturbances, vomiting, hypokalaemia, cardiovascular collapse and cardiac and respiratory arrest. Hypotension, if not treated, may progress rapidly to shock. Electrocardiograms (ECG) may reveal atrial standstill, nodal rhythm, prolonged intraventricular conduction time, broadening of the QRS complex, and progressive bradycardia leading to ventricular fibrillation and/or arrest. •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): Amodiaquine is an antimalarial drug.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Amodiaquine interact? Information: •Drug A: Abatacept •Drug B: Amodiaquine •Severity: MODERATE •Description: The metabolism of Amodiaquine 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): For treatment of acute malarial attacks in non-immune subjects. •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): Amodiaquine, a 4-aminoquinoline similar to chloroquine in structure and activity, has been used as both an antimalarial and an anti-inflammatory agent for more than 40 years. Amodiaquine is at least as effective as chloroquine, and is effective against some chloroquine-resistant strains, although resistance to amodiaquine has been reported. The mode of action of amodiaquine has not yet been determined. 4-Aminoquinolines depress cardiac muscle, impair cardiac conductivity, and produce vasodilatation with resultant hypotension. They depress respiration and cause diplopia, dizziness and nausea. •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 plasmodicidal action of amodiaquine is not completely certain. Like other quinoline derivatives, it is thought to inhibit heme polymerase activity. This results in accumulation of free heme, which is toxic to the parasites. The drug binds the free heme preventing the parasite from converting it to a form less toxic. This drug-heme complex is toxic and disrupts membrane function. •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 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): 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 biotransformation to desethylamodiaquine (the principal biologically active metabolite) is the predominant route of amodiaquine clearance with such a considerable first pass effect that very little orally administered amodiaquine escapes untransformed into the systemic circulation. •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): 5.2 ± 1.7 (range 0.4 to 5.5) 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): LD 50 (mouse, intraperitoneal) 225 mg/kg, LD 50 (mouse, oral) 550 mg/kg. Symptoms of overdose include headache, drowsiness, visual disturbances, vomiting, hypokalaemia, cardiovascular collapse and cardiac and respiratory arrest. Hypotension, if not treated, may progress rapidly to shock. Electrocardiograms (ECG) may reveal atrial standstill, nodal rhythm, prolonged intraventricular conduction time, broadening of the QRS complex, and progressive bradycardia leading to ventricular fibrillation and/or arrest. •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): Amodiaquine is an antimalarial drug. 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 Amoxapine interact?

•Drug A: Abatacept •Drug B: Amoxapine •Severity: MAJOR •Description: The metabolism of Amoxapine 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 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 in patients with neurotic or reactive depressive disorders as well as endogenous and psychotic depressions. May also be used to treat depression accompanied by anxiety or agitation. •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): Amoxapine is a tricyclic antidepressant of the dibenzoxazepine class, chemically distinct from the dibenzodiazepines, dibenzocycloheptenes, and dibenzoxepines. It has a mild sedative component to its action. The mechanism of its clinical action in man is not well understood. In animals, amoxapine reduced the uptake of nor-epinephirine and serotonin and blocked the response of dopamine receptors to dopamine. Amoxapine is not a monoamine oxidase inhibitor. Clinical studies have demonstrated that amoxapine has a more rapid onset of action than either amitriptyline or imipramine •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): Amoxapine acts by decreasing the reuptake of norepinephrine and serotonin (5-HT). •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 almost completely absorbed from the GI tract. Peak plasma concentrations occur within 1-2 hours of oral administration of a single 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): Widely distributed in body tissues with highest concentrations found in lungs, spleen, kidneys, heart, and brain. Lower concentrations can be detected in testes and muscle. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro tests show that amoxapine binding to human plasma proteins is approximately 90%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Amoxapine is almost completely metabolized in the liver to its major metabolite, 8-hydroxyamoxapine, and a minor metabolite, 7-hydroxyamoxapine. Both metabolites are phamacologically inactive and have half-lives of approximately 30 and 6.5 hours, respectively. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 60-69% of a single orally administered dose of amoxapine is excreted in urine, principally as conjugated metabolites. 7-18% of the dose is excrete feces mainly as unconjugated metabolites. Less than 5% of the dose is excreted as unchanged drug 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): 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): Toxic manifestations of amoxapine overdosage differ significantly from those of other tricyclic antidepressants. Serious cardiovascular effects are seldom if ever observed. However, CNS effects, particularly grand mal convulsions, occur frequently, and treatment should be directed primarily toward prevention or control of seizures. Status epilepticus may develop and constitutes a neurologic emergency. Coma and acidosis are other serious complications of substantial amoxapine overdosage in some cases. Renal failure may develop two to five days after toxic overdose in patients who may appear otherwise recovered. Acute tubular necrosis with rhabdomuolysis and myolobinurla is the most common renal complication in such cases. This reaction probably occurs in less than 5% of overdose cases, and typically in those who have experienced multiple seizures. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amoxapin Amoxapina Amoxapine Amoxapinum Amoxepine Desmethylloxapin •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): Amoxapine is a tricyclic antidepressant used in the treatment of neurotic or reactive depressive disorders and endogenous or psychotic 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 CYP2D6 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Amoxapine interact? Information: •Drug A: Abatacept •Drug B: Amoxapine •Severity: MAJOR •Description: The metabolism of Amoxapine 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 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 in patients with neurotic or reactive depressive disorders as well as endogenous and psychotic depressions. May also be used to treat depression accompanied by anxiety or agitation. •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): Amoxapine is a tricyclic antidepressant of the dibenzoxazepine class, chemically distinct from the dibenzodiazepines, dibenzocycloheptenes, and dibenzoxepines. It has a mild sedative component to its action. The mechanism of its clinical action in man is not well understood. In animals, amoxapine reduced the uptake of nor-epinephirine and serotonin and blocked the response of dopamine receptors to dopamine. Amoxapine is not a monoamine oxidase inhibitor. Clinical studies have demonstrated that amoxapine has a more rapid onset of action than either amitriptyline or imipramine •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): Amoxapine acts by decreasing the reuptake of norepinephrine and serotonin (5-HT). •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 almost completely absorbed from the GI tract. Peak plasma concentrations occur within 1-2 hours of oral administration of a single 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): Widely distributed in body tissues with highest concentrations found in lungs, spleen, kidneys, heart, and brain. Lower concentrations can be detected in testes and muscle. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro tests show that amoxapine binding to human plasma proteins is approximately 90%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Amoxapine is almost completely metabolized in the liver to its major metabolite, 8-hydroxyamoxapine, and a minor metabolite, 7-hydroxyamoxapine. Both metabolites are phamacologically inactive and have half-lives of approximately 30 and 6.5 hours, respectively. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 60-69% of a single orally administered dose of amoxapine is excreted in urine, principally as conjugated metabolites. 7-18% of the dose is excrete feces mainly as unconjugated metabolites. Less than 5% of the dose is excreted as unchanged drug 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): 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): Toxic manifestations of amoxapine overdosage differ significantly from those of other tricyclic antidepressants. Serious cardiovascular effects are seldom if ever observed. However, CNS effects, particularly grand mal convulsions, occur frequently, and treatment should be directed primarily toward prevention or control of seizures. Status epilepticus may develop and constitutes a neurologic emergency. Coma and acidosis are other serious complications of substantial amoxapine overdosage in some cases. Renal failure may develop two to five days after toxic overdose in patients who may appear otherwise recovered. Acute tubular necrosis with rhabdomuolysis and myolobinurla is the most common renal complication in such cases. This reaction probably occurs in less than 5% of overdose cases, and typically in those who have experienced multiple seizures. •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amoxapin Amoxapina Amoxapine Amoxapinum Amoxepine Desmethylloxapin •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): Amoxapine is a tricyclic antidepressant used in the treatment of neurotic or reactive depressive disorders and endogenous or psychotic 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 CYP2D6 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Amphetamine interact?

•Drug A: Abatacept •Drug B: Amphetamine •Severity: MODERATE •Description: The metabolism of Amphetamine 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): Amphetamine is indicated for the treatment of attention-deficit/hyperactivity disorders (ADHD) as well as for the treatment of central nervous system disorders such as narcolepsy. ADHD is a complex disorder associated with the substantial heterogeneity in etiology, clinical presentation, and treatment outcome. ADHD comes from a complex interplay between interdependent genetic and non-genetic factors which cause complex mental disorders in children and teenagers. On the other hand, narcolepsy is a chronic sleep disorder typically resenting during adolescence and characterized by excessive daytime sleepiness. Amphetamine is also being used nowadays off-label for the treatment of obesity, depression and chronic 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): From its mechanism of action, it has been demonstrated that amphetamine augments the concentration of noradrenaline in the prefrontal cortex and dopamine in the striatum on a dose and time-dependent manner. The indistinct release of neurotransmitters which include adrenaline is known to produce cardiovascular side effects. There are old reports of a cognitive enhancement related to the administration of amphetamine in which improvements in intelligence test scores were reported. In ADHD, amphetamine has been largely showed to produce remarkable improvements in school performance, behavior, and demeanor. The effect was shown to be produced through both racemic forms and to this date, the use of racemic forms 3:1 (D:L) is very common. The therapeutic effect of amphetamine on serotonin does not seem to have a significant clinical effect on ADHD as observed on comparative studies with amphetamine and fenfluramine, a powerful serotonin releasing factor. However, the indirect effect on serotonin might have an effect on the depression and anxiety profile of ADHD. Studies regarding the illicit use of amphetamine in which heavy consumers were studied proved the generation of a paranoid state which flagged this drug as a psychiatric danger compound. This observation was supported by the continuous reports of misuse in patients under depression. •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): It is important to consider that amphetamine has a very similar structure to the catecholamine neurotransmitters mainly on the presence of a long planar conformation, the presence of an aromatic ring and nitrogen in the aryl side chain. Amphetamine, as well as other catecholamines, is taken into presynaptic nerve terminals by the association with two sodium ions and one chloride ion. The complex of the amphetamine with the ions is actively transported by monoamine reuptake transporters. As amphetamine acts competitively with the endogenous monoamines, the greater the number of amphetamines the more internalized amphetamine will be found. Once inside the presynaptic terminal, amphetamine displaces other monoamines to be stored by VMAT2 which produces the pumping of the neurotransmitters into the synapse by a process called retro-transport. This process of release of neurotransmitters is approximately fourfold more potent in the d-isomer for the release of dopamine. The mechanism of action of amphetamine is complemented by the inhibition of the reuptake and of monoamine oxidase which acts synergistically to produce a significant increase the monoamine concentration. This activity is not done as an inhibitor per se but more as a competitive substrate and thus, amphetamine is known to be a weak dopamine reuptake inhibitor, moderate noradrenaline reuptake inhibitor and very weak serotonin reuptake inhibitor. From this specific action, the l-isomer is known to be significantly less potent. Lastly, amphetamine is known to be an inhibitor of the mitochondrial-bound enzyme MAO which is the catalytic enzyme in charge of degrading all the excess of neurotransmitters. This mechanism of action is often overpassed as amphetamine is a weak MAO inhibitor but this mechanism cannot be dismissed. •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): Amphetamine is well absorbed in the gut and as it is a weak base hence the more basic the environment the more of the drug is found in a lipid-soluble form and the absorption through lipid-rich cell membranes is highly favored. The peak response of amphetamine occurs 1-3 hours after oral administration and approximately 15 minutes after injection and it presents a bioavailability of over 75%. Complete amphetamine absorption is usually done after 4-6 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): Amphetamine is reported to have a high volume of distribution of 4 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The reported protein binding of amphetamine is relatively low and register to be of 20%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Amphetamine is known to be metabolized by the liver under the action of the CYP2D6. The metabolic pathway of amphetamine is mainly defined by aromatic hydroxylation, aliphatic hydroxylation, and n-dealkylation. The formed metabolites in this pathway are 4-hydroxyamphetamine, 4-hydroxynorephedrine, hippuric acid, benzoic acid, benzyl methyl ketone, and p-hydroxyamphetamine which is known to be a potent hallucinogen. However, a significant part of the original compound remains unchanged. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The elimination of amphetamine is mainly via the urine from which about 40% of the excreted dose is found as unchanged amphetamine. About 90% of the administered amphetamine is eliminated 3 days after oral administration. The rate of elimination of amphetamine highly depends on the urine pH in which acidic pH will produce a higher excretion of amphetamine and basic pH produces a lower excretion. •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 amphetamine highly depends on the isomer. For d-amphetamine, the reported half-life is of approximately 9-11 hours while for l-amphetamine the half-life is reported to be of 11-14 hours. The urine pH can modify this pharmacokinetic parameter which can vary from 7 hours in acid urine to 34 hours for alkaline urine. •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 normal clearance rate is of 0.7 L.h/kg. This clearance has been shown to get significantly reduced in patients with renal impairment reaching a value of 0.4 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 mean lethal serum concentration is reported to be of 6.4 mg/l. Acute amphetamine overdose can lead to hyperthermia, respiratory depression, seizures, metabolic acidosis, renal failure, hepatic injury, and coma. Some of the neurologic effects have been shown to be agitation, aggressive behavior, irritability, headache, and hallucinations. In the cardiovascular site, there have been reports of arrhythmia, cardiomyopathy, myocardial infarction or ischemic stroke. Lastly, in the GI tract, there are reports if abdominal pain, vomiting, diarrhea, cramps, anorexia and GI hemorrhage. A dose of 1-2 g of amphetamine is known to cause severe intoxication but some chronic abusers can report usage of even 5-15 g per day. In animal studies, there is no evidence of carcinogenic potential, not clastogenic or to affect fertility or early embryonic development. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Adderall, Adzenys, Dyanavel, Evekeo, Mydayis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): alpha-Methylbenzeneethaneamine Amfetamina Amfetamine Amfetaminum Amphetamine beta-Aminopropylbenzene beta-Phenylisopropylamin Desoxynorephedrine rac-amphetamine •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): Amphetamine is a CNS stimulant and sympathomimetic agent indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Amphetamine interact? Information: •Drug A: Abatacept •Drug B: Amphetamine •Severity: MODERATE •Description: The metabolism of Amphetamine 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): Amphetamine is indicated for the treatment of attention-deficit/hyperactivity disorders (ADHD) as well as for the treatment of central nervous system disorders such as narcolepsy. ADHD is a complex disorder associated with the substantial heterogeneity in etiology, clinical presentation, and treatment outcome. ADHD comes from a complex interplay between interdependent genetic and non-genetic factors which cause complex mental disorders in children and teenagers. On the other hand, narcolepsy is a chronic sleep disorder typically resenting during adolescence and characterized by excessive daytime sleepiness. Amphetamine is also being used nowadays off-label for the treatment of obesity, depression and chronic 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): From its mechanism of action, it has been demonstrated that amphetamine augments the concentration of noradrenaline in the prefrontal cortex and dopamine in the striatum on a dose and time-dependent manner. The indistinct release of neurotransmitters which include adrenaline is known to produce cardiovascular side effects. There are old reports of a cognitive enhancement related to the administration of amphetamine in which improvements in intelligence test scores were reported. In ADHD, amphetamine has been largely showed to produce remarkable improvements in school performance, behavior, and demeanor. The effect was shown to be produced through both racemic forms and to this date, the use of racemic forms 3:1 (D:L) is very common. The therapeutic effect of amphetamine on serotonin does not seem to have a significant clinical effect on ADHD as observed on comparative studies with amphetamine and fenfluramine, a powerful serotonin releasing factor. However, the indirect effect on serotonin might have an effect on the depression and anxiety profile of ADHD. Studies regarding the illicit use of amphetamine in which heavy consumers were studied proved the generation of a paranoid state which flagged this drug as a psychiatric danger compound. This observation was supported by the continuous reports of misuse in patients under depression. •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): It is important to consider that amphetamine has a very similar structure to the catecholamine neurotransmitters mainly on the presence of a long planar conformation, the presence of an aromatic ring and nitrogen in the aryl side chain. Amphetamine, as well as other catecholamines, is taken into presynaptic nerve terminals by the association with two sodium ions and one chloride ion. The complex of the amphetamine with the ions is actively transported by monoamine reuptake transporters. As amphetamine acts competitively with the endogenous monoamines, the greater the number of amphetamines the more internalized amphetamine will be found. Once inside the presynaptic terminal, amphetamine displaces other monoamines to be stored by VMAT2 which produces the pumping of the neurotransmitters into the synapse by a process called retro-transport. This process of release of neurotransmitters is approximately fourfold more potent in the d-isomer for the release of dopamine. The mechanism of action of amphetamine is complemented by the inhibition of the reuptake and of monoamine oxidase which acts synergistically to produce a significant increase the monoamine concentration. This activity is not done as an inhibitor per se but more as a competitive substrate and thus, amphetamine is known to be a weak dopamine reuptake inhibitor, moderate noradrenaline reuptake inhibitor and very weak serotonin reuptake inhibitor. From this specific action, the l-isomer is known to be significantly less potent. Lastly, amphetamine is known to be an inhibitor of the mitochondrial-bound enzyme MAO which is the catalytic enzyme in charge of degrading all the excess of neurotransmitters. This mechanism of action is often overpassed as amphetamine is a weak MAO inhibitor but this mechanism cannot be dismissed. •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): Amphetamine is well absorbed in the gut and as it is a weak base hence the more basic the environment the more of the drug is found in a lipid-soluble form and the absorption through lipid-rich cell membranes is highly favored. The peak response of amphetamine occurs 1-3 hours after oral administration and approximately 15 minutes after injection and it presents a bioavailability of over 75%. Complete amphetamine absorption is usually done after 4-6 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): Amphetamine is reported to have a high volume of distribution of 4 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The reported protein binding of amphetamine is relatively low and register to be of 20%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Amphetamine is known to be metabolized by the liver under the action of the CYP2D6. The metabolic pathway of amphetamine is mainly defined by aromatic hydroxylation, aliphatic hydroxylation, and n-dealkylation. The formed metabolites in this pathway are 4-hydroxyamphetamine, 4-hydroxynorephedrine, hippuric acid, benzoic acid, benzyl methyl ketone, and p-hydroxyamphetamine which is known to be a potent hallucinogen. However, a significant part of the original compound remains unchanged. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The elimination of amphetamine is mainly via the urine from which about 40% of the excreted dose is found as unchanged amphetamine. About 90% of the administered amphetamine is eliminated 3 days after oral administration. The rate of elimination of amphetamine highly depends on the urine pH in which acidic pH will produce a higher excretion of amphetamine and basic pH produces a lower excretion. •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 amphetamine highly depends on the isomer. For d-amphetamine, the reported half-life is of approximately 9-11 hours while for l-amphetamine the half-life is reported to be of 11-14 hours. The urine pH can modify this pharmacokinetic parameter which can vary from 7 hours in acid urine to 34 hours for alkaline urine. •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 normal clearance rate is of 0.7 L.h/kg. This clearance has been shown to get significantly reduced in patients with renal impairment reaching a value of 0.4 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 mean lethal serum concentration is reported to be of 6.4 mg/l. Acute amphetamine overdose can lead to hyperthermia, respiratory depression, seizures, metabolic acidosis, renal failure, hepatic injury, and coma. Some of the neurologic effects have been shown to be agitation, aggressive behavior, irritability, headache, and hallucinations. In the cardiovascular site, there have been reports of arrhythmia, cardiomyopathy, myocardial infarction or ischemic stroke. Lastly, in the GI tract, there are reports if abdominal pain, vomiting, diarrhea, cramps, anorexia and GI hemorrhage. A dose of 1-2 g of amphetamine is known to cause severe intoxication but some chronic abusers can report usage of even 5-15 g per day. In animal studies, there is no evidence of carcinogenic potential, not clastogenic or to affect fertility or early embryonic development. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Adderall, Adzenys, Dyanavel, Evekeo, Mydayis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): alpha-Methylbenzeneethaneamine Amfetamina Amfetamine Amfetaminum Amphetamine beta-Aminopropylbenzene beta-Phenylisopropylamin Desoxynorephedrine rac-amphetamine •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): Amphetamine is a CNS stimulant and sympathomimetic agent indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). 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 Amsacrine interact?

•Drug A: Abatacept •Drug B: Amsacrine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Amsacrine 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 acute myeloid leukaemia. •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): Amsacrine is an aminoacridine derivative that is a potent intercalating antineoplastic agent. It is effective in the treatment of acute leukemias and malignant lymphomas, but has poor activity in the treatment of solid tumors. It is frequently used in combination with other antineoplastic agents in chemotherapy protocols. It produces consistent but acceptable myelosuppression and cardiotoxic effects. •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): Amsacrine binds to DNA through intercalation and external binding. It has a base specificity for A-T pairs. Rapidly dividing cells are two to four times more sensitive to amsacrine than are resting cells. Amsacrine appears to cleave DNA by inducing double stranded breaks. Amsacrine also targets and inhibits topoisomerase II. Cytotoxicity is greatest during the S phase of the cell cycle when topoisomerase levels are at a maximum. •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): Poorly 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): 96-98% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Extensive, primarily hepatic, converted to glutathione conjugate. •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): 8-9 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 nausea and vomiting, diarrhea, some cardiotoxicity (rarely). •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acridinyl anisidide Amsacrina Amsacrine Amsacrinum m-AMSA mAMSA •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): Amsacrine is a cytotoxic agent used to induce remission in acute adult leukemia that is not adequately responsive to other agents.

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 Amsacrine interact? Information: •Drug A: Abatacept •Drug B: Amsacrine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Amsacrine 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 acute myeloid leukaemia. •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): Amsacrine is an aminoacridine derivative that is a potent intercalating antineoplastic agent. It is effective in the treatment of acute leukemias and malignant lymphomas, but has poor activity in the treatment of solid tumors. It is frequently used in combination with other antineoplastic agents in chemotherapy protocols. It produces consistent but acceptable myelosuppression and cardiotoxic effects. •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): Amsacrine binds to DNA through intercalation and external binding. It has a base specificity for A-T pairs. Rapidly dividing cells are two to four times more sensitive to amsacrine than are resting cells. Amsacrine appears to cleave DNA by inducing double stranded breaks. Amsacrine also targets and inhibits topoisomerase II. Cytotoxicity is greatest during the S phase of the cell cycle when topoisomerase levels are at a maximum. •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): Poorly 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): 96-98% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Extensive, primarily hepatic, converted to glutathione conjugate. •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): 8-9 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 nausea and vomiting, diarrhea, some cardiotoxicity (rarely). •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acridinyl anisidide Amsacrina Amsacrine Amsacrinum m-AMSA mAMSA •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): Amsacrine is a cytotoxic agent used to induce remission in acute adult leukemia that is not adequately responsive to other agents. 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 Anagrelide interact?

•Drug A: Abatacept •Drug B: Anagrelide •Severity: MAJOR •Description: The metabolism of Anagrelide 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): Anagrelide is indicated for the treatment of thrombocythemia, secondary to malignant neoplasms, to reduce platelet count and the associated risk of thrombosis. It is also beneficial in the amelioration of thrombocythemia symptoms including thrombo-hemorrhagic events. •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): Anagrelide decreases platelet counts by suppressing transcription factors necessary for the synthesis and maturation of platelet-producing cells. The drug itself appears to have a relatively short residence time in the body necessitating twice or four times daily dosing. However, given that the pharmacological effect of anagrelide therapy is reliant on a gradual suppression of platelet-producing cells, it may take 7 to 14 days for its administration to be reflected in reduced platelet counts - for this reason any changes to anagrelide doses should not exceed 0.5 mg/day in any one week. Evidence from animal studies suggests anagrelide may impair female fertility. Female patients of reproductive age should be advised of the potential for adverse effects on fertility prior to initiating 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): The exact mechanism by which anagrelide lowers platelet count is unclear. Evidence from human trials suggests a dose-related suppression of megakaryocyte maturation, the cells responsible for platelet production - blood drawn from patients receiving anagrelide showed a disruption to the post-mitotic phase of megakaryocyte development and a subsequent reduction in their size and ploidy. This may be achieved via indirect suppression of certain transcription factors required for megakaryocytopoeisis, including GATA-1 and FOG-1. Anagrelide is a known inhibitor of phosphodiesterase 3A (PDE3A), although its platelet-lowering effects appear unrelated to this inhibition. While PDE3 inhibitors, as a class, can inhibit platelet aggregation, this effect is only seen at higher anagrelide doses (i.e. greater than those required to reduce platelet count). Modulation of PDE3A has been implicated in causing cell cycle arrest and apoptosis in cancer cells expressing both PDE3A and SLFN12, and may be of value in the treatment of gastrointestinal stromal tumours. •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 bioavailability of anagrelide is approximately 70%. Given on an empty stomach, the C max is reached within 1 hour (T max ) of administration. Co-administration with food slightly lowers the C max and increases the AUC, but not to a clinically significant extent. •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): Anagrelide is extensively metabolized, primarily in the liver by cytochrome P450 1A2 (CYP1A2), into two major metabolites: 6,7-dichloro-3-hydroxy-1,5 dihydro-imidazo[2,1-b]quinazolin-2-one (3-hydroxy anagrelide) and 2-amino-5,6-dichloro-3,4,-dihydroquinazoline (RL603). The 3-hydroxy metabolite is considered pharmacologically active and carries a similar potency and efficacy in regards to its platelet-lowering effects, but inhibits PDE3 with a potency 40x greater than that of the parent drug. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following metabolism, urinary excretion of metabolites appears to be the primary means of anagrelide elimination. Less than 1% of an administered dose is recovered in the urine as unchanged parent drug, while approximately 3% and 16-20% of the administered dose is recovered as 3-hydroxy anagrelide and RL603, 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 t 1/2 of anagrelide and its active metabolite, 3-hydroxy anagrelide, are approximately 1.5 hours and 2.5 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): The oral LD 50 of anagrelide as reported in rats and mice is >1500mg/kg and >2500mg/kg, respectively. Symptoms of overdose may include hypotension, sinus tachycardia, and vomiting. As the therapeutic effect of anagrelide (i.e. platelet reduction) is dose-related, significant thrombocytopenia is expected in instances of overdose. Treatment of overdose should involve careful monitoring of platelet counts and complications such as bleeding. Employ symptomatic and supportive measures if clinically indicated. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Agrylin, Xagrid •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): Anagrelide is a platelet-reducing agent used to treat thrombocythemia, and its related complications, secondary to myeloproliferative neoplasms.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Anagrelide interact? Information: •Drug A: Abatacept •Drug B: Anagrelide •Severity: MAJOR •Description: The metabolism of Anagrelide 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): Anagrelide is indicated for the treatment of thrombocythemia, secondary to malignant neoplasms, to reduce platelet count and the associated risk of thrombosis. It is also beneficial in the amelioration of thrombocythemia symptoms including thrombo-hemorrhagic events. •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): Anagrelide decreases platelet counts by suppressing transcription factors necessary for the synthesis and maturation of platelet-producing cells. The drug itself appears to have a relatively short residence time in the body necessitating twice or four times daily dosing. However, given that the pharmacological effect of anagrelide therapy is reliant on a gradual suppression of platelet-producing cells, it may take 7 to 14 days for its administration to be reflected in reduced platelet counts - for this reason any changes to anagrelide doses should not exceed 0.5 mg/day in any one week. Evidence from animal studies suggests anagrelide may impair female fertility. Female patients of reproductive age should be advised of the potential for adverse effects on fertility prior to initiating 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): The exact mechanism by which anagrelide lowers platelet count is unclear. Evidence from human trials suggests a dose-related suppression of megakaryocyte maturation, the cells responsible for platelet production - blood drawn from patients receiving anagrelide showed a disruption to the post-mitotic phase of megakaryocyte development and a subsequent reduction in their size and ploidy. This may be achieved via indirect suppression of certain transcription factors required for megakaryocytopoeisis, including GATA-1 and FOG-1. Anagrelide is a known inhibitor of phosphodiesterase 3A (PDE3A), although its platelet-lowering effects appear unrelated to this inhibition. While PDE3 inhibitors, as a class, can inhibit platelet aggregation, this effect is only seen at higher anagrelide doses (i.e. greater than those required to reduce platelet count). Modulation of PDE3A has been implicated in causing cell cycle arrest and apoptosis in cancer cells expressing both PDE3A and SLFN12, and may be of value in the treatment of gastrointestinal stromal tumours. •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 bioavailability of anagrelide is approximately 70%. Given on an empty stomach, the C max is reached within 1 hour (T max ) of administration. Co-administration with food slightly lowers the C max and increases the AUC, but not to a clinically significant extent. •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): Anagrelide is extensively metabolized, primarily in the liver by cytochrome P450 1A2 (CYP1A2), into two major metabolites: 6,7-dichloro-3-hydroxy-1,5 dihydro-imidazo[2,1-b]quinazolin-2-one (3-hydroxy anagrelide) and 2-amino-5,6-dichloro-3,4,-dihydroquinazoline (RL603). The 3-hydroxy metabolite is considered pharmacologically active and carries a similar potency and efficacy in regards to its platelet-lowering effects, but inhibits PDE3 with a potency 40x greater than that of the parent drug. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following metabolism, urinary excretion of metabolites appears to be the primary means of anagrelide elimination. Less than 1% of an administered dose is recovered in the urine as unchanged parent drug, while approximately 3% and 16-20% of the administered dose is recovered as 3-hydroxy anagrelide and RL603, 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 t 1/2 of anagrelide and its active metabolite, 3-hydroxy anagrelide, are approximately 1.5 hours and 2.5 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): The oral LD 50 of anagrelide as reported in rats and mice is >1500mg/kg and >2500mg/kg, respectively. Symptoms of overdose may include hypotension, sinus tachycardia, and vomiting. As the therapeutic effect of anagrelide (i.e. platelet reduction) is dose-related, significant thrombocytopenia is expected in instances of overdose. Treatment of overdose should involve careful monitoring of platelet counts and complications such as bleeding. Employ symptomatic and supportive measures if clinically indicated. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Agrylin, Xagrid •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): Anagrelide is a platelet-reducing agent used to treat thrombocythemia, and its related complications, secondary to myeloproliferative neoplasms. 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 Anakinra interact?

•Drug A: Abatacept •Drug B: Anakinra •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Anakinra is combined with Abatacept. •Extended Description: Anakinra may enhance the adverse effects of Abatacept and increase the risk of infection. A 2006 randomized controlled trial found that abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events and is therefore not recommended for use in combination with biologic therapy. The FDA recommends avoiding concurrent administration of abatacept with other biologic rheumatoid arthritis therapies, such as anakinra. However, a retrospective case series from 2011 of 4 patients with systemic juvenile idiopathic arthritis (sJIA) found this combination to be beneficial to patients with refractory sJIA, "allowing dose reduction of both anakinra and corticosteroids while improving arthritis joint count, as well as controlling systemic features of disease" . Further evidence is needed to confirm this case series and extrapolation to other patient demographics and disease states. •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): Anakinra is an interleukin-1 receptor antagonist indicated for the reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis (RA), in patients 18 years of age or older who have failed one or more disease-modifying antirheumatic drugs (DMARDs). Anakinra can be used alone or in combination with DMARDs other than Tumor Necrosis Factor (TNF) blocking agents. Anakinra is also indicated for the treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID) and the treatment of Deficiency of Interleukin-1 Receptor Antagonist (DIRA). Anakinra is also used off-label for the treatment of several inflammatory diseases. The FDA has issued an emergency use authorization (EUA) for the emergency use of anakinra for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults with positive results of direct SARS-CoV-2 viral testing with pneumonia requiring supplemental oxygen (low- or high-flow oxygen) who are at risk of progressing to severe respiratory failure and likely to have an elevated plasma soluble urokinase plasminogen activator receptor (suPAR). Since anakinra is approved for this condition under EUA, the drug should only be used when there are no alternative treatment 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): Anakinra is a recombinant human interleukin-1 receptor antagonist (IL-1Ra) that blocks the biologic activity of interleukin-1 (IL-1) by competitively inhibiting its ability to bind to the IL-1 type I receptor (IL-1RI). IL-1 production is higher in inflammatory diseases such as rheumatoid arthritis, where the amount of naturally occurring IL-1Ra cannot compete with the high level of IL-1 present. Anakinra has been associated with a higher probability of developing a severe infection, and the use of TNF blocking agents can increase this incidence. Hypersensitivity reactions have been reported in patients using anakinra. The prevalence of allergic reactions may be higher in patients with deficiency of interleukin-1 receptor antagonist (DIRA), since they lack the naturally occurring IL-1Ra. Anakinra can also decrease neutrophil counts in patients. Therefore, neutrophil counts should be assessed before initiating anakinra. •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): Interleukin-1 (IL-1) plays an important role in inflammation and immunological responses. Inflammatory stimuli trigger its production, and it binds to the IL-1 receptor to activate a wide variety of mechanisms. The activity of the IL-1 receptor is also regulated by a naturally occurring IL-1 receptor antagonist (IL-1Ra) that competes for the binding sites of the IL-1 receptor. In rheumatoid arthritis (RA) patients, IL-1 levels are elevated, inducing cartilage degradation and the stimulation of bone resorption, and the amount of IL-1Ra in the synovium and synovial fluid of RA patients cannot compete with the high level of IL-1 present. Anakinra is a recombinant, non-glycosylated form of IL-1Ra that competes with and inhibits IL-1 by binding to the IL-1 receptor; therefore, the administration of this drug reduces the inflammatory response in RA patients. Anakinra can also be used in the treatment of neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of interleukin-1 receptor antagonist (DIRA). Patients with NOMID have spontaneous mutations in CIAS1/NLRP3, a gene that encodes cryopyrin, an inflammasome component. When activated, the inflammasome enhances and promotes the production of IL-1β, an isoform of IL-1. DIRA is an autoinflammatory disease caused by mutations in the IL1RN gene. These mutations reduce the amount of IL-1Ra that is secreted, leading to the unopposed action of IL-1. Anakinra controls NOMID and DIRA symptoms by inhibiting IL-1 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): The bioavailability of anakinra is 95% in healthy subjects administered a 70 mg subcutaneous bolus injection. In patients with rheumatoid arthritis (RA) administered a subcutaneous dose of anakinra, the maximum plasma concentration was detected 3 to 7 hours later. No unexpected accumulation was observed in RA patients receiving this drug for up to 24 weeks. In a phase 1, single-center, randomized, sequential single-dose escalation PK study done in patients with stable RA, AUC increased in a relatively dose-proportional manner. While the t max and C max fluctuated across the different doses provided to these patients (range from 0.5 to 6 mg/kg), clearance appeared to be consistent. In patients with neonatal-onset multisystem inflammatory disease (NOMID) treated with a subcutaneous dose of 3 mg/kg of anakinra for an average of 3.5 years (n=16), C max was 3628 ng/mL and C 24h was 203 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 adult subjects with rheumatoid arthritis (RA) treated with anakinra (n=35), the volume of distribution averaged 18.5 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): As a protein-based therapy, anakinra is expected to be metabolized by proteases throughout the body. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Anakinra is mostly excreted by the kidney; therefore, the risk of toxic reactions may increase in patients with impaired renal function. •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 with rheumatoid arthritis (RA), the terminal half-life of anakinra ranged from 4 to 6 hours. In patients with neonatal-onset multisystem inflammatory disease (NOMID), the median half-life of anakinra was 5.7 h (range=3.1-28.2, n=12). •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 rheumatoid arthritis (RA), the clearance of anakinra was relatively consistent for different dose levels. Clearance is variable and increases with increasing creatinine clearance and body weight. However, gender and age were not significant factors. In patients with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 mL/min) renal impairment, the mean plasma clearance of anakinra was 16% and 50% lower, respectively. In patients with severe renal insufficiency and end-stage renal disease (creatinine clearance < 30 mL/min), the mean plasma clearance of anakinra was 70% and 75% lower, respectively. •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 clinical trials done in patients with rheumatoid arthritis (RA) and neonatal-onset multisystem inflammatory disease (NOMID) treated with anakinra, no cases of overdose were reported. Sepsis trials were performed using mean calculated doses up to 35 times the ones given to patients with RA over 72 hours. Anakinra did not produce any serious toxicities at this dose range. In preclinical studies done in rats, where up to 100 mg/kg/day were administered either intravenously or subcutaneously over 14 days, and given at doses of 2, 20 or 200 mg/kg/day subcutaneously for 6 months, anakinra was well tolerated. Toxicity ranged from mild to moderate, and dose-related inflammation, hemorrhage and fibrosis at the injection site were detected in both rats and monkeys. The no observable adverse effect level (NOAEL) in rats receiving a daily subcutaneous dose of anakinra for 6 months was 2 mg/kg/day. In rats receiving a daily intravenous injection of anakinra for 14 or 28 days, the NOAEL was 30 mg/kg/day. The NOAEL in Rhesus monkeys was 150 mg/kg/day when anakinra was administered via intravenous infusion for 7 days, 10-30 mg/kg/day when administered via intravenous bolus injection for 14 days and 5 mg/kg/day when administered subcutaneously for 14 days. Anakinra had no effects on fertility and reproductive capacity in both male and female rats given the maximum recommended human dose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Kineret •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): Anakinra is a recombinant form of human interleukin-1 receptor antagonist used in the treatment of rheumatoid arthritis, neonatal-onset multisystem inflammatory disease and deficiency of interleukin-1 receptor antagonist (DIRA).

Anakinra may enhance the adverse effects of Abatacept and increase the risk of infection. A 2006 randomized controlled trial found that abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events and is therefore not recommended for use in combination with biologic therapy. The FDA recommends avoiding concurrent administration of abatacept with other biologic rheumatoid arthritis therapies, such as anakinra. However, a retrospective case series from 2011 of 4 patients with systemic juvenile idiopathic arthritis (sJIA) found this combination to be beneficial to patients with refractory sJIA, "allowing dose reduction of both anakinra and corticosteroids while improving arthritis joint count, as well as controlling systemic features of disease" . Further evidence is needed to confirm this case series and extrapolation to other patient demographics and disease states. The severity of the interaction is major.

Question: Does Abatacept and Anakinra interact? Information: •Drug A: Abatacept •Drug B: Anakinra •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Anakinra is combined with Abatacept. •Extended Description: Anakinra may enhance the adverse effects of Abatacept and increase the risk of infection. A 2006 randomized controlled trial found that abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events and is therefore not recommended for use in combination with biologic therapy. The FDA recommends avoiding concurrent administration of abatacept with other biologic rheumatoid arthritis therapies, such as anakinra. However, a retrospective case series from 2011 of 4 patients with systemic juvenile idiopathic arthritis (sJIA) found this combination to be beneficial to patients with refractory sJIA, "allowing dose reduction of both anakinra and corticosteroids while improving arthritis joint count, as well as controlling systemic features of disease" . Further evidence is needed to confirm this case series and extrapolation to other patient demographics and disease states. •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): Anakinra is an interleukin-1 receptor antagonist indicated for the reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis (RA), in patients 18 years of age or older who have failed one or more disease-modifying antirheumatic drugs (DMARDs). Anakinra can be used alone or in combination with DMARDs other than Tumor Necrosis Factor (TNF) blocking agents. Anakinra is also indicated for the treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID) and the treatment of Deficiency of Interleukin-1 Receptor Antagonist (DIRA). Anakinra is also used off-label for the treatment of several inflammatory diseases. The FDA has issued an emergency use authorization (EUA) for the emergency use of anakinra for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults with positive results of direct SARS-CoV-2 viral testing with pneumonia requiring supplemental oxygen (low- or high-flow oxygen) who are at risk of progressing to severe respiratory failure and likely to have an elevated plasma soluble urokinase plasminogen activator receptor (suPAR). Since anakinra is approved for this condition under EUA, the drug should only be used when there are no alternative treatment 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): Anakinra is a recombinant human interleukin-1 receptor antagonist (IL-1Ra) that blocks the biologic activity of interleukin-1 (IL-1) by competitively inhibiting its ability to bind to the IL-1 type I receptor (IL-1RI). IL-1 production is higher in inflammatory diseases such as rheumatoid arthritis, where the amount of naturally occurring IL-1Ra cannot compete with the high level of IL-1 present. Anakinra has been associated with a higher probability of developing a severe infection, and the use of TNF blocking agents can increase this incidence. Hypersensitivity reactions have been reported in patients using anakinra. The prevalence of allergic reactions may be higher in patients with deficiency of interleukin-1 receptor antagonist (DIRA), since they lack the naturally occurring IL-1Ra. Anakinra can also decrease neutrophil counts in patients. Therefore, neutrophil counts should be assessed before initiating anakinra. •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): Interleukin-1 (IL-1) plays an important role in inflammation and immunological responses. Inflammatory stimuli trigger its production, and it binds to the IL-1 receptor to activate a wide variety of mechanisms. The activity of the IL-1 receptor is also regulated by a naturally occurring IL-1 receptor antagonist (IL-1Ra) that competes for the binding sites of the IL-1 receptor. In rheumatoid arthritis (RA) patients, IL-1 levels are elevated, inducing cartilage degradation and the stimulation of bone resorption, and the amount of IL-1Ra in the synovium and synovial fluid of RA patients cannot compete with the high level of IL-1 present. Anakinra is a recombinant, non-glycosylated form of IL-1Ra that competes with and inhibits IL-1 by binding to the IL-1 receptor; therefore, the administration of this drug reduces the inflammatory response in RA patients. Anakinra can also be used in the treatment of neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of interleukin-1 receptor antagonist (DIRA). Patients with NOMID have spontaneous mutations in CIAS1/NLRP3, a gene that encodes cryopyrin, an inflammasome component. When activated, the inflammasome enhances and promotes the production of IL-1β, an isoform of IL-1. DIRA is an autoinflammatory disease caused by mutations in the IL1RN gene. These mutations reduce the amount of IL-1Ra that is secreted, leading to the unopposed action of IL-1. Anakinra controls NOMID and DIRA symptoms by inhibiting IL-1 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): The bioavailability of anakinra is 95% in healthy subjects administered a 70 mg subcutaneous bolus injection. In patients with rheumatoid arthritis (RA) administered a subcutaneous dose of anakinra, the maximum plasma concentration was detected 3 to 7 hours later. No unexpected accumulation was observed in RA patients receiving this drug for up to 24 weeks. In a phase 1, single-center, randomized, sequential single-dose escalation PK study done in patients with stable RA, AUC increased in a relatively dose-proportional manner. While the t max and C max fluctuated across the different doses provided to these patients (range from 0.5 to 6 mg/kg), clearance appeared to be consistent. In patients with neonatal-onset multisystem inflammatory disease (NOMID) treated with a subcutaneous dose of 3 mg/kg of anakinra for an average of 3.5 years (n=16), C max was 3628 ng/mL and C 24h was 203 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 adult subjects with rheumatoid arthritis (RA) treated with anakinra (n=35), the volume of distribution averaged 18.5 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): As a protein-based therapy, anakinra is expected to be metabolized by proteases throughout the body. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Anakinra is mostly excreted by the kidney; therefore, the risk of toxic reactions may increase in patients with impaired renal function. •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 with rheumatoid arthritis (RA), the terminal half-life of anakinra ranged from 4 to 6 hours. In patients with neonatal-onset multisystem inflammatory disease (NOMID), the median half-life of anakinra was 5.7 h (range=3.1-28.2, n=12). •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 rheumatoid arthritis (RA), the clearance of anakinra was relatively consistent for different dose levels. Clearance is variable and increases with increasing creatinine clearance and body weight. However, gender and age were not significant factors. In patients with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 mL/min) renal impairment, the mean plasma clearance of anakinra was 16% and 50% lower, respectively. In patients with severe renal insufficiency and end-stage renal disease (creatinine clearance < 30 mL/min), the mean plasma clearance of anakinra was 70% and 75% lower, respectively. •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 clinical trials done in patients with rheumatoid arthritis (RA) and neonatal-onset multisystem inflammatory disease (NOMID) treated with anakinra, no cases of overdose were reported. Sepsis trials were performed using mean calculated doses up to 35 times the ones given to patients with RA over 72 hours. Anakinra did not produce any serious toxicities at this dose range. In preclinical studies done in rats, where up to 100 mg/kg/day were administered either intravenously or subcutaneously over 14 days, and given at doses of 2, 20 or 200 mg/kg/day subcutaneously for 6 months, anakinra was well tolerated. Toxicity ranged from mild to moderate, and dose-related inflammation, hemorrhage and fibrosis at the injection site were detected in both rats and monkeys. The no observable adverse effect level (NOAEL) in rats receiving a daily subcutaneous dose of anakinra for 6 months was 2 mg/kg/day. In rats receiving a daily intravenous injection of anakinra for 14 or 28 days, the NOAEL was 30 mg/kg/day. The NOAEL in Rhesus monkeys was 150 mg/kg/day when anakinra was administered via intravenous infusion for 7 days, 10-30 mg/kg/day when administered via intravenous bolus injection for 14 days and 5 mg/kg/day when administered subcutaneously for 14 days. Anakinra had no effects on fertility and reproductive capacity in both male and female rats given the maximum recommended human dose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Kineret •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): Anakinra is a recombinant form of human interleukin-1 receptor antagonist used in the treatment of rheumatoid arthritis, neonatal-onset multisystem inflammatory disease and deficiency of interleukin-1 receptor antagonist (DIRA). Output: Anakinra may enhance the adverse effects of Abatacept and increase the risk of infection. A 2006 randomized controlled trial found that abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events and is therefore not recommended for use in combination with biologic therapy. The FDA recommends avoiding concurrent administration of abatacept with other biologic rheumatoid arthritis therapies, such as anakinra. However, a retrospective case series from 2011 of 4 patients with systemic juvenile idiopathic arthritis (sJIA) found this combination to be beneficial to patients with refractory sJIA, "allowing dose reduction of both anakinra and corticosteroids while improving arthritis joint count, as well as controlling systemic features of disease" . Further evidence is needed to confirm this case series and extrapolation to other patient demographics and disease states. The severity of the interaction is major.

Does Abatacept and Anastrozole interact?

•Drug A: Abatacept •Drug B: Anastrozole •Severity: MODERATE •Description: The metabolism of Anastrozole 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): Anastrozole is indicated as adjunct therapy in the treatment of hormone receptor-positive early breast cancer in postmenopausal women, and as a first-line treatment for hormone receptor-positive (or hormone receptor-unknown) locally advanced or metastatic breast cancer in postmenopausal women. It may also be used in the treatment of advanced breast cancer in postmenopausal women who experience disease progression despite treatment with tamoxifen. •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): Anastrozole prevents the conversion of adrenal androgens (e.g. testosterone ) to estrogen in peripheral and tumour tissues. As the growth of many breast cancers is stimulated and/or maintained by the presence of estrogen, anastrozole helps to treat these cancers by decreasing the levels of circulating estrogens. Anastrozole has a relatively long duration of action allowing for once daily dosing - serum estradiol is reduced by approximately 70% within 24 hours of beginning therapy with 1mg once daily, and levels remain suppressed for up to 6 days following cessation of therapy. The incidence of ischemic cardiovascular events was increased during anastrozole therapy and patients with pre-existing ischemic heart disease should consider the risks and benefits of anastrozole before beginning therapy. Anastrozole has also been reported to decrease spine and hip bone mineral density (BMD), so consideration should be given to monitoring of BMD in patients receiving long-term 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): Anastrazole exerts its anti-estrogenic effects via selective and competitive inhibition of the aromatase enzyme found predominantly in the adrenal glands, liver, and fatty tissues. Many breast cancers are hormone receptor-positive, meaning their growth is stimulated and/or maintained by the presence of hormones such as estrogen or progesterone. In postmenopausal women, estrogen is primarily derived from the conversion of adrenally-produced androgens into estrogens by the aromatase enzyme - by competitively inhibiting the biosynthesis of estrogen at these enzymes, anastrozole effectively suppresses circulating estrogen levels and, subsequently, the growth of hormone receptor-positive tumours. •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): Anastrozole is rapidly absorbed and T max is typically reached within 2 hours of dosing under fasted conditions. Coadministration with food reduces the rate but not the overall extent of absorption - mean C max decreased by 16% and the median T max was extended to 5 hours when anastrozole was administered 30 minutes after ingestion of food, though this relatively minor alteration in absorption kinetics is not expected to result in clinically significant effects. •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 anastrozole into brain tissue in mice is 3.19 mL/g. Distribution into the CNS is limited due to the activity of P-gp efflux pumps at the blood brain barrier, of which anastrozole is a substrate. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Anastrozole is 40% protein bound in plasma and appears to be independent of plasma concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Anastrozole is primarily metabolized in the liver via oxidation and glucuronidation to a number of inactive metabolites, including hydroxyanastrozole (both free and glucuronidated) and anastrozole glucuronide. Oxidation to hydroxyanastrozole is catalyzed predominantly by CYP3A4 (as well as CYP3A5 and CYP2C8, to a lesser extent) and the direct glucuronidation of anastrozole appears to be catalyzed mainly by UGT1A4. Anastrozole may also undergo N-dealkylation to form triazole and 3,5-Bis-(2-methylpropiononitrile)-benzoic acid. Labels for anastrozole state the main metabolite found in plasma following administration is triazole, but a recent pharmacokinetic study was unable to detect any products of N-dealkylation in vitro. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Approximately 10% of the administered dosage is eliminated 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): The elimination half-life of anastrozole is approximately 50 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): Anastrozole's clearance is mainly via hepatic metabolism and can therefore be altered in patients with hepatic impairment - patients with stable hepatic cirrhosis exhibit an apparent oral clearance approximately 30% lower compared with patients with normal liver function. Conversely, renal impairment has a negligible effect on total drug clearance as the renal route is a relatively minor clearance pathway for anastrozole. In volunteers with severe renal impairment, renal clearance was reduced by 50% while total clearance was only reduced by approximately 10%. •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 oral TDLo in a human woman is 1.68 mg/kg given intermittently over the course of 12 weeks. Knowledge of the signs and symptoms of anastrozole overdose is incomplete as there are no documented descriptions of a patient receiving more than 60mg, a dose which was administered to a healthy male volunteer and was well-tolerated. There is no antidote for anastrozole and treatment should be supportive and symptomatic, including close monitoring of patient vital signs. As anastrozole exhibits relatively low protein binding, dialysis may be helpful and should be considered in select cases. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Arimidex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Anastrozol Anastrozole •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): Anastrozole is a competitive, selective, non-steroidal aromatase inhibitor used as adjuvant therapy for the treatment of hormone receptor-positive 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 CYP2C8 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Anastrozole interact? Information: •Drug A: Abatacept •Drug B: Anastrozole •Severity: MODERATE •Description: The metabolism of Anastrozole 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): Anastrozole is indicated as adjunct therapy in the treatment of hormone receptor-positive early breast cancer in postmenopausal women, and as a first-line treatment for hormone receptor-positive (or hormone receptor-unknown) locally advanced or metastatic breast cancer in postmenopausal women. It may also be used in the treatment of advanced breast cancer in postmenopausal women who experience disease progression despite treatment with tamoxifen. •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): Anastrozole prevents the conversion of adrenal androgens (e.g. testosterone ) to estrogen in peripheral and tumour tissues. As the growth of many breast cancers is stimulated and/or maintained by the presence of estrogen, anastrozole helps to treat these cancers by decreasing the levels of circulating estrogens. Anastrozole has a relatively long duration of action allowing for once daily dosing - serum estradiol is reduced by approximately 70% within 24 hours of beginning therapy with 1mg once daily, and levels remain suppressed for up to 6 days following cessation of therapy. The incidence of ischemic cardiovascular events was increased during anastrozole therapy and patients with pre-existing ischemic heart disease should consider the risks and benefits of anastrozole before beginning therapy. Anastrozole has also been reported to decrease spine and hip bone mineral density (BMD), so consideration should be given to monitoring of BMD in patients receiving long-term 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): Anastrazole exerts its anti-estrogenic effects via selective and competitive inhibition of the aromatase enzyme found predominantly in the adrenal glands, liver, and fatty tissues. Many breast cancers are hormone receptor-positive, meaning their growth is stimulated and/or maintained by the presence of hormones such as estrogen or progesterone. In postmenopausal women, estrogen is primarily derived from the conversion of adrenally-produced androgens into estrogens by the aromatase enzyme - by competitively inhibiting the biosynthesis of estrogen at these enzymes, anastrozole effectively suppresses circulating estrogen levels and, subsequently, the growth of hormone receptor-positive tumours. •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): Anastrozole is rapidly absorbed and T max is typically reached within 2 hours of dosing under fasted conditions. Coadministration with food reduces the rate but not the overall extent of absorption - mean C max decreased by 16% and the median T max was extended to 5 hours when anastrozole was administered 30 minutes after ingestion of food, though this relatively minor alteration in absorption kinetics is not expected to result in clinically significant effects. •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 anastrozole into brain tissue in mice is 3.19 mL/g. Distribution into the CNS is limited due to the activity of P-gp efflux pumps at the blood brain barrier, of which anastrozole is a substrate. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Anastrozole is 40% protein bound in plasma and appears to be independent of plasma concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Anastrozole is primarily metabolized in the liver via oxidation and glucuronidation to a number of inactive metabolites, including hydroxyanastrozole (both free and glucuronidated) and anastrozole glucuronide. Oxidation to hydroxyanastrozole is catalyzed predominantly by CYP3A4 (as well as CYP3A5 and CYP2C8, to a lesser extent) and the direct glucuronidation of anastrozole appears to be catalyzed mainly by UGT1A4. Anastrozole may also undergo N-dealkylation to form triazole and 3,5-Bis-(2-methylpropiononitrile)-benzoic acid. Labels for anastrozole state the main metabolite found in plasma following administration is triazole, but a recent pharmacokinetic study was unable to detect any products of N-dealkylation in vitro. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Approximately 10% of the administered dosage is eliminated 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): The elimination half-life of anastrozole is approximately 50 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): Anastrozole's clearance is mainly via hepatic metabolism and can therefore be altered in patients with hepatic impairment - patients with stable hepatic cirrhosis exhibit an apparent oral clearance approximately 30% lower compared with patients with normal liver function. Conversely, renal impairment has a negligible effect on total drug clearance as the renal route is a relatively minor clearance pathway for anastrozole. In volunteers with severe renal impairment, renal clearance was reduced by 50% while total clearance was only reduced by approximately 10%. •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 oral TDLo in a human woman is 1.68 mg/kg given intermittently over the course of 12 weeks. Knowledge of the signs and symptoms of anastrozole overdose is incomplete as there are no documented descriptions of a patient receiving more than 60mg, a dose which was administered to a healthy male volunteer and was well-tolerated. There is no antidote for anastrozole and treatment should be supportive and symptomatic, including close monitoring of patient vital signs. As anastrozole exhibits relatively low protein binding, dialysis may be helpful and should be considered in select cases. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Arimidex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Anastrozol Anastrozole •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): Anastrozole is a competitive, selective, non-steroidal aromatase inhibitor used as adjuvant therapy for the treatment of hormone receptor-positive 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 CYP2C8 substrates. The severity of the interaction is moderate.

Does Abatacept and Anifrolumab interact?

•Drug A: Abatacept •Drug B: Anifrolumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Anifrolumab. •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): Anifrolumab is indicated in the treatment of adults with moderate to severe systemic lupus erythematosus who are receiving standard 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): Anifrolumab is a type 1 interferon receptor (IFNAR) inhibiting IgG1κ monoclonal antibody indicated in the treatment of adults with moderate to severe systemic lupus erythematosus. It has a long duration of action as it is given every 4 weeks. Patients should be counseled regarding the risks of serious infections, hypersensitivity reactions, and malignancies. In patients with SLE, following the administration of anifrolumab- at 300 mg dose, via intravenous infusion every 4 weeks for 52 weeks, neutralization (≥80%) of a type I IFN gene signature was observed from Week 4 to Week 52 in blood samples of patients with elevated levels of type I IFN inducible genes and returned to baseline levels within 8 to 12 weeks following withdrawal of anifrolumab at the end of the 52-week treatment period. However, the clinical relevance of the type I IFN gene signature neutralization is unclear. In SLE patients with positive anti-dsDNA antibodies at baseline (Trials 2 and 3), treatment with anifrolumab 300 mg led to numerical reductions in anti-dsDNA antibodies over time through Week 52. In patients with low complement levels (C3 and C4), increases in complement levels were observed in patients receiving anifrolumab through Week 52. •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): Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting multiple systems in the body. SLE may manifest as a rash on the skin, and can progress to life-threatening autoimmune reactions in the kidney or nervous system. Type 1 interferon pathway activation has been identified as a mediator of pathogenesis in SLE, and the level of type 1 interferon expression is correlated with severity of SLE. Activation of the type 1 interferon receptor (INFAR1) by interferons alpha, beta, epsilon, kappa, and omega lead to stimulation of gene transcription. Activation of INFAR1 and INFAR2 lead to phosphorylation of STAT1 and STAT2, which are translocated with interferon regulatory factor 9 (IRF9) to the cell nucleus to activate the interferon-stimulated response element (ISRE). Activation of ISRE leads to the expression of many proinflammatory and immunomodulatory proteins, as well as the activation of a positive feedback loop that produces more type 1 interferons. Interferon alpha stimulates monocytes to mature into myeloid dendritic cells that express self antigens. CD4+ and CD8+ T-cells, as well as B cells, that are autoreactive will respond to the self antigens and induce inflammmation and apoptosis in cells. This self-reactive immune response damages otherwise healthy tissue throughout the body. Anifrolumab is an immunoglobulin gamma 1 kappa (IgG1κ) monoclonal antibody that selectively binds to subunit 1 of INFAR1. This binding inhibits type I IFN signaling, thereby blocking the biological activity of type I IFNs. Anifrolumab also induces the internalization of IFNAR1, thereby reducing the levels of cell surface IFNAR1 available for receptor assembly. Blockade of receptor-mediated type I IFN signaling inhibits IFN-responsive gene expression as well as downstream inflammatory and immunological processes. Inhibition of type I IFN blocks plasma cell differentiation and normalizes peripheral T-cell subsets. The Fc region of anifrolumab carries the triple mutaion L234F/L235E/P331S to prevent binding of the Fc region of the antibody to cell surface Fc receptors. In a phase IIb clinical trial, the primary endpoint was reached by 34.3% of patients in the 300 mg treatment group, 28.8% of patients in the 1000 mg treatment group, and 17.6% of patients in the placebo group. Patients with higher interferon-stimulated gene transcription at baseline showed a greater response to treatment. •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 PK of anifrolumab was studied in adult patients with SLE following intravenous doses ranging from 100 to 1000 mg once every 4 weeks, and healthy volunteers following a single intravenous dose at 300 mg. Anifrolumab exhibits non-linear PK in the dose range of 100 mg to 1000 mg with more than dose-proportional increases in the exposure as measured by AUC. Following the 300 mg every 4 weeks intravenous administrations of anifrolumab, a steady state was reached by Day 85. The accumulation ratio was approximately 1.36 for C max and 2.49 for C trough. A 300 mg intravenous dose reaches a mean C max of 82.4 µg/mL, with a T max of 0.03 days, and an AUC of 907 day*µg/mL. A 300 mg subcutaneous dose reaches a mean C max of 36.2 µg/mL, with a T max of 4.1 days, and an AUC of 785 day*µg/mL. A 600 mg subcutaneous dose reaches a mean C max of 63.9 µg/mL, with a T max of 7.0 days, and an AUC of 1828 day*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): Based on population PK analysis, the estimated volume of distribution at steady state for a typical patient with SLE (69.1 kg) is 6.23 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): Monoclonal antibodies are mainly catabolized to smaller oligopeptides and individual amino acids. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Monoclonal IgG is predominantly eliminated by catabolism to individual amino acids that are either recycled in the body or metabolized for energy. •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 elimination half life anifrolumab in a phase 1 trial in patients with scleroderma was 0.84 days for a 0.1 mg/kg single dose, 1.24 days for a 0.3 mg/kg single dose, 2.96 days for a 1.0 mg/kg single dose, 4.07 days for a 3.0 mg/kg single dose, and 7.70 days for a 10.0 mg/kg single 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): Following the administration of anifrolumab at a dose of 300 mg via intravenous infusion every 4 weeks, the estimated systemic clearance (CL) for anifrolumab was 0.193 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): Data regarding overdose is not readily available. In a phase 1 clinical trial, patients given a single dose of 20.0 mg/kg experienced upper respiratory tract infections, headache, diarrhea, and nausea. 2 patients in the 3.0 mg/kg single dose group experienced osteomyelitis and skin ulcer. A single patient in the 1.0 mg/kg/week group developed chronic myelogenous leukemia. The frequency and severity of adverse effects does not appear to be closely related to dose. In the event of an overdose, treat patients with symptomatic and supportive measures. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Saphnelo •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): Anifrolumab is a monoclonal antibody that inhibits type 1 interferon receptors, indicated in the treatment of moderate to severe systemic lupus erythematosus.

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 Anifrolumab interact? Information: •Drug A: Abatacept •Drug B: Anifrolumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Anifrolumab. •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): Anifrolumab is indicated in the treatment of adults with moderate to severe systemic lupus erythematosus who are receiving standard 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): Anifrolumab is a type 1 interferon receptor (IFNAR) inhibiting IgG1κ monoclonal antibody indicated in the treatment of adults with moderate to severe systemic lupus erythematosus. It has a long duration of action as it is given every 4 weeks. Patients should be counseled regarding the risks of serious infections, hypersensitivity reactions, and malignancies. In patients with SLE, following the administration of anifrolumab- at 300 mg dose, via intravenous infusion every 4 weeks for 52 weeks, neutralization (≥80%) of a type I IFN gene signature was observed from Week 4 to Week 52 in blood samples of patients with elevated levels of type I IFN inducible genes and returned to baseline levels within 8 to 12 weeks following withdrawal of anifrolumab at the end of the 52-week treatment period. However, the clinical relevance of the type I IFN gene signature neutralization is unclear. In SLE patients with positive anti-dsDNA antibodies at baseline (Trials 2 and 3), treatment with anifrolumab 300 mg led to numerical reductions in anti-dsDNA antibodies over time through Week 52. In patients with low complement levels (C3 and C4), increases in complement levels were observed in patients receiving anifrolumab through Week 52. •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): Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting multiple systems in the body. SLE may manifest as a rash on the skin, and can progress to life-threatening autoimmune reactions in the kidney or nervous system. Type 1 interferon pathway activation has been identified as a mediator of pathogenesis in SLE, and the level of type 1 interferon expression is correlated with severity of SLE. Activation of the type 1 interferon receptor (INFAR1) by interferons alpha, beta, epsilon, kappa, and omega lead to stimulation of gene transcription. Activation of INFAR1 and INFAR2 lead to phosphorylation of STAT1 and STAT2, which are translocated with interferon regulatory factor 9 (IRF9) to the cell nucleus to activate the interferon-stimulated response element (ISRE). Activation of ISRE leads to the expression of many proinflammatory and immunomodulatory proteins, as well as the activation of a positive feedback loop that produces more type 1 interferons. Interferon alpha stimulates monocytes to mature into myeloid dendritic cells that express self antigens. CD4+ and CD8+ T-cells, as well as B cells, that are autoreactive will respond to the self antigens and induce inflammmation and apoptosis in cells. This self-reactive immune response damages otherwise healthy tissue throughout the body. Anifrolumab is an immunoglobulin gamma 1 kappa (IgG1κ) monoclonal antibody that selectively binds to subunit 1 of INFAR1. This binding inhibits type I IFN signaling, thereby blocking the biological activity of type I IFNs. Anifrolumab also induces the internalization of IFNAR1, thereby reducing the levels of cell surface IFNAR1 available for receptor assembly. Blockade of receptor-mediated type I IFN signaling inhibits IFN-responsive gene expression as well as downstream inflammatory and immunological processes. Inhibition of type I IFN blocks plasma cell differentiation and normalizes peripheral T-cell subsets. The Fc region of anifrolumab carries the triple mutaion L234F/L235E/P331S to prevent binding of the Fc region of the antibody to cell surface Fc receptors. In a phase IIb clinical trial, the primary endpoint was reached by 34.3% of patients in the 300 mg treatment group, 28.8% of patients in the 1000 mg treatment group, and 17.6% of patients in the placebo group. Patients with higher interferon-stimulated gene transcription at baseline showed a greater response to treatment. •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 PK of anifrolumab was studied in adult patients with SLE following intravenous doses ranging from 100 to 1000 mg once every 4 weeks, and healthy volunteers following a single intravenous dose at 300 mg. Anifrolumab exhibits non-linear PK in the dose range of 100 mg to 1000 mg with more than dose-proportional increases in the exposure as measured by AUC. Following the 300 mg every 4 weeks intravenous administrations of anifrolumab, a steady state was reached by Day 85. The accumulation ratio was approximately 1.36 for C max and 2.49 for C trough. A 300 mg intravenous dose reaches a mean C max of 82.4 µg/mL, with a T max of 0.03 days, and an AUC of 907 day*µg/mL. A 300 mg subcutaneous dose reaches a mean C max of 36.2 µg/mL, with a T max of 4.1 days, and an AUC of 785 day*µg/mL. A 600 mg subcutaneous dose reaches a mean C max of 63.9 µg/mL, with a T max of 7.0 days, and an AUC of 1828 day*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): Based on population PK analysis, the estimated volume of distribution at steady state for a typical patient with SLE (69.1 kg) is 6.23 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): Monoclonal antibodies are mainly catabolized to smaller oligopeptides and individual amino acids. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Monoclonal IgG is predominantly eliminated by catabolism to individual amino acids that are either recycled in the body or metabolized for energy. •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 elimination half life anifrolumab in a phase 1 trial in patients with scleroderma was 0.84 days for a 0.1 mg/kg single dose, 1.24 days for a 0.3 mg/kg single dose, 2.96 days for a 1.0 mg/kg single dose, 4.07 days for a 3.0 mg/kg single dose, and 7.70 days for a 10.0 mg/kg single 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): Following the administration of anifrolumab at a dose of 300 mg via intravenous infusion every 4 weeks, the estimated systemic clearance (CL) for anifrolumab was 0.193 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): Data regarding overdose is not readily available. In a phase 1 clinical trial, patients given a single dose of 20.0 mg/kg experienced upper respiratory tract infections, headache, diarrhea, and nausea. 2 patients in the 3.0 mg/kg single dose group experienced osteomyelitis and skin ulcer. A single patient in the 1.0 mg/kg/week group developed chronic myelogenous leukemia. The frequency and severity of adverse effects does not appear to be closely related to dose. In the event of an overdose, treat patients with symptomatic and supportive measures. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Saphnelo •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): Anifrolumab is a monoclonal antibody that inhibits type 1 interferon receptors, indicated in the treatment of moderate to severe systemic lupus erythematosus. 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 Anthrax immune globulin human interact?

•Drug A: Abatacept •Drug B: Anthrax immune globulin human •Severity: MODERATE •Description: The therapeutic efficacy of Anthrax immune globulin human 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. •Indication (Drug B): Anthrax immune globulin is indicated for the treatment of inhalational anthrax in adult and pediatric patients in combination with appropriate antibacterial drugs. •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): Polyclonal anthrax immune globulin is a passive immunizing agent that neutralizes anthrax toxin by binding to Protective Antigen (PA) to prevent PA-mediated cellular entry of anthrax edema factor and lethal factor. It is administered in combination with appropriate antibiotic therapy as the immunoglobulin itself is not known to have direct antibacterial activity against anthrax bacteria, which otherwise may continue to grow and produce anthrax toxins. •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 levels were reached immediately after infusion and then declined over the duration of study (84 days). Mean activity remained above the lower limit of quantitation (5 milliunits per mL) over the entire 84-day post-dose period for the three doses studied. Cmax was found to be 83.0 mU/mL while Tmax was found to be 0.116 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): 5714.8 mL •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): 24.3 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): 174.2 mL/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 to Anthrasil observed in >5% of healthy volunteers in clinical trials were headache, infusion site pain and swelling, nausea, and back pain. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Anthrasil •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): Anthrax immune globulin human is an immunizing agent used for the treatment of inhalational anthrax in adult and pediatric patients in combination with antibacterial agents.

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 Anthrax immune globulin human interact? Information: •Drug A: Abatacept •Drug B: Anthrax immune globulin human •Severity: MODERATE •Description: The therapeutic efficacy of Anthrax immune globulin human 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. •Indication (Drug B): Anthrax immune globulin is indicated for the treatment of inhalational anthrax in adult and pediatric patients in combination with appropriate antibacterial drugs. •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): Polyclonal anthrax immune globulin is a passive immunizing agent that neutralizes anthrax toxin by binding to Protective Antigen (PA) to prevent PA-mediated cellular entry of anthrax edema factor and lethal factor. It is administered in combination with appropriate antibiotic therapy as the immunoglobulin itself is not known to have direct antibacterial activity against anthrax bacteria, which otherwise may continue to grow and produce anthrax toxins. •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 levels were reached immediately after infusion and then declined over the duration of study (84 days). Mean activity remained above the lower limit of quantitation (5 milliunits per mL) over the entire 84-day post-dose period for the three doses studied. Cmax was found to be 83.0 mU/mL while Tmax was found to be 0.116 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): 5714.8 mL •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): 24.3 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): 174.2 mL/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 to Anthrasil observed in >5% of healthy volunteers in clinical trials were headache, infusion site pain and swelling, nausea, and back pain. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Anthrasil •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): Anthrax immune globulin human is an immunizing agent used for the treatment of inhalational anthrax in adult and pediatric patients in combination with antibacterial agents. 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 Anthrax vaccine interact?

•Drug A: Abatacept •Drug B: Anthrax vaccine •Severity: MINOR •Description: The therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Abatacept. •Extended Description: Immunosuppressive therapies, including chemotherapy, corticosteroids (used in high-doses longer than 2 weeks), and radiation therapy may reduce the response of the anthrax vaccine BioThrax. •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

Immunosuppressive therapies, including chemotherapy, corticosteroids (used in high-doses longer than 2 weeks), and radiation therapy may reduce the response of the anthrax vaccine BioThrax. The severity of the interaction is minor.

Question: Does Abatacept and Anthrax vaccine interact? Information: •Drug A: Abatacept •Drug B: Anthrax vaccine •Severity: MINOR •Description: The therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Abatacept. •Extended Description: Immunosuppressive therapies, including chemotherapy, corticosteroids (used in high-doses longer than 2 weeks), and radiation therapy may reduce the response of the anthrax vaccine BioThrax. •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: Immunosuppressive therapies, including chemotherapy, corticosteroids (used in high-doses longer than 2 weeks), and radiation therapy may reduce the response of the anthrax vaccine BioThrax. The severity of the interaction is minor.

Does Abatacept and Antilymphocyte immunoglobulin (horse) interact?

•Drug A: Abatacept •Drug B: Antilymphocyte immunoglobulin (horse) •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Antilymphocyte immunoglobulin (horse). •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 prevention of renal transplant rejection and for the treatment of aplastic anemia. •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): During infusion of 10 to 15 mg/kg/day, the mean peak value (n = 27 renal transplant patients) was found to be 727 ± 310 μg/mL. •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 half-life of equine immunoglobulin after ATGAM infusion was found to be 5.7 ± 3.0 days in one group of recipients. The range for half-life was 1.5 to 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): 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 most commonly reported adverse reactions (occurring in greater than 10% of patients) are pyrexia, chills, rash, thrombocytopenia, leukopenia and arthralgia. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Atgam •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): Antilymphocyte immunoglobulin (horse) is a primarily IgG immune globulin used to manage allograft rejection in renal transplant 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 Antilymphocyte immunoglobulin (horse) interact? Information: •Drug A: Abatacept •Drug B: Antilymphocyte immunoglobulin (horse) •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Antilymphocyte immunoglobulin (horse). •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 prevention of renal transplant rejection and for the treatment of aplastic anemia. •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): During infusion of 10 to 15 mg/kg/day, the mean peak value (n = 27 renal transplant patients) was found to be 727 ± 310 μg/mL. •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 half-life of equine immunoglobulin after ATGAM infusion was found to be 5.7 ± 3.0 days in one group of recipients. The range for half-life was 1.5 to 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): 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 most commonly reported adverse reactions (occurring in greater than 10% of patients) are pyrexia, chills, rash, thrombocytopenia, leukopenia and arthralgia. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Atgam •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): Antilymphocyte immunoglobulin (horse) is a primarily IgG immune globulin used to manage allograft rejection in renal transplant 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 Antipyrine interact?

•Drug A: Abatacept •Drug B: Antipyrine •Severity: MODERATE •Description: The metabolism of Antipyrine 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): Antipyrine is an analgesic often used to test effects of other drugs on liver enzymes. In combination with benzocaine in otic solutions, antipyrine is indicated for the symptomatic relief of acute otitis media arising from various etiologies. •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): Antipyrine is an analgesic and antipyretic that has been given by mouth and as ear drops. Antipyrine is often used in testing the effects of other drugs or diseases on drug-metabolizing enzymes in the liver. (From Martindale, The Extra Pharmacopoeia, 30th ed, p29) •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): Antipyrine is thought to act primarily in the CNS, increasing the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1, COX-2, and COX-3 enzymes involved in prostaglandin (PG) 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): 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): Analgesine Antipyrine Fenazon Fenazona Phenazon Phenazone •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): Antipyrine is an antipyretic agent used for the symptomatic treatment of acute otitis media, most commonly in combination with benzocaine.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Antipyrine interact? Information: •Drug A: Abatacept •Drug B: Antipyrine •Severity: MODERATE •Description: The metabolism of Antipyrine 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): Antipyrine is an analgesic often used to test effects of other drugs on liver enzymes. In combination with benzocaine in otic solutions, antipyrine is indicated for the symptomatic relief of acute otitis media arising from various etiologies. •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): Antipyrine is an analgesic and antipyretic that has been given by mouth and as ear drops. Antipyrine is often used in testing the effects of other drugs or diseases on drug-metabolizing enzymes in the liver. (From Martindale, The Extra Pharmacopoeia, 30th ed, p29) •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): Antipyrine is thought to act primarily in the CNS, increasing the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1, COX-2, and COX-3 enzymes involved in prostaglandin (PG) 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): 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): Analgesine Antipyrine Fenazon Fenazona Phenazon Phenazone •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): Antipyrine is an antipyretic agent used for the symptomatic treatment of acute otitis media, most commonly in combination with benzocaine. 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 Antithymocyte immunoglobulin (rabbit) interact?

•Drug A: Abatacept •Drug B: Antithymocyte immunoglobulin (rabbit) •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) 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 prevention of renal transplant rejection •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): Antithymocyte Globulin (ATG) is a concentrated anti-human T-lymphocyte immunoglobulin preparation derived from rabbits after immunization with a T-lympoblast cell line. ATG is an immunosuppressive product for the prevention and treatment of acute rejection following organ transplantation. ATG reduces the host immune response against tissue transplants or organ allografts. •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 to multiple, T-cell specific antigens leading to T-lymphocyte cell death via complement mediated cytotoxicity or apoptosis. •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): T-cell depletion usually observed within 1 day after initiating therapy. Average 21.5 and 87 mcg/mL 4–8 hours post-infusion after first and last IV doses, respectively, when given for 7–11 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): 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): Most likely removed by opsonization via the reticuloendothelial system when bound to T lymphocytes, 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): 2-3 days, may increase after multiple doses 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): 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): Not known whether ATG (rabbit) distributes into human milk; however, other immunoglobulins are distributed into human milk. •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): Antithymocyte immunoglobulin (rabbit) is a purified form of rabbit anti-thymocyte antibodies used for immunosuppression in patients receiving kidney transplants.

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 Antithymocyte immunoglobulin (rabbit) interact? Information: •Drug A: Abatacept •Drug B: Antithymocyte immunoglobulin (rabbit) •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) 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 prevention of renal transplant rejection •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): Antithymocyte Globulin (ATG) is a concentrated anti-human T-lymphocyte immunoglobulin preparation derived from rabbits after immunization with a T-lympoblast cell line. ATG is an immunosuppressive product for the prevention and treatment of acute rejection following organ transplantation. ATG reduces the host immune response against tissue transplants or organ allografts. •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 to multiple, T-cell specific antigens leading to T-lymphocyte cell death via complement mediated cytotoxicity or apoptosis. •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): T-cell depletion usually observed within 1 day after initiating therapy. Average 21.5 and 87 mcg/mL 4–8 hours post-infusion after first and last IV doses, respectively, when given for 7–11 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): 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): Most likely removed by opsonization via the reticuloendothelial system when bound to T lymphocytes, 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): 2-3 days, may increase after multiple doses 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): 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): Not known whether ATG (rabbit) distributes into human milk; however, other immunoglobulins are distributed into human milk. •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): Antithymocyte immunoglobulin (rabbit) is a purified form of rabbit anti-thymocyte antibodies used for immunosuppression in patients receiving kidney transplants. 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 Apalutamide interact?

•Drug A: Abatacept •Drug B: Apalutamide •Severity: MODERATE •Description: The metabolism of Apalutamide 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): Apalutamide is indicated for the treatment of patients with metastatic castration-sensitive prostate cancer and non-metastatic castration-resistant prostate 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): In androgen receptors (AR)-overexpressing LNCaP cells, apaludatamide was reported to have a 7 to 10-fold greater affinity to the AR than bicalutamide. Additionally, apalutamide still possesses total antagonistic activity in AR-overexpressing cell lines with bicalutamide-resistance mutations such as T878A and W741C. In castrate mice with LNCaP/AR(cs) tumors, apalutamide produced tumor regression (defined by >50% regression in tumor volume) in 8 mice compared to only 1 for bicalutamide. The apalutamide-treated tumors also have a 60% decrease in proliferative index and a 10-fold increase in apoptotic rate compared with vehicle. In an open-label, uncontrolled, multicenter, single-arm dedicated QT study in 45 patients with CRPC, an exposure-QT analysis suggested a concentration-dependent increase in QTcF for apalutamide and its active metabolite. Apalutamide demonstrated antitumor activity in the mouse xenograft models of prostate cancer, where it decreased tumor cell proliferation and reduced tumor volume. •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): Persistent androgen receptor (AR) signaling is a common feature of castration-resistant prostate cancer (CRPC), attributed to AR gene amplification, AR gene mutation, increased AR expression, or increased androgen biosynthesis in prostate tumors. Apalutamide is an antagonist of AR that binds directly to the ligand-binding domain of the AR with the IC50 of 16 nM. Upon binding, apalutamide disrupts AR signalling, inhibits DNA binding, and impedes AR-mediated gene transcription. Apalutamide impairs the translocation of AR from the cytoplasm to the nucleus thus reducing the concentrations of AR available to interact with the androgen response elements (AREs). Upon treatment with apalutamide, AR was not recruited to the DNA promoter regions. Its main metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third of the activity of apalutamide in an in vitro transcriptional reporter assay. •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 absolute oral bioavailability was approximately 100%. The median time to achieve peak plasma concentration (t max ) was 2 hours (range: 1 to 5 hours). The major active metabolite N-desmethyl apalutamide C max was 5.9 mcg/mL (1.0) and AUC was 124 mcg·h/mL (23) at steady-state after the recommended dosage. Administration of apalutamide to healthy subjects under fasting conditions and with a high-fat meal (approximately 500 to 600 fat calories, 250 carbohydrate calories, and 150 protein calories) resulted in no clinically relevant changes in C max and AUC. The median time to reach t max was delayed approximately 2 hours with food. Following administration of the recommended dosage, apalutamide steady-state was achieved after 4 weeks and the mean accumulation ratio was approximately 5-fold. Apalutamide C max was 6.0 mcg/mL (1.7) and AUC was 100 mcg·h/mL (32) at steady-state. Daily fluctuations in apalutamide plasma concentrations were low, with the mean peak-to-trough ratio of 1.63. Oral administration of four 60 mg apalutamide tablets dispersed in applesauce resulted in no clinically relevant changes in Cmax and AUC compared to the administration of four intact 60 mg tablets under fasting conditions. •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 apparent volume of distribution at steady state of apalutamide was approximately 276 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Apalutamide was 96% and N-desmethyl apalutamide was 95% bound to plasma proteins with no concentration dependency. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism is the main route of elimination of apalutamide. Apalutamide is primarily metabolized by CYP2C8 and CYP3A4 to form active metabolite, N-desmethyl apalutamide. The contribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 37%, respectively at steady-state. The auto-induction of CYP3A4-mediated metabolism by apalutamide may explain the increase in CYP3A4 enzymatic activity at steady-state. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Apalutamide and its main active metabolite are subject to both renal and focal elimination. Up to 70 days following a single oral administration of radiolabeled apalutamide, 65% of the dose was recovered in urine (1.2% of dose as unchanged apalutamide and 2.7% as N-desmethyl apalutamide) and 24% was recovered in feces (1.5% of dose as unchanged apalutamide and 2% as N-desmethyl apalutamide). •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 effective half-life for apalutamide in patients with NM-CRPC was approximately 3 days 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 CL/F of apalutamide was 1.3 L/h after single dosing and increased to 2.0 L/h at steady-state after once-daily dosing likely due to CYP3A4 auto-induction. The auto-induction effect likely reached its maximum at the recommended dosage because exposure to apalutamide across the dose range of 30 to 480 mg is dose-proportional. •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 no known specific antidote for apalutamide overdose. In the event of an overdose, stop apalutamide, undertake general supportive measures until clinical toxicity has been diminished or resolved. The safety and efficacy of apalutamide have not been established in females. Based on findings from animals and its mechanism of action, apalutamide can cause fetal harm and loss of pregnancy when administered to a pregnant female. There are no available data on apalutamide use in pregnant women to inform a drug-associated risk. In an animal reproduction study, oral administration of apalutamide to pregnant rats during and after organogenesis resulted in fetal abnormalities and embryo-fetal lethality at maternal exposures ≥ 2 times the human clinical exposure (AUC) at the recommended dose. In a 2-year carcinogenicity study in male rats, apalutamide was administered by oral gavage at doses of 5, 15 and 50 mg/kg/day. Apalutamide increased the incidence of Leydig interstitial cell adenoma in the testes at doses ≥ 5 mg/kg/day (0.2 times the human exposure based on AUC). The findings in the testes are considered to be related to the pharmacological activity of apalutamide. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Oral administration of apalutamide to male rasH2 transgenic mice for 6 months did not result in increased incidence of neoplasms at doses up to 30 mg/kg/day. Apalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either in vitro chromosome aberration assay or the in vivo rat bone marrow micronucleus assay or the in vivo rat Comet assay. In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), atrophy of the prostate gland and seminal vesicles, aspermia/hypospermia, tubular degeneration and/or hyperplasia or hypertrophy of the interstitial cells in the reproductive system were observed at ≥ 25 mg/kg/day in rats (1.4 times the human exposure based on AUC) and ≥ 2.5 mg/kg/day in dogs (0.9 times the human exposure based on AUC). In a fertility study in male rats, a decrease in sperm concentration and motility, increased abnormal sperm morphology, lower copulation and fertility rates (upon pairing with untreated females) along with reduced weights of the secondary sex glands and epididymis were observed following 4 weeks of dosing at ≥ 25 mg/kg/day (0.8 times the human exposure based on AUC). A reduced number of live fetuses due to increased pre- and/or post-implantation loss was observed following 4 weeks of 150 mg/kg/day administration (5.7 times the human exposure based on AUC). Effects on male rats were reversible after 8 weeks from the last apalutamide administration. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Erleada •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): Apalutamide is an androgen receptor inhibitor used to treat non-metastatic castration-resistant and metastatic castration-sensitive prostate 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 CYP2C8 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Apalutamide interact? Information: •Drug A: Abatacept •Drug B: Apalutamide •Severity: MODERATE •Description: The metabolism of Apalutamide 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): Apalutamide is indicated for the treatment of patients with metastatic castration-sensitive prostate cancer and non-metastatic castration-resistant prostate 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): In androgen receptors (AR)-overexpressing LNCaP cells, apaludatamide was reported to have a 7 to 10-fold greater affinity to the AR than bicalutamide. Additionally, apalutamide still possesses total antagonistic activity in AR-overexpressing cell lines with bicalutamide-resistance mutations such as T878A and W741C. In castrate mice with LNCaP/AR(cs) tumors, apalutamide produced tumor regression (defined by >50% regression in tumor volume) in 8 mice compared to only 1 for bicalutamide. The apalutamide-treated tumors also have a 60% decrease in proliferative index and a 10-fold increase in apoptotic rate compared with vehicle. In an open-label, uncontrolled, multicenter, single-arm dedicated QT study in 45 patients with CRPC, an exposure-QT analysis suggested a concentration-dependent increase in QTcF for apalutamide and its active metabolite. Apalutamide demonstrated antitumor activity in the mouse xenograft models of prostate cancer, where it decreased tumor cell proliferation and reduced tumor volume. •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): Persistent androgen receptor (AR) signaling is a common feature of castration-resistant prostate cancer (CRPC), attributed to AR gene amplification, AR gene mutation, increased AR expression, or increased androgen biosynthesis in prostate tumors. Apalutamide is an antagonist of AR that binds directly to the ligand-binding domain of the AR with the IC50 of 16 nM. Upon binding, apalutamide disrupts AR signalling, inhibits DNA binding, and impedes AR-mediated gene transcription. Apalutamide impairs the translocation of AR from the cytoplasm to the nucleus thus reducing the concentrations of AR available to interact with the androgen response elements (AREs). Upon treatment with apalutamide, AR was not recruited to the DNA promoter regions. Its main metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third of the activity of apalutamide in an in vitro transcriptional reporter assay. •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 absolute oral bioavailability was approximately 100%. The median time to achieve peak plasma concentration (t max ) was 2 hours (range: 1 to 5 hours). The major active metabolite N-desmethyl apalutamide C max was 5.9 mcg/mL (1.0) and AUC was 124 mcg·h/mL (23) at steady-state after the recommended dosage. Administration of apalutamide to healthy subjects under fasting conditions and with a high-fat meal (approximately 500 to 600 fat calories, 250 carbohydrate calories, and 150 protein calories) resulted in no clinically relevant changes in C max and AUC. The median time to reach t max was delayed approximately 2 hours with food. Following administration of the recommended dosage, apalutamide steady-state was achieved after 4 weeks and the mean accumulation ratio was approximately 5-fold. Apalutamide C max was 6.0 mcg/mL (1.7) and AUC was 100 mcg·h/mL (32) at steady-state. Daily fluctuations in apalutamide plasma concentrations were low, with the mean peak-to-trough ratio of 1.63. Oral administration of four 60 mg apalutamide tablets dispersed in applesauce resulted in no clinically relevant changes in Cmax and AUC compared to the administration of four intact 60 mg tablets under fasting conditions. •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 apparent volume of distribution at steady state of apalutamide was approximately 276 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Apalutamide was 96% and N-desmethyl apalutamide was 95% bound to plasma proteins with no concentration dependency. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism is the main route of elimination of apalutamide. Apalutamide is primarily metabolized by CYP2C8 and CYP3A4 to form active metabolite, N-desmethyl apalutamide. The contribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 37%, respectively at steady-state. The auto-induction of CYP3A4-mediated metabolism by apalutamide may explain the increase in CYP3A4 enzymatic activity at steady-state. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Apalutamide and its main active metabolite are subject to both renal and focal elimination. Up to 70 days following a single oral administration of radiolabeled apalutamide, 65% of the dose was recovered in urine (1.2% of dose as unchanged apalutamide and 2.7% as N-desmethyl apalutamide) and 24% was recovered in feces (1.5% of dose as unchanged apalutamide and 2% as N-desmethyl apalutamide). •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 effective half-life for apalutamide in patients with NM-CRPC was approximately 3 days 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 CL/F of apalutamide was 1.3 L/h after single dosing and increased to 2.0 L/h at steady-state after once-daily dosing likely due to CYP3A4 auto-induction. The auto-induction effect likely reached its maximum at the recommended dosage because exposure to apalutamide across the dose range of 30 to 480 mg is dose-proportional. •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 no known specific antidote for apalutamide overdose. In the event of an overdose, stop apalutamide, undertake general supportive measures until clinical toxicity has been diminished or resolved. The safety and efficacy of apalutamide have not been established in females. Based on findings from animals and its mechanism of action, apalutamide can cause fetal harm and loss of pregnancy when administered to a pregnant female. There are no available data on apalutamide use in pregnant women to inform a drug-associated risk. In an animal reproduction study, oral administration of apalutamide to pregnant rats during and after organogenesis resulted in fetal abnormalities and embryo-fetal lethality at maternal exposures ≥ 2 times the human clinical exposure (AUC) at the recommended dose. In a 2-year carcinogenicity study in male rats, apalutamide was administered by oral gavage at doses of 5, 15 and 50 mg/kg/day. Apalutamide increased the incidence of Leydig interstitial cell adenoma in the testes at doses ≥ 5 mg/kg/day (0.2 times the human exposure based on AUC). The findings in the testes are considered to be related to the pharmacological activity of apalutamide. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Oral administration of apalutamide to male rasH2 transgenic mice for 6 months did not result in increased incidence of neoplasms at doses up to 30 mg/kg/day. Apalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either in vitro chromosome aberration assay or the in vivo rat bone marrow micronucleus assay or the in vivo rat Comet assay. In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), atrophy of the prostate gland and seminal vesicles, aspermia/hypospermia, tubular degeneration and/or hyperplasia or hypertrophy of the interstitial cells in the reproductive system were observed at ≥ 25 mg/kg/day in rats (1.4 times the human exposure based on AUC) and ≥ 2.5 mg/kg/day in dogs (0.9 times the human exposure based on AUC). In a fertility study in male rats, a decrease in sperm concentration and motility, increased abnormal sperm morphology, lower copulation and fertility rates (upon pairing with untreated females) along with reduced weights of the secondary sex glands and epididymis were observed following 4 weeks of dosing at ≥ 25 mg/kg/day (0.8 times the human exposure based on AUC). A reduced number of live fetuses due to increased pre- and/or post-implantation loss was observed following 4 weeks of 150 mg/kg/day administration (5.7 times the human exposure based on AUC). Effects on male rats were reversible after 8 weeks from the last apalutamide administration. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Erleada •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): Apalutamide is an androgen receptor inhibitor used to treat non-metastatic castration-resistant and metastatic castration-sensitive prostate 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 CYP2C8 substrates. The severity of the interaction is moderate.

Does Abatacept and Apixaban interact?

•Drug A: Abatacept •Drug B: Apixaban •Severity: MODERATE •Description: The metabolism of Apixaban 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): Apixaban is indicated for reducing the risk of stroke and systemic embolism in patients who have nonvalvular atrial fibrillation, prophylaxis of deep vein thrombosis(DVT) leading to pulmonary embolism(PE) in patients after a hip or knee replacement surgery, and treatment of DVT and PE to reduce the risk of recurrence. •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): Apixaban selectively inhibits factor Xa in its free and bound forms, independant of antithrombin III. Apixaban also inhibits prothrominase. These effects prevent the formation of a thrombus. •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): Apixaban selectively inhibits factor Xa in its free and bound forms, independant of antithrombin III. Apixaban also inhibits prothrominase. These effects prevent the formation of a thrombus. •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): Apixaban is approximately 50% bioavailable though other studies report 43-46% oral bioavailability. •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): Approximately 21L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 92-94%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): 50% of the orally administered dose is excreted as the unchanged parent compound, however 25% of the dose is excreted as O-demethyl apixaban sulfate. All apixaban metabolites account for approximately 32% of the excreted dose though the structure of all metabolites are not well defined. Apixaban is mainly metabolized by cytochrome p450(CYP)3A4 and to a lesser extent by CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2J2. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 56% of an orally administered dose is recovered in the feces and 24.5-28.8% of the dose is recovered in the urine. 83-88% of the dose recovered in the urine was the unchanged 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): 12.7±8.55h. •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): 3.3L/h though other studies report 4876mL/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): Animal studies have shown an increased risk of maternal bleeding during pregnancy but no increase in fetal malformations or fetal or maternal deaths. It is unknown if this animal data also translates to humans so apixaban should only be used in pregnancy if the benefits outweigh the risks. It is not know whether apixaban is safe and effective in labor and during birth, though animal studies have shown an increased rate of maternal bleeding. Animal studies in rats show apixaban excreted in milk, though it is not know if this also applies to humans. Nursing mothers should either stop breastfeeding or stop taking apixaban depending on the risk and benefit of each option. Studies to determine safety and effectiveness in pediatric patients have yet to be performed. Studies that involved geriatric patients (at least 75 years old) saw no difference in safety or effectiveness compared to younger patients, though geriatric patients at an especially advanced age may be more susceptible to adverse effects. Dosage adjustments for patients with end stage renal disease(ESRD) are based on estimates of pharmacokinetic principles and not clinical study. Patients with ESRD may experience pharmacodynamics similar to those seen in well controlled studies but it may not lead to the same clinical effects. Dosage adjustments are not necessary in mild hepatic impairment. In moderate hepatic impairment patients may already experience abnormalities in coagulation and so no dose recommendations are possible. Apixaban is not recommended for patients with severe hepatic impairment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Eliquis •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): Apixaban is an anticoagulant used for the prophylaxis of stroke and systemic embolism in nonvalvular atrial fibrillation, and deep vein thrombosis(DVT) leading to pulmonary embolism(PE), including in patients after a hip or knee replacement 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 CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Apixaban interact? Information: •Drug A: Abatacept •Drug B: Apixaban •Severity: MODERATE •Description: The metabolism of Apixaban 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): Apixaban is indicated for reducing the risk of stroke and systemic embolism in patients who have nonvalvular atrial fibrillation, prophylaxis of deep vein thrombosis(DVT) leading to pulmonary embolism(PE) in patients after a hip or knee replacement surgery, and treatment of DVT and PE to reduce the risk of recurrence. •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): Apixaban selectively inhibits factor Xa in its free and bound forms, independant of antithrombin III. Apixaban also inhibits prothrominase. These effects prevent the formation of a thrombus. •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): Apixaban selectively inhibits factor Xa in its free and bound forms, independant of antithrombin III. Apixaban also inhibits prothrominase. These effects prevent the formation of a thrombus. •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): Apixaban is approximately 50% bioavailable though other studies report 43-46% oral bioavailability. •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): Approximately 21L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 92-94%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): 50% of the orally administered dose is excreted as the unchanged parent compound, however 25% of the dose is excreted as O-demethyl apixaban sulfate. All apixaban metabolites account for approximately 32% of the excreted dose though the structure of all metabolites are not well defined. Apixaban is mainly metabolized by cytochrome p450(CYP)3A4 and to a lesser extent by CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2J2. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 56% of an orally administered dose is recovered in the feces and 24.5-28.8% of the dose is recovered in the urine. 83-88% of the dose recovered in the urine was the unchanged 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): 12.7±8.55h. •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): 3.3L/h though other studies report 4876mL/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): Animal studies have shown an increased risk of maternal bleeding during pregnancy but no increase in fetal malformations or fetal or maternal deaths. It is unknown if this animal data also translates to humans so apixaban should only be used in pregnancy if the benefits outweigh the risks. It is not know whether apixaban is safe and effective in labor and during birth, though animal studies have shown an increased rate of maternal bleeding. Animal studies in rats show apixaban excreted in milk, though it is not know if this also applies to humans. Nursing mothers should either stop breastfeeding or stop taking apixaban depending on the risk and benefit of each option. Studies to determine safety and effectiveness in pediatric patients have yet to be performed. Studies that involved geriatric patients (at least 75 years old) saw no difference in safety or effectiveness compared to younger patients, though geriatric patients at an especially advanced age may be more susceptible to adverse effects. Dosage adjustments for patients with end stage renal disease(ESRD) are based on estimates of pharmacokinetic principles and not clinical study. Patients with ESRD may experience pharmacodynamics similar to those seen in well controlled studies but it may not lead to the same clinical effects. Dosage adjustments are not necessary in mild hepatic impairment. In moderate hepatic impairment patients may already experience abnormalities in coagulation and so no dose recommendations are possible. Apixaban is not recommended for patients with severe hepatic impairment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Eliquis •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): Apixaban is an anticoagulant used for the prophylaxis of stroke and systemic embolism in nonvalvular atrial fibrillation, and deep vein thrombosis(DVT) leading to pulmonary embolism(PE), including in patients after a hip or knee replacement 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 CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Apomorphine interact?

•Drug A: Abatacept •Drug B: Apomorphine •Severity: MODERATE •Description: The metabolism of Apomorphine 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): Apomorphine is indicated to treat acute, intermittent treatment of hypomobility, off episodes associated with advanced 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): Apomorphine is a dopaminergic agonist that may stimulate regions of the brain involved in motor control. It has a short duration of action and a wide therapeutic index as large overdoses are necessary for significant toxicity. Patients should be counselled regarding the risk of nausea, vomiting, daytime somnolence, hypotension, oral mucosal irritation, falls, hallucinations, psychotic-like behaviour, impulsive behaviour, withdrawal hyperpyrexia, and prolongation of the QT interval. Given the incidence of nausea and vomiting in patients taking apomorphine, treatment with trimethobenzamide may be recommended prior to or during therapy. Antiemetic pretreatment may be started three days prior to beginning therapy with apomorphine - it should only be continued as long as is necessary and generally for no longer than two months. •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): Apomorphine is a non-ergoline dopamine agonist with high binding affinity to dopamine D2, D3, and D5 receptors. Stimulation of D2 receptors in the caudate-putamen, a region of the brain responsible for locomotor control, may be responsible for apomorphine's action. However, the means by which the cellular effects of apomorphine treat hypomobility of Parkinson's remain 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): Apomorphine has a plasma T max of 10-20 minutes and a cerebrospinal fluid T max. The C max and AUC of apomorphine vary significantly between patients, with 5- to 10-fold differences being reported. •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 subcutaneous apomorphine is 123-404L with an average of 218L. The apparent volume of distribution of sublingual apomorphine is 3630L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Apomorphine is expected to be 99.9% bound to human serum albumin, as no unbound apomorphine is detected. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Apomorphine is N-demethylated by CYP2B6, 2C8, 3A4, and 3A5. It can be glucuronidated by various UGTs, or sulfated by SULTs 1A1, 1A2, 1A3, 1E1, and 1B1. Approximately 60% of sublingual apomorphine is eliminated as a sulfate conjugate, though the structure of these sulfate conjugates are not readily available. The remainder of an apomorphine dose is eliminated as apomorphine glucuronide and norapomorphine glucuronide. Only 0.3% of subcutaneous apomorphine is recovered as the unchanged parent drug. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Data regarding apomorphine's route of elimination is not readily available. A study in rats has shown apomorphine is predominantly 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 elimination half life of a 15mg sublingual dose of apomorphine is 1.7h, while the terminal elimination half life of an intravenous dose is 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): The clearance of a 15mg sublingual dose of apomorphine is 1440L/h, while the clearance of an intravenous dose is 223L/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): Patients experiencing an overdose of apomorphine may present with nausea, hypotension, and loss of consciousness. Treat patients with symptomatic and supportive measures. The intraperitoneal LD 50 in mice is 145µg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Apokyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Apomorfina Apomorphin Apomorphine •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): Apomorphine is a morphine derivative D2 dopamine agonist used to treat hypomobile "off" episodes of advanced 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 CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Apomorphine interact? Information: •Drug A: Abatacept •Drug B: Apomorphine •Severity: MODERATE •Description: The metabolism of Apomorphine 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): Apomorphine is indicated to treat acute, intermittent treatment of hypomobility, off episodes associated with advanced 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): Apomorphine is a dopaminergic agonist that may stimulate regions of the brain involved in motor control. It has a short duration of action and a wide therapeutic index as large overdoses are necessary for significant toxicity. Patients should be counselled regarding the risk of nausea, vomiting, daytime somnolence, hypotension, oral mucosal irritation, falls, hallucinations, psychotic-like behaviour, impulsive behaviour, withdrawal hyperpyrexia, and prolongation of the QT interval. Given the incidence of nausea and vomiting in patients taking apomorphine, treatment with trimethobenzamide may be recommended prior to or during therapy. Antiemetic pretreatment may be started three days prior to beginning therapy with apomorphine - it should only be continued as long as is necessary and generally for no longer than two months. •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): Apomorphine is a non-ergoline dopamine agonist with high binding affinity to dopamine D2, D3, and D5 receptors. Stimulation of D2 receptors in the caudate-putamen, a region of the brain responsible for locomotor control, may be responsible for apomorphine's action. However, the means by which the cellular effects of apomorphine treat hypomobility of Parkinson's remain 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): Apomorphine has a plasma T max of 10-20 minutes and a cerebrospinal fluid T max. The C max and AUC of apomorphine vary significantly between patients, with 5- to 10-fold differences being reported. •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 subcutaneous apomorphine is 123-404L with an average of 218L. The apparent volume of distribution of sublingual apomorphine is 3630L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Apomorphine is expected to be 99.9% bound to human serum albumin, as no unbound apomorphine is detected. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Apomorphine is N-demethylated by CYP2B6, 2C8, 3A4, and 3A5. It can be glucuronidated by various UGTs, or sulfated by SULTs 1A1, 1A2, 1A3, 1E1, and 1B1. Approximately 60% of sublingual apomorphine is eliminated as a sulfate conjugate, though the structure of these sulfate conjugates are not readily available. The remainder of an apomorphine dose is eliminated as apomorphine glucuronide and norapomorphine glucuronide. Only 0.3% of subcutaneous apomorphine is recovered as the unchanged parent drug. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Data regarding apomorphine's route of elimination is not readily available. A study in rats has shown apomorphine is predominantly 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 elimination half life of a 15mg sublingual dose of apomorphine is 1.7h, while the terminal elimination half life of an intravenous dose is 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): The clearance of a 15mg sublingual dose of apomorphine is 1440L/h, while the clearance of an intravenous dose is 223L/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): Patients experiencing an overdose of apomorphine may present with nausea, hypotension, and loss of consciousness. Treat patients with symptomatic and supportive measures. The intraperitoneal LD 50 in mice is 145µg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Apokyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Apomorfina Apomorphin Apomorphine •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): Apomorphine is a morphine derivative D2 dopamine agonist used to treat hypomobile "off" episodes of advanced 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 CYP2B6 substrates. The severity of the interaction is moderate.

Does Abatacept and Apremilast interact?

•Drug A: Abatacept •Drug B: Apremilast •Severity: MAJOR •Description: The therapeutic efficacy of Apremilast can be decreased when used in combination with Abatacept. •Extended Description: The concomitant administration of apremilast with biologics for rheumatoid arthritis treatment has not been formally evaluated. Several studies have demonstrated that biologic agents frequently used in the treatment of psoriasis or rheumatoid arthritis may impact the metabolism of hepatic cytochrome enzyme substrates (such as apremilast) by stimulating cytochrome enzyme activities. Apremilast is a CYP3A4 substrate, and induction of this enzyme may lead to decreased therapeutic efficacy resulting from increased metabolism. •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): Apremilast is indicated for the treatment of adults with active psoriatic arthritis and adults with oral ulcers associated with Behcet's Disease. In addition, apremilast is indicated for the treatment of plaque psoriasis, of any severity, in adult patients who are candidates for phototherapy or systemic 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): Apremilast reduces but does not completely inhibit various inflammatory cytokines such as IL-1α, IL-6, IL-8, IL-10 MCP-1, MIP-1β, MMP-3, and TNF-α, relieving the symptoms of psoriasis and Behcet's disease, which are caused by an increase in these inflammatory mediators. This drug has also been proven to be effective in relieving the pain associated with oral ulcers in Behcet's disease. Apremilast may cause unwanted weight loss and worsen depression, leading to suicidal thoughts or actions. It is advisable to monitor for symptoms of depression and seek medical attention if they occur, especially in patients with pre-existing depression. The need for apremilast should be carefully assessed along with the risk of worsening depression and suicide. If weight loss occurs, the degree of weight loss should be evaluated, and consideration should be made for the possible discontinuation of apremilast. •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 full mechanism of action of this drug is not fully established, however, it is known that apremilast is an inhibitor of phosphodiesterase 4 (PDE4), which mediates the activity of cyclic adenosine monophosphate (cAMP), a second messenger. The inhibition of PDE4 by apremilast leads to increased intracellular cAMP levels. An increase in cAMP results in the suppression of inflammation by decreasing the expression of TNF-α, IL-17, IL-23, and other inflammatory mediators. The above inflammatory mediators have been implicated in various psoriatic conditions as well as Behcet's disease, leading to their undesirable inflammatory symptoms such as mouth ulcers, skin lesions, and arthritis. Apremilast administration leads to a cascade which eventually decreases the levels of the above mediators, relieving inflammatory symptoms. •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): An oral dose of apremilast is well-absorbed and the absolute bioavailability is approximately 73%. Tmax is approximately 2.5 hours and Cmax has been reported to be approximately 584 ng/mL in one pharmacokinetic study. Food intake does not appear to affect apremilast 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): The average apparent volume of distribution (Vd) is about 87 L, suggesting that apremilast is distributed in the extravascular compartment. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of apremilast is about 68%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Apremilast is heavily metabolized by various pathways, which include oxidation, hydrolysis, in addition to conjugation. About 23 metabolites are produced from its metabolism. The CYP3A4 primarily mediates the oxidative metabolism of this drug, with smaller contributions from CYP1A2 and CYP2A6 enzymes. The main metabolite of apremilast, M12, is an inactive glucuronide conjugate form of the O-demethylated drug. Some other major metabolites, M14 and M16, are significantly less active in the inhibition of PDE4 and inflammatory mediators than their parent drug, apremilast. After an oral dose, unchanged apremilast (45%) and the inactive metabolite, O-desmethyl apremilast glucuronide (39%) are found in the plasma. Minor metabolites M7 and M17 are active, but are only present in about 2% or less of apremilast concentrations, and likely not significant contributors to the actions of apremilast. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Only 3% and 7% of an apremilast dose are detected in the urine and feces as unchanged drug, respectively, indicating extensive metabolism and high absorption. •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 this drug ranges from 6-9 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 patients, the plasma clearance of apremilast is about 10 L/hour. •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 mice was greater than 2000 mg/kg in mice. In rats, oral LD50 was 2000 mg/kg males and 300 mg/kg in females. Overdose information In healthy subjects receiving a maximum dose of 100 mg (given as 50 mg twice daily) for about 5 days, no significant toxicity was observed. In cases of an overdose, supportive and symptomatic treatment should be administered. Contact the local poison control center for the most recent overdose management for apremilast. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Otezla •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Aprémilast Apremilast Apremilastum •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): Apremilast is a non-steroidal medication used for the treatment of inflammatory conditions such as psoriasis and psoriatic arthritis.

The concomitant administration of apremilast with biologics for rheumatoid arthritis treatment has not been formally evaluated. Several studies have demonstrated that biologic agents frequently used in the treatment of psoriasis or rheumatoid arthritis may impact the metabolism of hepatic cytochrome enzyme substrates (such as apremilast) by stimulating cytochrome enzyme activities. Apremilast is a CYP3A4 substrate, and induction of this enzyme may lead to decreased therapeutic efficacy resulting from increased metabolism. The severity of the interaction is major.

Question: Does Abatacept and Apremilast interact? Information: •Drug A: Abatacept •Drug B: Apremilast •Severity: MAJOR •Description: The therapeutic efficacy of Apremilast can be decreased when used in combination with Abatacept. •Extended Description: The concomitant administration of apremilast with biologics for rheumatoid arthritis treatment has not been formally evaluated. Several studies have demonstrated that biologic agents frequently used in the treatment of psoriasis or rheumatoid arthritis may impact the metabolism of hepatic cytochrome enzyme substrates (such as apremilast) by stimulating cytochrome enzyme activities. Apremilast is a CYP3A4 substrate, and induction of this enzyme may lead to decreased therapeutic efficacy resulting from increased metabolism. •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): Apremilast is indicated for the treatment of adults with active psoriatic arthritis and adults with oral ulcers associated with Behcet's Disease. In addition, apremilast is indicated for the treatment of plaque psoriasis, of any severity, in adult patients who are candidates for phototherapy or systemic 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): Apremilast reduces but does not completely inhibit various inflammatory cytokines such as IL-1α, IL-6, IL-8, IL-10 MCP-1, MIP-1β, MMP-3, and TNF-α, relieving the symptoms of psoriasis and Behcet's disease, which are caused by an increase in these inflammatory mediators. This drug has also been proven to be effective in relieving the pain associated with oral ulcers in Behcet's disease. Apremilast may cause unwanted weight loss and worsen depression, leading to suicidal thoughts or actions. It is advisable to monitor for symptoms of depression and seek medical attention if they occur, especially in patients with pre-existing depression. The need for apremilast should be carefully assessed along with the risk of worsening depression and suicide. If weight loss occurs, the degree of weight loss should be evaluated, and consideration should be made for the possible discontinuation of apremilast. •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 full mechanism of action of this drug is not fully established, however, it is known that apremilast is an inhibitor of phosphodiesterase 4 (PDE4), which mediates the activity of cyclic adenosine monophosphate (cAMP), a second messenger. The inhibition of PDE4 by apremilast leads to increased intracellular cAMP levels. An increase in cAMP results in the suppression of inflammation by decreasing the expression of TNF-α, IL-17, IL-23, and other inflammatory mediators. The above inflammatory mediators have been implicated in various psoriatic conditions as well as Behcet's disease, leading to their undesirable inflammatory symptoms such as mouth ulcers, skin lesions, and arthritis. Apremilast administration leads to a cascade which eventually decreases the levels of the above mediators, relieving inflammatory symptoms. •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): An oral dose of apremilast is well-absorbed and the absolute bioavailability is approximately 73%. Tmax is approximately 2.5 hours and Cmax has been reported to be approximately 584 ng/mL in one pharmacokinetic study. Food intake does not appear to affect apremilast 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): The average apparent volume of distribution (Vd) is about 87 L, suggesting that apremilast is distributed in the extravascular compartment. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of apremilast is about 68%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Apremilast is heavily metabolized by various pathways, which include oxidation, hydrolysis, in addition to conjugation. About 23 metabolites are produced from its metabolism. The CYP3A4 primarily mediates the oxidative metabolism of this drug, with smaller contributions from CYP1A2 and CYP2A6 enzymes. The main metabolite of apremilast, M12, is an inactive glucuronide conjugate form of the O-demethylated drug. Some other major metabolites, M14 and M16, are significantly less active in the inhibition of PDE4 and inflammatory mediators than their parent drug, apremilast. After an oral dose, unchanged apremilast (45%) and the inactive metabolite, O-desmethyl apremilast glucuronide (39%) are found in the plasma. Minor metabolites M7 and M17 are active, but are only present in about 2% or less of apremilast concentrations, and likely not significant contributors to the actions of apremilast. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Only 3% and 7% of an apremilast dose are detected in the urine and feces as unchanged drug, respectively, indicating extensive metabolism and high absorption. •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 this drug ranges from 6-9 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 patients, the plasma clearance of apremilast is about 10 L/hour. •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 mice was greater than 2000 mg/kg in mice. In rats, oral LD50 was 2000 mg/kg males and 300 mg/kg in females. Overdose information In healthy subjects receiving a maximum dose of 100 mg (given as 50 mg twice daily) for about 5 days, no significant toxicity was observed. In cases of an overdose, supportive and symptomatic treatment should be administered. Contact the local poison control center for the most recent overdose management for apremilast. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Otezla •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Aprémilast Apremilast Apremilastum •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): Apremilast is a non-steroidal medication used for the treatment of inflammatory conditions such as psoriasis and psoriatic arthritis. Output: The concomitant administration of apremilast with biologics for rheumatoid arthritis treatment has not been formally evaluated. Several studies have demonstrated that biologic agents frequently used in the treatment of psoriasis or rheumatoid arthritis may impact the metabolism of hepatic cytochrome enzyme substrates (such as apremilast) by stimulating cytochrome enzyme activities. Apremilast is a CYP3A4 substrate, and induction of this enzyme may lead to decreased therapeutic efficacy resulting from increased metabolism. The severity of the interaction is major.

Does Abatacept and Aprepitant interact?

•Drug A: Abatacept •Drug B: Aprepitant •Severity: MODERATE •Description: The metabolism of Aprepitant 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 prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including high-dose cisplatin (in combination with other antiemetic agents). •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): Aprepitant, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT 3 ), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV). •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): Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepitant augments the antiemetic activity of the 5-HT 3 -receptor antagonist ondansetron and the corticosteroid ethasone and inhibits both the acute and delayed phases of cisplatin induced emesis. •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 mean absolute oral bioavailability of aprepitant is approximately 60 to 65%. •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): 70 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding is reported to be >95%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Aprepitant primarily undergoes CYP3A4-mediated metabolism, as well as minor metabolism mediated by CYP1A2 and CYP2C19. About seven metabolites of aprepitant have been identified in human plasma, which all retain weak pharmacological activity. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. •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): 9-13 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): Apparent plasma cl=62-90 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): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Aponvie, Cinvanti, Emend •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): Aprepitant is a substance P/neurokinin 1 receptor antagonist used to treat nausea and vomiting caused by chemotherapy and 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 CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Aprepitant interact? Information: •Drug A: Abatacept •Drug B: Aprepitant •Severity: MODERATE •Description: The metabolism of Aprepitant 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 prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including high-dose cisplatin (in combination with other antiemetic agents). •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): Aprepitant, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT 3 ), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV). •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): Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepitant augments the antiemetic activity of the 5-HT 3 -receptor antagonist ondansetron and the corticosteroid ethasone and inhibits both the acute and delayed phases of cisplatin induced emesis. •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 mean absolute oral bioavailability of aprepitant is approximately 60 to 65%. •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): 70 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding is reported to be >95%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Aprepitant primarily undergoes CYP3A4-mediated metabolism, as well as minor metabolism mediated by CYP1A2 and CYP2C19. About seven metabolites of aprepitant have been identified in human plasma, which all retain weak pharmacological activity. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. •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): 9-13 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): Apparent plasma cl=62-90 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): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Aponvie, Cinvanti, Emend •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): Aprepitant is a substance P/neurokinin 1 receptor antagonist used to treat nausea and vomiting caused by chemotherapy and 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 CYP3A5 substrates. The severity of the interaction is moderate.

Does Abatacept and Arformoterol interact?

•Drug A: Abatacept •Drug B: Arformoterol •Severity: MODERATE •Description: The metabolism of Arformoterol 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): Arformoterol is indicated in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. •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): Arformoterol, the active (R,R)-enantiomer of formoterol, is a selective long-acting β2-adrenergic receptor agonist (beta2-agonist) that has two-fold greater potency than racemic formoterol (which contains both the (S,S) and (R,R)-enantiomers). The (S,S)-enantiomer is about 1,000-fold less potent as a β2-agonist than the (R,R)-enantiomer. Arformoterol seems to have little or no effect on β1-adrenergic 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): While it is recognized that β2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and β1-receptors are the predominant receptors in the heart, data indicate that there are also β2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective β2-agonists may have cardiac effects. The pharmacologic effects of β2-adrenoceptor agonist drugs, including arformoterol, are at least in part attributable to the stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3,5-adenosine monophosphate (cyclic AMP). Increased intracellular cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of the release of proinflammatory mediators from cells, especially from mast cells. In vitro tests show that arformoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Arformoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-response. •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 patients with COPD, the mean peak plasma concentration (C max ) and AUC 0-12h following twice daily administration for 14 days were 4.3 pg/mL and 34.5 pg.hr/mL, respectively. The time to peak plasma concentration (T max ) was approximately 0.5 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): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The binding of arformoterol to human plasma proteins in vitro was 52-65% at concentrations of 0.25, 0.5 and 1.0 ng/mL of radiolabeled arformoterol. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Arformoterol was almost entirely metabolized following oral administration of 35 mcg of radiolabeled arformoterol in eight healthy subjects. Direct conjugation of arformoterol with glucuronic acid was the major metabolic pathway. O-Desmethylation is a secondary route catalyzed by the CYP enzymes CYP2D6 and CYP2C19. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following the administration of a single oral dose of arformoterol to eight healthy subjects, 63% of the administered dose was recovered in the urine and 11% in the feces within 48 hours. After 14 days, a total of 89% of the total dose had been recovered - 67% in the urine and 22% in the feces - with approximately 1% remaining 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): In COPD patients given 15 mcg inhaled arformoterol twice a day for 14 days, the mean terminal half-life of arformoterol was 26 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 male subjects, the clearance of a single oral dose of arformoterol was 8.9 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): A death was reported in dogs after a single oral dose of 5 mg/kg (approximately 4500 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose. Arformoterol should not be used more often or at higher doses than recommended, or conjunction with other medications containing long-acting beta 2 -agonists. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Brovana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Arformoterol •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): Arformoterol is a beta-2 adrenergic agonist and bronchodilator used for long-term, symptomatic treatment of reversible bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Arformoterol interact? Information: •Drug A: Abatacept •Drug B: Arformoterol •Severity: MODERATE •Description: The metabolism of Arformoterol 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): Arformoterol is indicated in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. •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): Arformoterol, the active (R,R)-enantiomer of formoterol, is a selective long-acting β2-adrenergic receptor agonist (beta2-agonist) that has two-fold greater potency than racemic formoterol (which contains both the (S,S) and (R,R)-enantiomers). The (S,S)-enantiomer is about 1,000-fold less potent as a β2-agonist than the (R,R)-enantiomer. Arformoterol seems to have little or no effect on β1-adrenergic 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): While it is recognized that β2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and β1-receptors are the predominant receptors in the heart, data indicate that there are also β2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective β2-agonists may have cardiac effects. The pharmacologic effects of β2-adrenoceptor agonist drugs, including arformoterol, are at least in part attributable to the stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3,5-adenosine monophosphate (cyclic AMP). Increased intracellular cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of the release of proinflammatory mediators from cells, especially from mast cells. In vitro tests show that arformoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Arformoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-response. •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 patients with COPD, the mean peak plasma concentration (C max ) and AUC 0-12h following twice daily administration for 14 days were 4.3 pg/mL and 34.5 pg.hr/mL, respectively. The time to peak plasma concentration (T max ) was approximately 0.5 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): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The binding of arformoterol to human plasma proteins in vitro was 52-65% at concentrations of 0.25, 0.5 and 1.0 ng/mL of radiolabeled arformoterol. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Arformoterol was almost entirely metabolized following oral administration of 35 mcg of radiolabeled arformoterol in eight healthy subjects. Direct conjugation of arformoterol with glucuronic acid was the major metabolic pathway. O-Desmethylation is a secondary route catalyzed by the CYP enzymes CYP2D6 and CYP2C19. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following the administration of a single oral dose of arformoterol to eight healthy subjects, 63% of the administered dose was recovered in the urine and 11% in the feces within 48 hours. After 14 days, a total of 89% of the total dose had been recovered - 67% in the urine and 22% in the feces - with approximately 1% remaining 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): In COPD patients given 15 mcg inhaled arformoterol twice a day for 14 days, the mean terminal half-life of arformoterol was 26 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 male subjects, the clearance of a single oral dose of arformoterol was 8.9 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): A death was reported in dogs after a single oral dose of 5 mg/kg (approximately 4500 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose. Arformoterol should not be used more often or at higher doses than recommended, or conjunction with other medications containing long-acting beta 2 -agonists. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Brovana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Arformoterol •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): Arformoterol is a beta-2 adrenergic agonist and bronchodilator used for long-term, symptomatic treatment of reversible bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. 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 Aripiprazole lauroxil interact?

•Drug A: Abatacept •Drug B: Aripiprazole lauroxil •Severity: MODERATE •Description: The metabolism of Aripiprazole lauroxil 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): Aripiprazole lauroxil is indicated for the treatment of schizophrenia and related psychotic 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): Aripiprazole, which is a major pharmacological metabolite of aripiprazole lauroxil, serves to improve the positive and negative symptoms of schizophrenia by modulating dopaminergic signalling pathways. Aripiprazole lauroxil is reported to have minimal effects on sexual function or prolactin 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): The pharmacological activity of aripiprazole lauroxil is thought to be mainly mediated by its metabolite aripiprazole, and to a lesser extent, dehydro-aripiprazole. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at the serotonin 5-HT2A receptor. The desired outcome of antipsuchotic agents in schizophrenia is to inhibit dopaminergic transmission in the limbic system and enhance dopaminergic transmission in the prefrontal cortex. As a partial agonist at D2 receptors in the mesolimbic dopaminergic pathway, aripiprazole acts as a functional antagonist in the mesolimbic dopamine pathway and reduces the extent of dopaminergic pathway activity. This results in reduced positive symptoms in schizophrenia and extrapyramidal motor side effects. In contrast, aripiprazole is thought to act as a functional agonist in the mesocortical pathway, where reduced dopamine activity is seen in association with negative symptoms and cognitive impairment. Antagonism at 5-HT2A receptors by aripiprazole alleviates the negative symptoms and cognitive impairment of schizophrenia. 5-HT2A receptors are Gi/Go-coupled that upon activation, produce neuronal inhibition via decreased neuronal excitability and decreased transmitter release at the nerve terminals. In the nigrostriatal pathway, 5-HT2A regulates the release of dopamine. Through antagonism of 5-HT2A receptors, aripiprazole disinhibits the release of dopamine in the striatum and enhance the levels of the transmitters at the nerve terminals. The combined effects of D2 and 5-HT2A antagonism are thought to counteract the increased dopamine function causing increased extrapyramidal side effects. Blocking 5-HT2A receptors may also lead to the modulation of glutamate release in the mesocortical circuit, which is a transmitter that plays a role in schizophrenia. 5-HT1A receptors are autoreceptors that inhibit 5-HT release upon activation. Aripiprazole is a partial agonist at theses receptors and reduces 5-HT release; this results in potentiated dopamine release in the striatum and prefrontal cortex. It is reported that therapeutic doses of aripiprazole occupies up to 90% of brain D2 receptors in a dose-dependent manner. Apripiprazole targets different receptors that lead to drug-related adverse reactions; for example, the antagonist activity at the alpha-1 adrenergic receptors results in orthostatic hypotension. Aripiprazole's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. •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 extended-release intramuscular injection of aripiprazole lauroxil, aripiprazole can be detected in the systemic circulation from 5 to 6 days and is continued to be released for an additional 36 days. The concentrations of aripiprazole increases with consecutive doses of aripiprazole lauroxil and the steady state is reached following the fourth monthly injection. The systemic exposure to aripiprazole was similar when comparing deltoid and gluteal intramuscular injections. •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 population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of aripiprazole lauroxil was 268 L, indicating extensive extravascular distribution following absorption. Health human volunteer study indicates that aripiprazole crosses the blood-brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Serum protein binding of aripiprazole and its major metabolite is >99% at therapeutic concentrations, where they are primarily bound to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Aripiprazole lauroxil is hydrolyzed to form N-hydroxymethyl-aripiprazole via esterases. N-hydroxymethyl-aripiprazole undergoes a rapid, nonenzymatic spontaneous cleavage, or water-mediated hydrolysis, to form aripiprazole, which mainly contributes to the pharmacological actions of aripiprazole lauroxil. Aripiprazole is further metabolized by hepatic CYP3A4 and CYP2D6 to form dehydro-aripiprazole, which retains some pharmacological activity. Dehydro-aripiprazole displays affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma. Cytochrome P450 2D6 is subject to genetic polymorphism, which results in pharmacokinetic differences among CYP2D6 metabolizer phenotypes and dosage adjustments accordingly. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Based on the pharmacokinetic study for aripiprazole, less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged 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 aripiprazole terminal elimination half-life ranged from 29.2 days to 34.9 days after every 4-week injection of aripiprazole lauroxil 441, 662 and 882 mg. •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 rats, the clearance for aripiprazole lauroxil was 0.32 ± 0.11 L/h/kg following injection of aripiprazole lauroxil molar equivalent to 5 mg aripiprazole/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): LD50 in rat following intramuscular injection was >60 mg aripiprazole equivalents. Oral LD50 of aripiprazole in female rat, male rat, and monkey were 705 mg/kg, 965 mg/kg, and >2000 mg/kg, respectively. Most common adverse reaction of aripiprazole was akathisia. A case of drug overdosage occurred followinga acute ingestion of 1260 mg aripiprazole, which is approximately 42 times the maximum recommended daily dose. Overdose was associated with vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. Aripiprazole is an antipsychotic drug that may develop Neuroleptic Malignant Syndrome (NMS), which is manifested with hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. In case of NMS, aripiprazole should be discontinued immediately, and intensive symptomatic treatment and medical monitoring should be initiated. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Aristada •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): Aripiprazole lauroxil is an antipsychotic used to treat 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 Aripiprazole lauroxil interact? Information: •Drug A: Abatacept •Drug B: Aripiprazole lauroxil •Severity: MODERATE •Description: The metabolism of Aripiprazole lauroxil 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): Aripiprazole lauroxil is indicated for the treatment of schizophrenia and related psychotic 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): Aripiprazole, which is a major pharmacological metabolite of aripiprazole lauroxil, serves to improve the positive and negative symptoms of schizophrenia by modulating dopaminergic signalling pathways. Aripiprazole lauroxil is reported to have minimal effects on sexual function or prolactin 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): The pharmacological activity of aripiprazole lauroxil is thought to be mainly mediated by its metabolite aripiprazole, and to a lesser extent, dehydro-aripiprazole. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at the serotonin 5-HT2A receptor. The desired outcome of antipsuchotic agents in schizophrenia is to inhibit dopaminergic transmission in the limbic system and enhance dopaminergic transmission in the prefrontal cortex. As a partial agonist at D2 receptors in the mesolimbic dopaminergic pathway, aripiprazole acts as a functional antagonist in the mesolimbic dopamine pathway and reduces the extent of dopaminergic pathway activity. This results in reduced positive symptoms in schizophrenia and extrapyramidal motor side effects. In contrast, aripiprazole is thought to act as a functional agonist in the mesocortical pathway, where reduced dopamine activity is seen in association with negative symptoms and cognitive impairment. Antagonism at 5-HT2A receptors by aripiprazole alleviates the negative symptoms and cognitive impairment of schizophrenia. 5-HT2A receptors are Gi/Go-coupled that upon activation, produce neuronal inhibition via decreased neuronal excitability and decreased transmitter release at the nerve terminals. In the nigrostriatal pathway, 5-HT2A regulates the release of dopamine. Through antagonism of 5-HT2A receptors, aripiprazole disinhibits the release of dopamine in the striatum and enhance the levels of the transmitters at the nerve terminals. The combined effects of D2 and 5-HT2A antagonism are thought to counteract the increased dopamine function causing increased extrapyramidal side effects. Blocking 5-HT2A receptors may also lead to the modulation of glutamate release in the mesocortical circuit, which is a transmitter that plays a role in schizophrenia. 5-HT1A receptors are autoreceptors that inhibit 5-HT release upon activation. Aripiprazole is a partial agonist at theses receptors and reduces 5-HT release; this results in potentiated dopamine release in the striatum and prefrontal cortex. It is reported that therapeutic doses of aripiprazole occupies up to 90% of brain D2 receptors in a dose-dependent manner. Apripiprazole targets different receptors that lead to drug-related adverse reactions; for example, the antagonist activity at the alpha-1 adrenergic receptors results in orthostatic hypotension. Aripiprazole's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. •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 extended-release intramuscular injection of aripiprazole lauroxil, aripiprazole can be detected in the systemic circulation from 5 to 6 days and is continued to be released for an additional 36 days. The concentrations of aripiprazole increases with consecutive doses of aripiprazole lauroxil and the steady state is reached following the fourth monthly injection. The systemic exposure to aripiprazole was similar when comparing deltoid and gluteal intramuscular injections. •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 population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of aripiprazole lauroxil was 268 L, indicating extensive extravascular distribution following absorption. Health human volunteer study indicates that aripiprazole crosses the blood-brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Serum protein binding of aripiprazole and its major metabolite is >99% at therapeutic concentrations, where they are primarily bound to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Aripiprazole lauroxil is hydrolyzed to form N-hydroxymethyl-aripiprazole via esterases. N-hydroxymethyl-aripiprazole undergoes a rapid, nonenzymatic spontaneous cleavage, or water-mediated hydrolysis, to form aripiprazole, which mainly contributes to the pharmacological actions of aripiprazole lauroxil. Aripiprazole is further metabolized by hepatic CYP3A4 and CYP2D6 to form dehydro-aripiprazole, which retains some pharmacological activity. Dehydro-aripiprazole displays affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma. Cytochrome P450 2D6 is subject to genetic polymorphism, which results in pharmacokinetic differences among CYP2D6 metabolizer phenotypes and dosage adjustments accordingly. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Based on the pharmacokinetic study for aripiprazole, less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged 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 aripiprazole terminal elimination half-life ranged from 29.2 days to 34.9 days after every 4-week injection of aripiprazole lauroxil 441, 662 and 882 mg. •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 rats, the clearance for aripiprazole lauroxil was 0.32 ± 0.11 L/h/kg following injection of aripiprazole lauroxil molar equivalent to 5 mg aripiprazole/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): LD50 in rat following intramuscular injection was >60 mg aripiprazole equivalents. Oral LD50 of aripiprazole in female rat, male rat, and monkey were 705 mg/kg, 965 mg/kg, and >2000 mg/kg, respectively. Most common adverse reaction of aripiprazole was akathisia. A case of drug overdosage occurred followinga acute ingestion of 1260 mg aripiprazole, which is approximately 42 times the maximum recommended daily dose. Overdose was associated with vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. Aripiprazole is an antipsychotic drug that may develop Neuroleptic Malignant Syndrome (NMS), which is manifested with hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. In case of NMS, aripiprazole should be discontinued immediately, and intensive symptomatic treatment and medical monitoring should be initiated. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Aristada •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): Aripiprazole lauroxil is an antipsychotic used to treat 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 Aripiprazole interact?

•Drug A: Abatacept •Drug B: Aripiprazole •Severity: MODERATE •Description: The metabolism of Aripiprazole 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): Aripiprazole is indicated for the treatment of acute manic and mixed episodes associated with bipolar I disorder, irritability associated with autism spectrum disorder, schizophrenia, and Tourette's disorder. It is also used as an adjunctive treatment of major depressive disorder.[L45859 An injectable formulation of aripiprazole is indicated for agitation associated with schizophrenia or bipolar mania. Finally, an extended-release, bimonthly injection formulation of aripiprazole is indicated for the treatment of adult schizophrenia and maintenance therapy for adult bipolar I disorder. •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): Aripiprazole exhibits high affinity for dopamine D 2 and D 3, serotonin 5-HT 1a and 5-HT 2a receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D 4, serotonin 5-HT 2c and 5-HT 7, alpha 1 -adrenergic and histamine H 1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM). •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 antipsychotic action of aripiprazole is likely due to its partial agonist activity on D2 and 5-HT 1A receptors as well as its antagonist activity at 5-HT 2A receptors; however, the exact mechanism has not been fully elucidated. One of the mechanisms that have been proposed is that aripiprazole both stimulates and inhibits dopamine as it engages the D2 receptor. It lowers dopamine neuronal firing at high dopamine concentrations and increases dopamine firing at low concentrations. Its partial agonist activity gives aripiprazole an intermediate level of dopaminergic neuronal tone between full agonist and antagonist of the D2 receptor. In addition, some adverse effects may be due to action on other receptors.[L4620] For example, orthostatic hypotension may be explained by antagonism of the adrenergic alpha-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): Tablet: Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%. ABILIFY can be administered with or without food. Administration of a 15 mg ABILIFY tablet with a standard high-fat meal did not significantly affect the C max or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T max by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole. Oral Solution: Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher than that from the tablet formulation. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution-to-tablet ratios of geometric mean C max and AUC values were 122% and 114%, respectively. The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional between the doses of 5 mg to 30 mg. Extended-release injectable suspension, bimonthly injection: Aripiprazole absorption into the systemic circulation is prolonged following gluteal intramuscular injection due to the low solubility of aripiprazole particles. The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over 2 months following gluteal injection(s). Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with T max ranging between 1 to 49 days following multiple gluteal administrations of 960 mg. •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 of aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged 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 elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively. For populations that are poor CYP2D6 metabolizers, the half-life of aripiprazole is 146 hours and these patients should be treated with half the normal dose. Other studies have reported a half-life of 61.03±19.59 hours for aripiprazole and 279±299 hours for the active metabolite. •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 aripiprazole was estimated to be 0.8mL/min/kg. Other studies have also reported a clearance rate of 3297±1042mL/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): Neonates exposed to antipsychotic drugs, including ABILIFY, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotics, including ABILIFY, during pregnancy. In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival. ABILIFY has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral ABILIFY have been reported worldwide. These include overdoses with oral ABILIFY alone and in combination with other substances. No fatality was reported with ABILIFY alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral ABILIFY (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving oral ABILIFY ingestions up to 195 mg with no fatalities. Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral ABILIFY overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with ABILIFY overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. No specific information is available on the treatment of overdose with ABILIFY. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Charcoal: In the event of an overdose of ABILIFY, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of ABILIFY, decreased the mean AUC and C max of aripiprazole by 50%. Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with ABILIFY, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins. Lifetime carcinogenicity studies were conducted in ICR mice, F344 rats, and Sprague-Dawley (SD) rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2, 0.5, 2 and 5 times and 0.3, 1 and 3 times the MRHD of 30 mg/day based on mg/m2 body surface area, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day, which are 3, 6, 13 and 19 times the MRHD based on mg/m2 body surface area. Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the MRHD). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the MRHD); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (19 times the MRHD). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2-receptor antagonism and hyperprolactinemia. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13 week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4 week and 13 week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear. The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, increased numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans. Female rats were treated orally with aripiprazole from 2 weeks prior to mating through gestation Day 7 at doses of 2, 6, and 20 mg/kg/day, which are 0.6, 2, and 6 times the MRHD of 30 mg/day based on mg/m2 body surface area. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 2 and 6 times the MRHD, and decreased fetal weight was seen at 6 times the MRHD. Male rats were treated orally with aripiprazole from 9 weeks prior to mating through mating at doses of 20, 40, and 60 mg/kg/day, which are 6, 13, and 19 times the MRHD of 30 mg/day based on mg/m2 body surface area. Disturbances in spermatogenesis were seen at 19 times the MRHD and prostate atrophy was seen at 13 and 19 times the MRHD without impairment of fertility. Pharmacokinetic properties in patients 10-17 years of age are similar to that of adults once body weight has been corrected for. No dosage adjustment is necessary in elderly patients however aripiprazole is not approved for Alzheimer's associated psychosis. Patients classified as CYP2D6 poor metabolizers should be prescribed half the regular dose of aripiprazole. Hepatic and renal function as well as sex, race, and smoking status do not affect dosage requirements for aripiprazole •Brand Names (Drug A): Orencia •Brand Names (Drug B): Abilify •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): Aripiprazole is an atypical antipsychotic used in the treatment of a wide variety of mood and psychotic disorders, such as schizophrenia, bipolar I, major depressive disorder, irritability associated with autism, and Tourette's 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 CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Aripiprazole interact? Information: •Drug A: Abatacept •Drug B: Aripiprazole •Severity: MODERATE •Description: The metabolism of Aripiprazole 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): Aripiprazole is indicated for the treatment of acute manic and mixed episodes associated with bipolar I disorder, irritability associated with autism spectrum disorder, schizophrenia, and Tourette's disorder. It is also used as an adjunctive treatment of major depressive disorder.[L45859 An injectable formulation of aripiprazole is indicated for agitation associated with schizophrenia or bipolar mania. Finally, an extended-release, bimonthly injection formulation of aripiprazole is indicated for the treatment of adult schizophrenia and maintenance therapy for adult bipolar I disorder. •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): Aripiprazole exhibits high affinity for dopamine D 2 and D 3, serotonin 5-HT 1a and 5-HT 2a receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D 4, serotonin 5-HT 2c and 5-HT 7, alpha 1 -adrenergic and histamine H 1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM). •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 antipsychotic action of aripiprazole is likely due to its partial agonist activity on D2 and 5-HT 1A receptors as well as its antagonist activity at 5-HT 2A receptors; however, the exact mechanism has not been fully elucidated. One of the mechanisms that have been proposed is that aripiprazole both stimulates and inhibits dopamine as it engages the D2 receptor. It lowers dopamine neuronal firing at high dopamine concentrations and increases dopamine firing at low concentrations. Its partial agonist activity gives aripiprazole an intermediate level of dopaminergic neuronal tone between full agonist and antagonist of the D2 receptor. In addition, some adverse effects may be due to action on other receptors.[L4620] For example, orthostatic hypotension may be explained by antagonism of the adrenergic alpha-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): Tablet: Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%. ABILIFY can be administered with or without food. Administration of a 15 mg ABILIFY tablet with a standard high-fat meal did not significantly affect the C max or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T max by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole. Oral Solution: Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher than that from the tablet formulation. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution-to-tablet ratios of geometric mean C max and AUC values were 122% and 114%, respectively. The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional between the doses of 5 mg to 30 mg. Extended-release injectable suspension, bimonthly injection: Aripiprazole absorption into the systemic circulation is prolonged following gluteal intramuscular injection due to the low solubility of aripiprazole particles. The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over 2 months following gluteal injection(s). Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with T max ranging between 1 to 49 days following multiple gluteal administrations of 960 mg. •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 of aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged 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 elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively. For populations that are poor CYP2D6 metabolizers, the half-life of aripiprazole is 146 hours and these patients should be treated with half the normal dose. Other studies have reported a half-life of 61.03±19.59 hours for aripiprazole and 279±299 hours for the active metabolite. •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 aripiprazole was estimated to be 0.8mL/min/kg. Other studies have also reported a clearance rate of 3297±1042mL/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): Neonates exposed to antipsychotic drugs, including ABILIFY, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotics, including ABILIFY, during pregnancy. In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival. ABILIFY has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral ABILIFY have been reported worldwide. These include overdoses with oral ABILIFY alone and in combination with other substances. No fatality was reported with ABILIFY alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral ABILIFY (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving oral ABILIFY ingestions up to 195 mg with no fatalities. Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral ABILIFY overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with ABILIFY overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. No specific information is available on the treatment of overdose with ABILIFY. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Charcoal: In the event of an overdose of ABILIFY, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of ABILIFY, decreased the mean AUC and C max of aripiprazole by 50%. Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with ABILIFY, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins. Lifetime carcinogenicity studies were conducted in ICR mice, F344 rats, and Sprague-Dawley (SD) rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2, 0.5, 2 and 5 times and 0.3, 1 and 3 times the MRHD of 30 mg/day based on mg/m2 body surface area, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day, which are 3, 6, 13 and 19 times the MRHD based on mg/m2 body surface area. Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the MRHD). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the MRHD); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (19 times the MRHD). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2-receptor antagonism and hyperprolactinemia. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13 week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4 week and 13 week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear. The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, increased numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans. Female rats were treated orally with aripiprazole from 2 weeks prior to mating through gestation Day 7 at doses of 2, 6, and 20 mg/kg/day, which are 0.6, 2, and 6 times the MRHD of 30 mg/day based on mg/m2 body surface area. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 2 and 6 times the MRHD, and decreased fetal weight was seen at 6 times the MRHD. Male rats were treated orally with aripiprazole from 9 weeks prior to mating through mating at doses of 20, 40, and 60 mg/kg/day, which are 6, 13, and 19 times the MRHD of 30 mg/day based on mg/m2 body surface area. Disturbances in spermatogenesis were seen at 19 times the MRHD and prostate atrophy was seen at 13 and 19 times the MRHD without impairment of fertility. Pharmacokinetic properties in patients 10-17 years of age are similar to that of adults once body weight has been corrected for. No dosage adjustment is necessary in elderly patients however aripiprazole is not approved for Alzheimer's associated psychosis. Patients classified as CYP2D6 poor metabolizers should be prescribed half the regular dose of aripiprazole. Hepatic and renal function as well as sex, race, and smoking status do not affect dosage requirements for aripiprazole •Brand Names (Drug A): Orencia •Brand Names (Drug B): Abilify •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): Aripiprazole is an atypical antipsychotic used in the treatment of a wide variety of mood and psychotic disorders, such as schizophrenia, bipolar I, major depressive disorder, irritability associated with autism, and Tourette's 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 CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Arsenic trioxide interact?

•Drug A: Abatacept •Drug B: Arsenic trioxide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Arsenic trioxide 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 induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression •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): Arsenic Trioxide is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy. •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 Arsenic Trioxide is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha. It is suspected that arsenic trioxide induces cancer cells to undergo apoptosis. •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): 75% bound •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Inorganic, lyophilized arsenic trioxide, when placed in solution, is immediately hydrolyzed to arsenous acid - this appears to be the pharmacologically active species of arsenic trioxide. Further metabolism involves the oxidation of arsenous acid to arsenic acid, and an oxidative methylation of arsenous acid to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) by methyltransferases in the liver. Both MMA and DMA have relatively long half-lives and can accumulate following multiple doses, the extent of which depends upon the dosing regimen in question. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Trivalent arsenic is mostly methylated in humans and 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): 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): Symptoms of overdose include convulsions, muscle weakness and confusion. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Trisenox •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): Arsenic trioxide is a chemotherapeutic agent used in the treatment of refractory or relapsed acute promyelocytic leukemia in patients with prior retinoid and anthracycline chemotherapy.

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 Arsenic trioxide interact? Information: •Drug A: Abatacept •Drug B: Arsenic trioxide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Arsenic trioxide 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 induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression •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): Arsenic Trioxide is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy. •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 Arsenic Trioxide is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha. It is suspected that arsenic trioxide induces cancer cells to undergo apoptosis. •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): 75% bound •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Inorganic, lyophilized arsenic trioxide, when placed in solution, is immediately hydrolyzed to arsenous acid - this appears to be the pharmacologically active species of arsenic trioxide. Further metabolism involves the oxidation of arsenous acid to arsenic acid, and an oxidative methylation of arsenous acid to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) by methyltransferases in the liver. Both MMA and DMA have relatively long half-lives and can accumulate following multiple doses, the extent of which depends upon the dosing regimen in question. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Trivalent arsenic is mostly methylated in humans and 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): 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): Symptoms of overdose include convulsions, muscle weakness and confusion. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Trisenox •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): Arsenic trioxide is a chemotherapeutic agent used in the treatment of refractory or relapsed acute promyelocytic leukemia in patients with prior retinoid and anthracycline chemotherapy. 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 Asenapine interact?

•Drug A: Abatacept •Drug B: Asenapine •Severity: MODERATE •Description: The metabolism of Asenapine 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 for treatment in psychosis, schizophrenia and schizoaffective disorders, manic disorders, and bipolar disorders as monotherapy or in combination. •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): Asenapine is a serotonin, dopamine, noradrenaline, and histamine antagonist in which asenapine possess more potent activity with serotonin receptors than dopamine. Sedation in patients is associated with asenapine's antagonist activity at histamine receptors. Its lower incidence of extrapyramidal effects are associated with the upregulation of D1 receptors. This upregulation occurs due to asenapine's dose-dependent effects on glutamate transmission in the brain. It does not have any significant activity with muscarinic, cholinergic receptors therefore symptoms associated with anticholinergic drug activity like dry mouth or constipation are not expected to be observed. Asenapine has a higher affinity for all aforementioned receptors compared to first-generation and second-generation antipsychotics except for 5-HT1A and 5-HT1B 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): Asenapine is an atypical antipsychotic multireceptor neuroleptic drug which shows strong 5HT2A (serotonin) and D2 (dopamine) receptor antagonism, which has been shown to enhance dopamine (DA) and acetylcholine (Ach) efflux in rat brains. Asenapine may improve cognitive function and negative symptoms in patients with schizophrenia. •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): Cmax, single 5 mg dose = 4 ng/mL (within 1 hour); Bioavailability, sublingual administration = 35%; Bioavailability, oral administration (swallowed) = <2%; Time to steady state, 5 mg = 3 days; Peak plasma concentration occurs within 0.5 to 1.5 hours. Doubling dose of asenapine results in 1.7-fold increase in maximum concentration and exposure. Drinking water within 2-5 minutes post administration of asenapine results in a decrease in 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): 20-25 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95% protein bound •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Asenapine is oxidized via CYP1A2 and undergoes direct glucuronidation via UGT1A4. Oxidation via CYP1A2 is asenapine's primary mode of metabolism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Urine (50%) and feces (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): 24 hours (range of 13.4 - 39.2 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): 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): Saphris, Secuado, Sycrest •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): Asenapine is an atypical antipsychotic used to treat patients with bipolar I disorder and patients with schizophrenia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Asenapine interact? Information: •Drug A: Abatacept •Drug B: Asenapine •Severity: MODERATE •Description: The metabolism of Asenapine 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 for treatment in psychosis, schizophrenia and schizoaffective disorders, manic disorders, and bipolar disorders as monotherapy or in combination. •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): Asenapine is a serotonin, dopamine, noradrenaline, and histamine antagonist in which asenapine possess more potent activity with serotonin receptors than dopamine. Sedation in patients is associated with asenapine's antagonist activity at histamine receptors. Its lower incidence of extrapyramidal effects are associated with the upregulation of D1 receptors. This upregulation occurs due to asenapine's dose-dependent effects on glutamate transmission in the brain. It does not have any significant activity with muscarinic, cholinergic receptors therefore symptoms associated with anticholinergic drug activity like dry mouth or constipation are not expected to be observed. Asenapine has a higher affinity for all aforementioned receptors compared to first-generation and second-generation antipsychotics except for 5-HT1A and 5-HT1B 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): Asenapine is an atypical antipsychotic multireceptor neuroleptic drug which shows strong 5HT2A (serotonin) and D2 (dopamine) receptor antagonism, which has been shown to enhance dopamine (DA) and acetylcholine (Ach) efflux in rat brains. Asenapine may improve cognitive function and negative symptoms in patients with schizophrenia. •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): Cmax, single 5 mg dose = 4 ng/mL (within 1 hour); Bioavailability, sublingual administration = 35%; Bioavailability, oral administration (swallowed) = <2%; Time to steady state, 5 mg = 3 days; Peak plasma concentration occurs within 0.5 to 1.5 hours. Doubling dose of asenapine results in 1.7-fold increase in maximum concentration and exposure. Drinking water within 2-5 minutes post administration of asenapine results in a decrease in 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): 20-25 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95% protein bound •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Asenapine is oxidized via CYP1A2 and undergoes direct glucuronidation via UGT1A4. Oxidation via CYP1A2 is asenapine's primary mode of metabolism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Urine (50%) and feces (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): 24 hours (range of 13.4 - 39.2 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): 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): Saphris, Secuado, Sycrest •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): Asenapine is an atypical antipsychotic used to treat patients with bipolar I disorder and patients with schizophrenia. 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 Astemizole interact?

•Drug A: Abatacept •Drug B: Astemizole •Severity: MAJOR •Description: The metabolism of Astemizole 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 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): Astemizole was indicated for use in the relieving allergy symptoms, particularly rhinitis and conjunctivitis. It has been withdrawn from the market however due to concerns of arrhythmias. •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): Astemizole is a second generation H 1 -receptor antagonist. It does not significantly cross the blood brain barrier and therefore does not cause drowsiness or CNS depression at normal doses. •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): Astemizole competes with histamine for binding at H 1 -receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of astemizole to H 1 -receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier and preferentially binds at H1 receptors in the peripehery rather than within the brain, CNS depression is minimal. Astemizole may also act on H 3 -receptors, producing adverse effects. •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 from the gastrointestinal tract. •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): 96.7% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Almost completely metabolized in the liver and primarily excreted in the feces. •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): 1 day •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 =2052mg/kg in mice •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Astemizol Astémizole Astemizole Astemizolum •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): Astemizole is a second generation antihistamine used to treat allergy symptoms.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Astemizole interact? Information: •Drug A: Abatacept •Drug B: Astemizole •Severity: MAJOR •Description: The metabolism of Astemizole 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 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): Astemizole was indicated for use in the relieving allergy symptoms, particularly rhinitis and conjunctivitis. It has been withdrawn from the market however due to concerns of arrhythmias. •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): Astemizole is a second generation H 1 -receptor antagonist. It does not significantly cross the blood brain barrier and therefore does not cause drowsiness or CNS depression at normal doses. •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): Astemizole competes with histamine for binding at H 1 -receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of astemizole to H 1 -receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier and preferentially binds at H1 receptors in the peripehery rather than within the brain, CNS depression is minimal. Astemizole may also act on H 3 -receptors, producing adverse effects. •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 from the gastrointestinal tract. •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): 96.7% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Almost completely metabolized in the liver and primarily excreted in the feces. •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): 1 day •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 =2052mg/kg in mice •Brand Names (Drug A): Orencia •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Astemizol Astémizole Astemizole Astemizolum •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): Astemizole is a second generation antihistamine used to treat allergy symptoms. 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 with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and AstraZeneca COVID-19 Vaccine interact?

•Drug A: Abatacept •Drug B: AstraZeneca COVID-19 Vaccine •Severity: MODERATE •Description: The therapeutic efficacy of AstraZeneca 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 AstraZeneca COVID-19 Vaccine interact? Information: •Drug A: Abatacept •Drug B: AstraZeneca COVID-19 Vaccine •Severity: MODERATE •Description: The therapeutic efficacy of AstraZeneca 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 Asunaprevir interact?

•Drug A: Abatacept •Drug B: Asunaprevir •Severity: MODERATE •Description: The metabolism of Asunaprevir 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): Asunaprevir is indicated in combination with other agents for the treatment of chronic hepatitis C in adult patients with hepatitis C virus genotypes 1 or 4 and compensated liver cirrhosis. Hepatitis C is a liver disease caused by the hepatitis C virus. The chronic state of this condition accounts for 60-80% of the cases from which the risk of cirrhosis of the liver within 20 years is of around 15-30%. The genotype 1 is the most common type of hepatitis C in the United States and the most difficult to treat. •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): Studies in vitro demonstrated a significant antiviral activity in HCV replicon cell systems with an EC50 of 4nm and 1nm against the HCV genotype 1a and 1b respectively. These studies showed a limited activity against the genotypes 2 and 3. This property makes asunaprevir a highly selective anti-HCV agent that is not effective against HCV closely related virus. Asunaprevir produce robust declines in HCV RNA levels in patients with HCV genotype 1 infection. In clinical studies, it has been shown that asunaprevir is well-tolerated and the mean maximum HCV RNA level reduction from baseline was of approximately 2.87 log10 IU/ml. Monotherapy clinical studies with asunaprevir showed a mean maximum decline of HCV RNA in the range of 0.28-2.87 log10 IU/ml when administered in increasing doses from 10-600 mg. When asunaprevir was used as a combination product, it was possible to obtain a sustained virological response (aviremia 24 weeks after completion of therapy) in 83-92% 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): Asunaprevir is a highly active HCV NS3 protease inhibitor. The genome of HCV has a positive polarity which allows it to be translated into a protein in the host cell without further transformation steps. However, the resultant protein needs to be divided by the enzyme NS3 protease into single proteins in order to be able to exert its enzymatic activity or structural role. Therefore, due to NS3 vital importance for viral replication, the inhibiting action of asunaprevir causes a robust antiviral 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): In preclinical studies, asunaprevir showed a high liver-to-plasma AUC ratio. It is rapidly absorbed within 30 minutes of administration. Clinical pharmacokinetic studies showed a T max of 2-4 hours. The pharmacokinetic profile act in a dose-proportional manner and in a dose of 100 mg the steady-state C max and AUC was 572 ng/ml and 1887 ng x h/mL. The absolute bioavailability is reported to be 9.3%. The absorption of asunaprevir is increased 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): The registered volume of distribution at steady state is 194 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding of asunaprevir is very high and it can reach more than 99% of the administered dose independently of the dose. In vitro studies with human Caco-2 cells indicated that asunaprevir is a substrate of P-gp, OATP1B1 and OATP2B1. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Asunaprevir is metabolized by the liver. The metabolism is mainly marked by oxidative reactions mediated by the activity of CYP3A. Asunaprevir seems to weakly induce its own metabolism and from the circulating dose, just about 5% of the administered dose is formed by metabolites. The metabolites of asunaprevir are formed after mono- and bis-oxidation, N-dealkylation, loss of isoquinoline ring and O-demethylation. All the metabolic reactions form about 15 metabolites and studies have reported that the main metabolic activity is performed by CYP3A4 and CYP3A5 with some minor activity from CYP2A6, CYP2B6, CYP2C9, CYP2C19 and CYP2D6. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Asunaprevir is primarily eliminated via the feces. From the administered dose, 84% is excreted by feces mainly as metabolites and less than 1% of the dose is recovered as metabolites in the urine. The proportion of unchanged asunaprevir recovered in feces represents only 7.5% of the 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): Clinical pharmacokinetic studies showed a mean terminal half-life of 15-20 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): Clinical pharmacokinetic studies showed a mean oral clearance of 302-491 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): Toxicity studies showed no carcinogenic nor genotoxic potential related to asunaprevir. In the case of overdose, clinical studies reported no unexpected adverse events. Asunaprevir had no effects on fertility in preclinical studies. It has been shown that asunaprevir gets localized in the GI tract and liver and thus, increased hepatic transaminases were observed as well as changes in iron metabolism and decreased serum proteins. These effects are not progressive and asunaprevir was generally well tolerated. •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): Asunaprevir is an NS3 protease inhibitor used to treat hepatitis C genotype 1b.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Asunaprevir interact? Information: •Drug A: Abatacept •Drug B: Asunaprevir •Severity: MODERATE •Description: The metabolism of Asunaprevir 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): Asunaprevir is indicated in combination with other agents for the treatment of chronic hepatitis C in adult patients with hepatitis C virus genotypes 1 or 4 and compensated liver cirrhosis. Hepatitis C is a liver disease caused by the hepatitis C virus. The chronic state of this condition accounts for 60-80% of the cases from which the risk of cirrhosis of the liver within 20 years is of around 15-30%. The genotype 1 is the most common type of hepatitis C in the United States and the most difficult to treat. •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): Studies in vitro demonstrated a significant antiviral activity in HCV replicon cell systems with an EC50 of 4nm and 1nm against the HCV genotype 1a and 1b respectively. These studies showed a limited activity against the genotypes 2 and 3. This property makes asunaprevir a highly selective anti-HCV agent that is not effective against HCV closely related virus. Asunaprevir produce robust declines in HCV RNA levels in patients with HCV genotype 1 infection. In clinical studies, it has been shown that asunaprevir is well-tolerated and the mean maximum HCV RNA level reduction from baseline was of approximately 2.87 log10 IU/ml. Monotherapy clinical studies with asunaprevir showed a mean maximum decline of HCV RNA in the range of 0.28-2.87 log10 IU/ml when administered in increasing doses from 10-600 mg. When asunaprevir was used as a combination product, it was possible to obtain a sustained virological response (aviremia 24 weeks after completion of therapy) in 83-92% 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): Asunaprevir is a highly active HCV NS3 protease inhibitor. The genome of HCV has a positive polarity which allows it to be translated into a protein in the host cell without further transformation steps. However, the resultant protein needs to be divided by the enzyme NS3 protease into single proteins in order to be able to exert its enzymatic activity or structural role. Therefore, due to NS3 vital importance for viral replication, the inhibiting action of asunaprevir causes a robust antiviral 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): In preclinical studies, asunaprevir showed a high liver-to-plasma AUC ratio. It is rapidly absorbed within 30 minutes of administration. Clinical pharmacokinetic studies showed a T max of 2-4 hours. The pharmacokinetic profile act in a dose-proportional manner and in a dose of 100 mg the steady-state C max and AUC was 572 ng/ml and 1887 ng x h/mL. The absolute bioavailability is reported to be 9.3%. The absorption of asunaprevir is increased 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): The registered volume of distribution at steady state is 194 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding of asunaprevir is very high and it can reach more than 99% of the administered dose independently of the dose. In vitro studies with human Caco-2 cells indicated that asunaprevir is a substrate of P-gp, OATP1B1 and OATP2B1. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Asunaprevir is metabolized by the liver. The metabolism is mainly marked by oxidative reactions mediated by the activity of CYP3A. Asunaprevir seems to weakly induce its own metabolism and from the circulating dose, just about 5% of the administered dose is formed by metabolites. The metabolites of asunaprevir are formed after mono- and bis-oxidation, N-dealkylation, loss of isoquinoline ring and O-demethylation. All the metabolic reactions form about 15 metabolites and studies have reported that the main metabolic activity is performed by CYP3A4 and CYP3A5 with some minor activity from CYP2A6, CYP2B6, CYP2C9, CYP2C19 and CYP2D6. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Asunaprevir is primarily eliminated via the feces. From the administered dose, 84% is excreted by feces mainly as metabolites and less than 1% of the dose is recovered as metabolites in the urine. The proportion of unchanged asunaprevir recovered in feces represents only 7.5% of the 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): Clinical pharmacokinetic studies showed a mean terminal half-life of 15-20 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): Clinical pharmacokinetic studies showed a mean oral clearance of 302-491 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): Toxicity studies showed no carcinogenic nor genotoxic potential related to asunaprevir. In the case of overdose, clinical studies reported no unexpected adverse events. Asunaprevir had no effects on fertility in preclinical studies. It has been shown that asunaprevir gets localized in the GI tract and liver and thus, increased hepatic transaminases were observed as well as changes in iron metabolism and decreased serum proteins. These effects are not progressive and asunaprevir was generally well tolerated. •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): Asunaprevir is an NS3 protease inhibitor used to treat hepatitis C genotype 1b. 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 Atazanavir interact?

•Drug A: Abatacept •Drug B: Atazanavir •Severity: MODERATE •Description: The metabolism of Atazanavir 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): Atazanavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 3 months of age and older weighing at least 5kg. Atazanavir is also indicated in combination with cobicistat and other antiretrovirals for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35kg. •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): Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). 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. Atazanavir 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. Atazanivir is pharmacologically related but structurally different from other protease inhibitors and other currently available antiretrovirals. Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC 50 values above the EC 50 values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity. HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir or atazanavir with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture for 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir and amprenavir, respectively, and did not appear to be cross-resistant. Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy subjects receiving atazanavir. In placebo-controlled Study AI424-076, the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram. Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 subjects with HIV-1 infection, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 msec •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): Atazanavir selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells by binding to the active site of HIV-1 protease, thus preventing the formation of mature virions. Atazanavir is not active against HIV-2. •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): Atazanavir is rapidly absorbed with a T max of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and C max values over the dose range of 200 to 800 mg once daily. A steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold. Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in C max relative to the fasting state. Administration of a single 400-mg dose of atazanavir with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in C max relative to the fasting state. Administration of atazanavir with either a light or high-fat meal decreased the coefficient of variation of AUC and C max by approximately one-half compared to the fasting state. Coadministration of a single 300-mg dose of atazanavir and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the C max and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the C max was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median T max increased from 2.0 to 5.0 hours. Coadministration of atazanavir with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and C max by approximately 25% compared to the fasting 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): In patients with HIV infection, the volume of distribution of atazanavir was estimated to be 88.3 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single 400-mg dose of C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drugs accounted for approximately 20% and 7% of the administered dose in the feces and urine, 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 mean elimination half-life of atazanavir in healthy subjects (n=214) and adult subjects with HIV-1 infection (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal. Elimination half-life in hepatically impaired is 12.1 hours (following a single 400 mg 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): In patients with HIV infection, the clearance of atazanavir was estimated to be 12.9 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): Evotaz, Reyataz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atazanavir Atazanavirum •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): Atazanavir is an antiviral protease inhibitor used in combination with other antiretrovirals for the treatment of HIV.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Atazanavir interact? Information: •Drug A: Abatacept •Drug B: Atazanavir •Severity: MODERATE •Description: The metabolism of Atazanavir 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): Atazanavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 3 months of age and older weighing at least 5kg. Atazanavir is also indicated in combination with cobicistat and other antiretrovirals for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35kg. •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): Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). 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. Atazanavir 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. Atazanivir is pharmacologically related but structurally different from other protease inhibitors and other currently available antiretrovirals. Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC 50 values above the EC 50 values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity. HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir or atazanavir with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture for 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir and amprenavir, respectively, and did not appear to be cross-resistant. Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy subjects receiving atazanavir. In placebo-controlled Study AI424-076, the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram. Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 subjects with HIV-1 infection, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 msec •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): Atazanavir selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells by binding to the active site of HIV-1 protease, thus preventing the formation of mature virions. Atazanavir is not active against HIV-2. •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): Atazanavir is rapidly absorbed with a T max of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and C max values over the dose range of 200 to 800 mg once daily. A steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold. Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in C max relative to the fasting state. Administration of a single 400-mg dose of atazanavir with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in C max relative to the fasting state. Administration of atazanavir with either a light or high-fat meal decreased the coefficient of variation of AUC and C max by approximately one-half compared to the fasting state. Coadministration of a single 300-mg dose of atazanavir and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the C max and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the C max was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median T max increased from 2.0 to 5.0 hours. Coadministration of atazanavir with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and C max by approximately 25% compared to the fasting 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): In patients with HIV infection, the volume of distribution of atazanavir was estimated to be 88.3 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single 400-mg dose of C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drugs accounted for approximately 20% and 7% of the administered dose in the feces and urine, 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 mean elimination half-life of atazanavir in healthy subjects (n=214) and adult subjects with HIV-1 infection (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal. Elimination half-life in hepatically impaired is 12.1 hours (following a single 400 mg 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): In patients with HIV infection, the clearance of atazanavir was estimated to be 12.9 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): Evotaz, Reyataz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atazanavir Atazanavirum •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): Atazanavir is an antiviral protease inhibitor used in combination with other antiretrovirals for the treatment of HIV. 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 Atenolol interact?

•Drug A: Abatacept •Drug B: Atenolol •Severity: MODERATE •Description: The metabolism of Atenolol 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: 1) Management of hypertension alone and in combination with other antihypertensives. 2) Management of angina pectoris associated with coronary atherosclerosis. 3) Management of acute myocardial infarction in hemodynamically stable patients with a heart rate greater than 50 beats per minutes and a systolic blood pressure above 100 mmHg. Off-label uses include: 1) Secondary prevention of myocardial infarction. 2) Management of heart failure. 3) Management of atrial fibrillation. 4) Management of supraventricular tachycardia. 5) Management of ventricular arrythmias such as congenital long-QT and arrhythmogenic right ventricular cardiomyopathy. 6) Management of symptomatic thyrotoxicosis in combination with methimazole. 7) Prophylaxis of migraine headaches. 8) Management of alcohol withdrawal. •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): Atenolol is a cardio-selective beta-blocker and as such exerts most of its effects on the heart. It acts as an antagonist to sympathetic innervation and prevents increases in heart rate, electrical conductivity, and contractility in the heart due to increased release of norepinephrine from the peripheral nervous system. Together the decreases in contractility and rate produce a reduction in cardiac output resulting in a compensatory increase in peripheral vascular resistance in the short-term. This response later declines to baseline with long-term use of atenolol. More importantly, this reduction in the work demanded of the myocardium also reduces oxygen demand which provides therapeutic benefit by reducing the mismatch of oxygen supply and demand in settings where coronary blood flow is limited, such as in coronary atherosclerosis. Reducing oxygen demand, particularly due to exercise, can reduce the frequency of angina pectoris symptoms and potentially improve survival of the remaining myocardium after myocardial infarction. The decrease in rate of sinoatrial node potentials, electrical conduction, slowing of potentials traveling through the atrioventricular node, and reduced frequency of ectopic potentials due to blockade of adrenergic beta receptors has led to benefit in arrhythmic conditions such as atrial fibrillation by controlling the rate of action potential generation and allowing for more effective coordinated contractions. Since a degree of sympathetic activity is necessary to maintain cardiac function, the reduced contractility induced by atenolol may precipitate or worsen heart failure, especially during volume overload. The effects of atenolol on blood pressure have been established, although it is less effective than alternative beta-blockers, but the mechanism has not yet been characterized. As a β1 selective drug, it does not act via the vasodilation produced by non-selective agents. Despite this there is a sustained reduction in peripheral vascular resistance, and consequently blood pressure, alongside a decrease in cardiac output. It is thought that atenolol's antihypertensive activity may be related to action on the central nervous system (CNS) or it's inhibition of the renin-aldosterone-angiotensin system rather than direct effects on the vasculature. Atenolol produces CNS effects similar to other beta-blockers, but does so to a lesser extent due to reduces ability to cross the blood-brain barrier. It has the potential to produce fatigue, depression, and sleep disturbances such as nightmares or insomnia. The exact mechanisms behind these have not been characterized but their occurrence must be considered as they represent clinically relevant adverse effects. Atenolol exerts some effects on the respiratory system although to a much lesser extent than non-selective beta-blockers. Interaction with β2 receptors in the airways can produce bronchoconstriction by blocking the relaxation of bronchial smooth muscle mediated by the sympathetic nervous system. The same action can interfere with β-agonist therapies used in asthma and chronic obstructive pulmonary disease. Unlike some other beta-blocker drugs, atenolol does not have intrinsic sympathomimetic or membrane stabilizing activity nor does it produce changes in glycemic control. •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): Atenolol is a cardioselective beta-blocker, called such because it selectively binds to the β1-adrenergic receptor as an antagonist up to a reported 26 fold more than β2 receptors. Selective activity at the β1 receptor produces cardioselectivity due to the higher population of this receptor in cardiac tissue. Some binding to β2 and possibly β3 receptors can still occur at therapeutic dosages but the effects mediated by antagonizing these are significantly reduced from those of non-selective agents. β1 and β2 receptors are G s coupled therefore antagonism of their activation reduces activity of adenylyl cyclase and its downstream signalling via cyclic adenosime monophosphate and protein kinase A (PKA). In cardiomyocytes PKA is thought to mediate activation of L-type calcium channels and ryanodine receptors through their phosphorylation. L-type calcium channels can then provide an initial rise in intracellular calcium and trigger the ryanodine receptors to release calcium stored in the sarcoplasmic reticulum (SR) and increased contractility. PKA also plays a role in the cessation of contraction by phosphorylating phospholamban which in turn increases the affinity of SR Ca ATPase to increase reuptake of calcium into the SR. It also phophorylates troponin I to reduce affinity of the protein for calcium. Both of these events lead to a reduction in contraction which, when coupled with the initial increase in contraction, allows for faster cycling and consequently higher heart rate with increased contractility. L-type calcium channels are also a major contributor to cardiac depolarization and their activation can increase frequency of action potentials and possibly the incidence of ectopic potentials. Similar inihibitory events occur in the bronchial smooth muscle to mediate relaxation including phosphorylation of myosin light-chain kinase, reducing its affinity for calcium. PKA also inhibits the excitatory G q coupled pathway by phosphorylating the inositol trisphosphate receptor and phospholipase C resulting in inhibition of intracellular calcium release. Antagonism of this activity by beta-blocker agents like atenolol can thus cause increased bronchoconstriction. •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 50% of an oral dose is absorbed from the gastrointestinal tract, with the remainder being excreted unchanged in the feces. Administering atenolol with food can decrease the AUC by about 20%. While atenolol can cross the blood-brain barrier, it does so slowly and to a small extent. •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 Vd of 63.8-112.5 L. Atenolol distributes into a central volume of 12.8-17.5 L along with two peripheral compartments with a combined volume of 51-95 L. Distribution takes about 3 hrs for the central compartment, 4 hrs for the shallower peripheral compartment, and 5-6 hrs for the deeper peripheral compartment. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 6-16% bound in plasma. Atenolol binds to two sites on human serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Minimal metabolism in the liver. The sole non-conjugated metabolite is the product of a hydroxylation reaction at the carbon between the amide and benzene groups. The only other metabolite to be confirmed is a glucuronide conjugate. These metabolites make up 5-8% and 2% of the renally excreted dose with 87-90% appearing as unchanged drug. The hydroxylated metabolite is exerts 1/10th the beta-blocking activity of atenolol. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 85% is eliminated by the kidneys following IV administration with 10% appearing 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): 6-7 hrs. •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 is estimated at 97.3-176.3 mL/min with a renal clearance of 95-168 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): LD 50 Values Mouse: 2 g/kg (Oral), 57 mg/kg (IV), 134 mg/kg (IP), 400 mg/kg (SC) Rat: 2 g/kg (Oral), 77 mg/kg (IV), 600 mg/kg (SC) Rabbit: 50 mg/kg (IV) Carcinogenicity & Mutagenicity Studies in rats and mice at doses of 300 mg/kg/day, equivalent to 150 times maximum recommended human dose, for durations of 18 and 24 months showed no carcinogenicity. One study in rats at doses of 500-1500 mg/kg/day, 250-750 times maximum human dose, resulted in increases benign adrenal medullary tumors in both sexes and increase mammary fibroadenomas in females. Atenolol showed no mutagenicity in the Ames test using S. typhinarium, dominant lethal test in mice, or in vivo cytogenetics test in chinese hamster ovary cells. Reproductive Toxicity No adverse effects on fertility were observed in either male or female mice after receiving doses of 200 mg/kg/day, equivalent to 200 times the maximum human dose. In humans, atenolol is known to cross the placenta and fetuses exposed to the drug have been reported to be smaller than expected considering gestational age. Embryo-fetal resorption has been observed in rats at doses of 50mg/kg/day, 50 times the max human dose, but not in rabbits at doses of 25mg/kg/day. Lactation Atenolol appears in breast milk at a ratio of 1.5-6.8 to plasma concentrations. It has been estimated that infant exposure occurs at 5.7-19.2% maternal weight-adjusted dosage. Effects in infants include bradycardia, hypothermia, and lethargy. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tenoretic, Tenormin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atenolol Atenololum •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): Atenolol is a synthetic beta-1 selective blocker used in the management of hypertension and chronic angina, and to reduce mortality in known or suspected myocardial infarction in hemodynamically stable patients.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Atenolol interact? Information: •Drug A: Abatacept •Drug B: Atenolol •Severity: MODERATE •Description: The metabolism of Atenolol 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: 1) Management of hypertension alone and in combination with other antihypertensives. 2) Management of angina pectoris associated with coronary atherosclerosis. 3) Management of acute myocardial infarction in hemodynamically stable patients with a heart rate greater than 50 beats per minutes and a systolic blood pressure above 100 mmHg. Off-label uses include: 1) Secondary prevention of myocardial infarction. 2) Management of heart failure. 3) Management of atrial fibrillation. 4) Management of supraventricular tachycardia. 5) Management of ventricular arrythmias such as congenital long-QT and arrhythmogenic right ventricular cardiomyopathy. 6) Management of symptomatic thyrotoxicosis in combination with methimazole. 7) Prophylaxis of migraine headaches. 8) Management of alcohol withdrawal. •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): Atenolol is a cardio-selective beta-blocker and as such exerts most of its effects on the heart. It acts as an antagonist to sympathetic innervation and prevents increases in heart rate, electrical conductivity, and contractility in the heart due to increased release of norepinephrine from the peripheral nervous system. Together the decreases in contractility and rate produce a reduction in cardiac output resulting in a compensatory increase in peripheral vascular resistance in the short-term. This response later declines to baseline with long-term use of atenolol. More importantly, this reduction in the work demanded of the myocardium also reduces oxygen demand which provides therapeutic benefit by reducing the mismatch of oxygen supply and demand in settings where coronary blood flow is limited, such as in coronary atherosclerosis. Reducing oxygen demand, particularly due to exercise, can reduce the frequency of angina pectoris symptoms and potentially improve survival of the remaining myocardium after myocardial infarction. The decrease in rate of sinoatrial node potentials, electrical conduction, slowing of potentials traveling through the atrioventricular node, and reduced frequency of ectopic potentials due to blockade of adrenergic beta receptors has led to benefit in arrhythmic conditions such as atrial fibrillation by controlling the rate of action potential generation and allowing for more effective coordinated contractions. Since a degree of sympathetic activity is necessary to maintain cardiac function, the reduced contractility induced by atenolol may precipitate or worsen heart failure, especially during volume overload. The effects of atenolol on blood pressure have been established, although it is less effective than alternative beta-blockers, but the mechanism has not yet been characterized. As a β1 selective drug, it does not act via the vasodilation produced by non-selective agents. Despite this there is a sustained reduction in peripheral vascular resistance, and consequently blood pressure, alongside a decrease in cardiac output. It is thought that atenolol's antihypertensive activity may be related to action on the central nervous system (CNS) or it's inhibition of the renin-aldosterone-angiotensin system rather than direct effects on the vasculature. Atenolol produces CNS effects similar to other beta-blockers, but does so to a lesser extent due to reduces ability to cross the blood-brain barrier. It has the potential to produce fatigue, depression, and sleep disturbances such as nightmares or insomnia. The exact mechanisms behind these have not been characterized but their occurrence must be considered as they represent clinically relevant adverse effects. Atenolol exerts some effects on the respiratory system although to a much lesser extent than non-selective beta-blockers. Interaction with β2 receptors in the airways can produce bronchoconstriction by blocking the relaxation of bronchial smooth muscle mediated by the sympathetic nervous system. The same action can interfere with β-agonist therapies used in asthma and chronic obstructive pulmonary disease. Unlike some other beta-blocker drugs, atenolol does not have intrinsic sympathomimetic or membrane stabilizing activity nor does it produce changes in glycemic control. •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): Atenolol is a cardioselective beta-blocker, called such because it selectively binds to the β1-adrenergic receptor as an antagonist up to a reported 26 fold more than β2 receptors. Selective activity at the β1 receptor produces cardioselectivity due to the higher population of this receptor in cardiac tissue. Some binding to β2 and possibly β3 receptors can still occur at therapeutic dosages but the effects mediated by antagonizing these are significantly reduced from those of non-selective agents. β1 and β2 receptors are G s coupled therefore antagonism of their activation reduces activity of adenylyl cyclase and its downstream signalling via cyclic adenosime monophosphate and protein kinase A (PKA). In cardiomyocytes PKA is thought to mediate activation of L-type calcium channels and ryanodine receptors through their phosphorylation. L-type calcium channels can then provide an initial rise in intracellular calcium and trigger the ryanodine receptors to release calcium stored in the sarcoplasmic reticulum (SR) and increased contractility. PKA also plays a role in the cessation of contraction by phosphorylating phospholamban which in turn increases the affinity of SR Ca ATPase to increase reuptake of calcium into the SR. It also phophorylates troponin I to reduce affinity of the protein for calcium. Both of these events lead to a reduction in contraction which, when coupled with the initial increase in contraction, allows for faster cycling and consequently higher heart rate with increased contractility. L-type calcium channels are also a major contributor to cardiac depolarization and their activation can increase frequency of action potentials and possibly the incidence of ectopic potentials. Similar inihibitory events occur in the bronchial smooth muscle to mediate relaxation including phosphorylation of myosin light-chain kinase, reducing its affinity for calcium. PKA also inhibits the excitatory G q coupled pathway by phosphorylating the inositol trisphosphate receptor and phospholipase C resulting in inhibition of intracellular calcium release. Antagonism of this activity by beta-blocker agents like atenolol can thus cause increased bronchoconstriction. •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 50% of an oral dose is absorbed from the gastrointestinal tract, with the remainder being excreted unchanged in the feces. Administering atenolol with food can decrease the AUC by about 20%. While atenolol can cross the blood-brain barrier, it does so slowly and to a small extent. •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 Vd of 63.8-112.5 L. Atenolol distributes into a central volume of 12.8-17.5 L along with two peripheral compartments with a combined volume of 51-95 L. Distribution takes about 3 hrs for the central compartment, 4 hrs for the shallower peripheral compartment, and 5-6 hrs for the deeper peripheral compartment. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 6-16% bound in plasma. Atenolol binds to two sites on human serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Minimal metabolism in the liver. The sole non-conjugated metabolite is the product of a hydroxylation reaction at the carbon between the amide and benzene groups. The only other metabolite to be confirmed is a glucuronide conjugate. These metabolites make up 5-8% and 2% of the renally excreted dose with 87-90% appearing as unchanged drug. The hydroxylated metabolite is exerts 1/10th the beta-blocking activity of atenolol. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): 85% is eliminated by the kidneys following IV administration with 10% appearing 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): 6-7 hrs. •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 is estimated at 97.3-176.3 mL/min with a renal clearance of 95-168 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): LD 50 Values Mouse: 2 g/kg (Oral), 57 mg/kg (IV), 134 mg/kg (IP), 400 mg/kg (SC) Rat: 2 g/kg (Oral), 77 mg/kg (IV), 600 mg/kg (SC) Rabbit: 50 mg/kg (IV) Carcinogenicity & Mutagenicity Studies in rats and mice at doses of 300 mg/kg/day, equivalent to 150 times maximum recommended human dose, for durations of 18 and 24 months showed no carcinogenicity. One study in rats at doses of 500-1500 mg/kg/day, 250-750 times maximum human dose, resulted in increases benign adrenal medullary tumors in both sexes and increase mammary fibroadenomas in females. Atenolol showed no mutagenicity in the Ames test using S. typhinarium, dominant lethal test in mice, or in vivo cytogenetics test in chinese hamster ovary cells. Reproductive Toxicity No adverse effects on fertility were observed in either male or female mice after receiving doses of 200 mg/kg/day, equivalent to 200 times the maximum human dose. In humans, atenolol is known to cross the placenta and fetuses exposed to the drug have been reported to be smaller than expected considering gestational age. Embryo-fetal resorption has been observed in rats at doses of 50mg/kg/day, 50 times the max human dose, but not in rabbits at doses of 25mg/kg/day. Lactation Atenolol appears in breast milk at a ratio of 1.5-6.8 to plasma concentrations. It has been estimated that infant exposure occurs at 5.7-19.2% maternal weight-adjusted dosage. Effects in infants include bradycardia, hypothermia, and lethargy. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tenoretic, Tenormin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atenolol Atenololum •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): Atenolol is a synthetic beta-1 selective blocker used in the management of hypertension and chronic angina, and to reduce mortality in known or suspected myocardial infarction in hemodynamically stable patients. 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 Atomoxetine interact?

•Drug A: Abatacept •Drug B: Atomoxetine •Severity: MODERATE •Description: The metabolism of Atomoxetine 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): Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children and 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): Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor used for the treatment of attention deficit hyperactivity disorder (ADHD). Atomoxetine has been shown to specifically increase norepinephrine and dopamine within the prefrontal cortex, which results in improved ADHD symptoms. Due to atomoxetine's noradrenergic activity, it also has effects on the cardiovascular system such as increased blood pressure and tachycardia. Sudden deaths, stroke, and myocardial infarction have been reported in patients taking atomoxetine at usual doses for ADHD. Atomoxetine should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate such as certain patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease. It should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experienced clinically important increases in blood pressure or heart rate. Although the role of atomoxetine in these cases is unknown, consideration should be given to not treating patients with clinically significant cardiac abnormalities. Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt cardiac evaluation. In general, particular care should be taken in treating ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in patients at risk for bipolar disorder. Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered. Atomoxetine capsules increased the risk of suicidal ideation in short-term studies in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). All pediatric patients being treated with atomoxetine should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Postmarketing reports indicate that atomoxetine can cause severe liver injury. Although no evidence of liver injury was detected in clinical trials of about 6000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to atomoxetine use in postmarketing experience. Rare cases of liver failure have also been reported, including a case that resulted in a liver transplant. Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted. Laboratory testing to determine liver enzyme levels should be done upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms). •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): Atomoxetine is known to be a potent and selective inhibitor of the norepinephrine transporter (NET), which prevents cellular reuptake of norepinephrine throughout the brain, which is thought to improve the symptoms of ADHD. More recently, positron emission tomography (PET) imaging studies in rhesus monkeys have shown that atomoxetine also binds to the serotonin transporter (SERT), and blocks the N-methyl-d-aspartate (NMDA) receptor, indicating a role for the glutamatergic system in the pathophysiology of ADHD. •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 pharmacokinetic profile of atomoxetine is highly dependent on cytochrome P450 2D6 genetic polymorphisms of the individual. A large fraction of the population (up to 10% of Caucasians and 2% of people of African descent and 1% of Asians) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of 21.6 hours) of atomoxetine compared with people with normal CYP2D6 activity. Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in extensive metabolizers (EMs) and 94% in poor metabolizers (PMs). Mean maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing with a maximal concentration of 350 ng/ml with an AUC of 2 mcg.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 reported volume of distribution of oral atomoxetine was 1.6-2.6 L/kg. The steady-state volume of distribution of intravenous atomoxetine was approximately 0.85 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At therapeutic concentrations, 98.7% of plasma atomoxetine is bound to protein, with 97.5% of that being bound to albumin, followed by alpha-1-acid glycoprotein and immunoglobulin G. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. People with reduced activity in the CYP2D6 pathway (also known as poor metabolizers or PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (also known as extensive metabolizers, or EMs). For PMs, the AUC of atomoxetine at steady-state is approximately 10-fold higher and Cmax is about 5-fold greater than for EMs. The major oxidative metabolite formed regardless of CYP2D6 status is 4-hydroxy-atomoxetine, which is rapidly glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter, but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs). In individuals that lack CYP2D6 activity, 4-hydroxyatomoxetine is still the primary metabolite, but is formed by several other cytochrome P450 enzymes and at a slower rate. Another minor metabolite, N-Desmethyl-atomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has much less pharmacological activity than atomoxetine and lower plasma concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose). Only a small fraction (less than 3%) of the atomoxetine dose is excreted as unchanged atomoxetine, indicating extensive biotransformation. •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 depends on the CYP2D6 genetic polymorphisms of the individual and can range from 3 to 5.6 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): The clearance rate of atomoxetine depends the CYP2D6 genetic polymorphisms of the individual and can range of 0.27-0.67 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): There is limited clinical trial experience with atomoxetine overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of atomoxetine capsules and at least one other drug. There have been no reports of death involving overdose of atomoxetine capsules alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving atomoxetine, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of atomoxetine capsules were gastrointestinal symptoms, somnolence, dizziness, tremor, and abnormal behavior. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth) have also been observed. Most events were mild to moderate. Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations. If symptoms of overdose are suspected, a Certified Poison Control Center should be consulted for up to date guidance and advice. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Strattera •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atomoxetina Atomoxetine Tomoxetina Tomoxetine Tomoxetinum •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): Atomoxetine is a selective norepinephrine reuptake inhibitor (SNRI) used in the management of Attention Deficit Hyperactivity Disorder (ADHD).

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Atomoxetine interact? Information: •Drug A: Abatacept •Drug B: Atomoxetine •Severity: MODERATE •Description: The metabolism of Atomoxetine 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): Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children and 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): Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor used for the treatment of attention deficit hyperactivity disorder (ADHD). Atomoxetine has been shown to specifically increase norepinephrine and dopamine within the prefrontal cortex, which results in improved ADHD symptoms. Due to atomoxetine's noradrenergic activity, it also has effects on the cardiovascular system such as increased blood pressure and tachycardia. Sudden deaths, stroke, and myocardial infarction have been reported in patients taking atomoxetine at usual doses for ADHD. Atomoxetine should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate such as certain patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease. It should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experienced clinically important increases in blood pressure or heart rate. Although the role of atomoxetine in these cases is unknown, consideration should be given to not treating patients with clinically significant cardiac abnormalities. Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt cardiac evaluation. In general, particular care should be taken in treating ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in patients at risk for bipolar disorder. Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered. Atomoxetine capsules increased the risk of suicidal ideation in short-term studies in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). All pediatric patients being treated with atomoxetine should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Postmarketing reports indicate that atomoxetine can cause severe liver injury. Although no evidence of liver injury was detected in clinical trials of about 6000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to atomoxetine use in postmarketing experience. Rare cases of liver failure have also been reported, including a case that resulted in a liver transplant. Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted. Laboratory testing to determine liver enzyme levels should be done upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms). •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): Atomoxetine is known to be a potent and selective inhibitor of the norepinephrine transporter (NET), which prevents cellular reuptake of norepinephrine throughout the brain, which is thought to improve the symptoms of ADHD. More recently, positron emission tomography (PET) imaging studies in rhesus monkeys have shown that atomoxetine also binds to the serotonin transporter (SERT), and blocks the N-methyl-d-aspartate (NMDA) receptor, indicating a role for the glutamatergic system in the pathophysiology of ADHD. •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 pharmacokinetic profile of atomoxetine is highly dependent on cytochrome P450 2D6 genetic polymorphisms of the individual. A large fraction of the population (up to 10% of Caucasians and 2% of people of African descent and 1% of Asians) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of 21.6 hours) of atomoxetine compared with people with normal CYP2D6 activity. Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in extensive metabolizers (EMs) and 94% in poor metabolizers (PMs). Mean maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing with a maximal concentration of 350 ng/ml with an AUC of 2 mcg.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 reported volume of distribution of oral atomoxetine was 1.6-2.6 L/kg. The steady-state volume of distribution of intravenous atomoxetine was approximately 0.85 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At therapeutic concentrations, 98.7% of plasma atomoxetine is bound to protein, with 97.5% of that being bound to albumin, followed by alpha-1-acid glycoprotein and immunoglobulin G. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. People with reduced activity in the CYP2D6 pathway (also known as poor metabolizers or PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (also known as extensive metabolizers, or EMs). For PMs, the AUC of atomoxetine at steady-state is approximately 10-fold higher and Cmax is about 5-fold greater than for EMs. The major oxidative metabolite formed regardless of CYP2D6 status is 4-hydroxy-atomoxetine, which is rapidly glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter, but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs). In individuals that lack CYP2D6 activity, 4-hydroxyatomoxetine is still the primary metabolite, but is formed by several other cytochrome P450 enzymes and at a slower rate. Another minor metabolite, N-Desmethyl-atomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has much less pharmacological activity than atomoxetine and lower plasma concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose). Only a small fraction (less than 3%) of the atomoxetine dose is excreted as unchanged atomoxetine, indicating extensive biotransformation. •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 depends on the CYP2D6 genetic polymorphisms of the individual and can range from 3 to 5.6 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): The clearance rate of atomoxetine depends the CYP2D6 genetic polymorphisms of the individual and can range of 0.27-0.67 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): There is limited clinical trial experience with atomoxetine overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of atomoxetine capsules and at least one other drug. There have been no reports of death involving overdose of atomoxetine capsules alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving atomoxetine, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of atomoxetine capsules were gastrointestinal symptoms, somnolence, dizziness, tremor, and abnormal behavior. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth) have also been observed. Most events were mild to moderate. Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations. If symptoms of overdose are suspected, a Certified Poison Control Center should be consulted for up to date guidance and advice. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Strattera •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atomoxetina Atomoxetine Tomoxetina Tomoxetine Tomoxetinum •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): Atomoxetine is a selective norepinephrine reuptake inhibitor (SNRI) used in the management of Attention Deficit Hyperactivity Disorder (ADHD). 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 Atorvastatin interact?

•Drug A: Abatacept •Drug B: Atorvastatin •Severity: MODERATE •Description: The metabolism of Atorvastatin 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): Atorvastatin is indicated for the treatment of several types of dyslipidemias, including primary hyperlipidemia and mixed dyslipidemia in adults, hypertriglyceridemia, primary dysbetalipoproteinemia, homozygous familial hypercholesterolemia, and heterozygous familial hypercholesterolemia in adolescent patients with failed dietary modifications. Dyslipidemia describes an elevation of plasma cholesterol, triglycerides or both as well as to the presence of low levels of high-density lipoprotein. This condition represents an increased risk for the development of atherosclerosis. Atorvastatin is indicated, in combination with dietary modifications, to prevent cardiovascular events in patients with cardiac risk factors and/or abnormal lipid profiles. Atorvastatin can be used as a preventive agent for myocardial infarction, stroke, revascularization, and angina, in patients without coronary heart disease but with multiple risk factors and in patients with type 2 diabetes without coronary heart disease but multiple risk factors. Atorvastatin may be used as a preventive agent for non-fatal myocardial infarction, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure and angina in patients with coronary heart disease. Prescribing of statin medications is considered standard practice following any cardiovascular events and for people with a moderate to high risk of development of CVD. Statin-indicated conditions include diabetes mellitus, clinical atherosclerosis (including myocardial infarction, acute coronary syndromes, stable angina, documented coronary artery disease, stroke, trans ischemic attack (TIA), documented carotid disease, peripheral artery disease, and claudication), abdominal aortic aneurysm, chronic kidney disease, and severely elevated LDL-C levels. •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): Atorvastatin is an oral antilipemic agent that reversibly inhibits HMG-CoA reductase. It lowers total cholesterol, low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apo B), non-high density lipoprotein-cholesterol (non-HDL-C), and triglyceride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease, and high ratios are associated with a higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, atorvastatin reduces the risk of cardiovascular morbidity and mortality. Elevated cholesterol levels (and high low-density lipoprotein (LDL) levels in particular) are an important risk factor for the development of CVD. Clinical studies have shown that atorvastatin reduces LDL-C and total cholesterol by 36-53%. In patients with dysbetalipoproteinemia, atorvastatin reduced the levels of intermediate-density lipoprotein cholesterol. It has also been suggested that atorvastatin can limit the extent of angiogenesis, which can be useful in the treatment of chronic subdural hematoma. Myopathy/Rhabdomyolysis Atorvastatin, like other HMG-CoA reductase inhibitors, is associated with a risk of drug-induced myopathy characterized by muscle pain, tenderness, or weakness in conjunction with elevated levels of creatine kinase (CK). Myopathy often manifests as rhabdomyolysis with or without acute renal failure secondary to myoglobinuria. The risk of statin-induced myopathy is dose-related, and the symptoms of myopathy are typically resolved upon drug discontinuation. Results from observational studies suggest that 10-15% of people taking statins may experience muscle aches at some point during treatment. Liver Dysfunction Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (> 3 times the upper limit of normal [ULN] occurring on two or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. This effect appears to be dose-related. Endocrine Effects Statins are associated with a risk of increased serum HbA1c and glucose levels. An in vitro study demonstrated a dose-dependent cytotoxic effect on human pancreatic islet β cells following treatment with atorvastatin. Moreover, insulin secretion rates decreased relative to control. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and may theoretically interfere with the production of adrenal and/or gonadal steroids. Clinical studies with atorvastatin and other HMG-CoA reductase inhibitors have suggested that these agents do not affect plasma cortisol concentrations, basal plasma testosterone concentration, or adrenal reserve. However, the effect of statins on male fertility has not been fully investigated. The effects of statins on the pituitary-gonadal axis in premenopausal women are unknown. Cardiovascular Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure. Lipoprotein A In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by the concomitant increase in Lp(a) lipoprotein concentrations. Present knowledge suggests the importance of high Lp(a) levels as an emerging risk factor for coronary heart disease. Further studies have demonstrated statins affect Lp(a) levels differently in patients with dyslipidemia depending on their apo(a) phenotype; statins increase Lp(a) levels exclusively in patients with the low molecular weight apo(a) phenotype. •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): Atorvastatin is a statin medication and a competitive inhibitor of the enzyme HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Atorvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low-density lipoprotein (LDL) receptors, which increases hepatic uptake of LDL. Atorvastatin also reduces Very-Low-Density Lipoprotein-Cholesterol (VLDL-C), serum triglycerides (TG) and Intermediate Density Lipoproteins (IDL), as well as the number of apolipoprotein B (apo B) containing particles, but increases High-Density Lipoprotein Cholesterol (HDL-C). In vitro and in vivo animal studies also demonstrate that atorvastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. These effects include improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response. Statins were also found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an essential role in leukocyte trafficking and T cell activation. •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): Atorvastatin presents a dose-dependent and non-linear pharmacokinetic profile. It is very rapidly absorbed after oral administration. After the administration of a dose of 40 mg, its peak plasma concentration of 28 ng/ml is reached 1-2 hours after initial administration with an AUC of about 200 ng∙h/ml. Atorvastatin undergoes extensive first-pass metabolism in the wall of the gut and the liver, resulting in an absolute oral bioavailability of 14%. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration. Administration of atorvastatin with food results in prolonged Tmax and a reduction in Cmax and AUC. Breast Cancer Resistance Protein (BCRP) is a membrane-bound protein that plays an important role in the absorption of atorvastatin. Evidence from pharmacogenetic studies of c.421C>A single nucleotide polymorphisms (SNPs) in the gene for BCRP has demonstrated that individuals with the 421AA genotype have reduced functional activity and 1.72-fold higher AUC for atorvastatin compared to study individuals with the control 421CC genotype. This has important implications for the variation in response to the drug in terms of efficacy and toxicity, particularly as the BCRP c.421C>A polymorphism occurs more frequently in Asian populations than in Caucasians. Other statin drugs impacted by this polymorphism include fluvastatin, simvastatin, and rosuvastatin. Genetic differences in the OATP1B1 (organic-anion-transporting polypeptide 1B1) hepatic transporter encoded by the SCLCO1B1 gene (Solute Carrier Organic Anion Transporter family member 1B1) have been shown to impact atorvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C single nucleotide polymorphism (SNP) in the gene encoding OATP1B1 (SLCO1B1) demonstrated that atorvastatin AUC was increased 2.45-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals. Other statin drugs impacted by this polymorphism include simvastatin, pitavastatin, rosuvastatin, and pravastatin. •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 reported volume of distribution of atorvastatin is of 380 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Atorvastatin is highly bound to plasma proteins and over 98% of the administered dose is found in a bound form. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Atorvastatin is highly metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products, primarily by Cytochrome P450 3A4 in the intestine and liver. Atorvastatin's metabolites undergo further lactonization via the formation of acyl glucuronide intermediates by the enzymes UGT1A1 and UGT1A3. These lactones can be hydrolyzed back to their corresponding acid forms and exist in equilibirum. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Atorvastatin and its metabolites are mainly eliminated in the bile without enterohepatic recirculation. The renal elimination of atorvastatin is very minimal and represents less than 1% of the eliminated 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 half-life of atorvastatin is 14 hours while the half-life of its metabolites can reach up to 30 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 registered total plasma clearance of atorvastatin is of 625 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 reported LD50 of oral atorvastatin in mice is higher than 5000 mg/kg. In cases of overdose with atorvastatin, there is reported symptoms of complicated breathing, jaundice, liver damage, dark urine, muscle pain, and seizures. In case of overdose, symptomatic treatment is recommended and due to the high plasma protein binding, hemodialysis is not expected to generate significant improvement. In carcinogenic studies with high doses of atorvastatin, evidence of rhabdomyosarcoma, fibrosarcoma, liver adenoma, and liver carcinoma were observed. In fertility studies with high doses of atorvastatin, there were events of aplasia, aspermia, low testis and epididymal weight, decreased sperm motility, decreased spermatid head concentration and increased abnormal sperm. Atorvastatin was shown to not be mutagenic in diverse mutagenic assays. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Atorvaliq, Caduet, Lipitor, Lypqozet •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): Atorvastatin is an HMG-CoA reductase inhibitor used to lower lipid levels and reduce the risk of cardiovascular disease including myocardial infarction and stroke.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Atorvastatin interact? Information: •Drug A: Abatacept •Drug B: Atorvastatin •Severity: MODERATE •Description: The metabolism of Atorvastatin 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): Atorvastatin is indicated for the treatment of several types of dyslipidemias, including primary hyperlipidemia and mixed dyslipidemia in adults, hypertriglyceridemia, primary dysbetalipoproteinemia, homozygous familial hypercholesterolemia, and heterozygous familial hypercholesterolemia in adolescent patients with failed dietary modifications. Dyslipidemia describes an elevation of plasma cholesterol, triglycerides or both as well as to the presence of low levels of high-density lipoprotein. This condition represents an increased risk for the development of atherosclerosis. Atorvastatin is indicated, in combination with dietary modifications, to prevent cardiovascular events in patients with cardiac risk factors and/or abnormal lipid profiles. Atorvastatin can be used as a preventive agent for myocardial infarction, stroke, revascularization, and angina, in patients without coronary heart disease but with multiple risk factors and in patients with type 2 diabetes without coronary heart disease but multiple risk factors. Atorvastatin may be used as a preventive agent for non-fatal myocardial infarction, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure and angina in patients with coronary heart disease. Prescribing of statin medications is considered standard practice following any cardiovascular events and for people with a moderate to high risk of development of CVD. Statin-indicated conditions include diabetes mellitus, clinical atherosclerosis (including myocardial infarction, acute coronary syndromes, stable angina, documented coronary artery disease, stroke, trans ischemic attack (TIA), documented carotid disease, peripheral artery disease, and claudication), abdominal aortic aneurysm, chronic kidney disease, and severely elevated LDL-C levels. •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): Atorvastatin is an oral antilipemic agent that reversibly inhibits HMG-CoA reductase. It lowers total cholesterol, low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apo B), non-high density lipoprotein-cholesterol (non-HDL-C), and triglyceride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease, and high ratios are associated with a higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, atorvastatin reduces the risk of cardiovascular morbidity and mortality. Elevated cholesterol levels (and high low-density lipoprotein (LDL) levels in particular) are an important risk factor for the development of CVD. Clinical studies have shown that atorvastatin reduces LDL-C and total cholesterol by 36-53%. In patients with dysbetalipoproteinemia, atorvastatin reduced the levels of intermediate-density lipoprotein cholesterol. It has also been suggested that atorvastatin can limit the extent of angiogenesis, which can be useful in the treatment of chronic subdural hematoma. Myopathy/Rhabdomyolysis Atorvastatin, like other HMG-CoA reductase inhibitors, is associated with a risk of drug-induced myopathy characterized by muscle pain, tenderness, or weakness in conjunction with elevated levels of creatine kinase (CK). Myopathy often manifests as rhabdomyolysis with or without acute renal failure secondary to myoglobinuria. The risk of statin-induced myopathy is dose-related, and the symptoms of myopathy are typically resolved upon drug discontinuation. Results from observational studies suggest that 10-15% of people taking statins may experience muscle aches at some point during treatment. Liver Dysfunction Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (> 3 times the upper limit of normal [ULN] occurring on two or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. This effect appears to be dose-related. Endocrine Effects Statins are associated with a risk of increased serum HbA1c and glucose levels. An in vitro study demonstrated a dose-dependent cytotoxic effect on human pancreatic islet β cells following treatment with atorvastatin. Moreover, insulin secretion rates decreased relative to control. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and may theoretically interfere with the production of adrenal and/or gonadal steroids. Clinical studies with atorvastatin and other HMG-CoA reductase inhibitors have suggested that these agents do not affect plasma cortisol concentrations, basal plasma testosterone concentration, or adrenal reserve. However, the effect of statins on male fertility has not been fully investigated. The effects of statins on the pituitary-gonadal axis in premenopausal women are unknown. Cardiovascular Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure. Lipoprotein A In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by the concomitant increase in Lp(a) lipoprotein concentrations. Present knowledge suggests the importance of high Lp(a) levels as an emerging risk factor for coronary heart disease. Further studies have demonstrated statins affect Lp(a) levels differently in patients with dyslipidemia depending on their apo(a) phenotype; statins increase Lp(a) levels exclusively in patients with the low molecular weight apo(a) phenotype. •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): Atorvastatin is a statin medication and a competitive inhibitor of the enzyme HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Atorvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low-density lipoprotein (LDL) receptors, which increases hepatic uptake of LDL. Atorvastatin also reduces Very-Low-Density Lipoprotein-Cholesterol (VLDL-C), serum triglycerides (TG) and Intermediate Density Lipoproteins (IDL), as well as the number of apolipoprotein B (apo B) containing particles, but increases High-Density Lipoprotein Cholesterol (HDL-C). In vitro and in vivo animal studies also demonstrate that atorvastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. These effects include improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response. Statins were also found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an essential role in leukocyte trafficking and T cell activation. •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): Atorvastatin presents a dose-dependent and non-linear pharmacokinetic profile. It is very rapidly absorbed after oral administration. After the administration of a dose of 40 mg, its peak plasma concentration of 28 ng/ml is reached 1-2 hours after initial administration with an AUC of about 200 ng∙h/ml. Atorvastatin undergoes extensive first-pass metabolism in the wall of the gut and the liver, resulting in an absolute oral bioavailability of 14%. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration. Administration of atorvastatin with food results in prolonged Tmax and a reduction in Cmax and AUC. Breast Cancer Resistance Protein (BCRP) is a membrane-bound protein that plays an important role in the absorption of atorvastatin. Evidence from pharmacogenetic studies of c.421C>A single nucleotide polymorphisms (SNPs) in the gene for BCRP has demonstrated that individuals with the 421AA genotype have reduced functional activity and 1.72-fold higher AUC for atorvastatin compared to study individuals with the control 421CC genotype. This has important implications for the variation in response to the drug in terms of efficacy and toxicity, particularly as the BCRP c.421C>A polymorphism occurs more frequently in Asian populations than in Caucasians. Other statin drugs impacted by this polymorphism include fluvastatin, simvastatin, and rosuvastatin. Genetic differences in the OATP1B1 (organic-anion-transporting polypeptide 1B1) hepatic transporter encoded by the SCLCO1B1 gene (Solute Carrier Organic Anion Transporter family member 1B1) have been shown to impact atorvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C single nucleotide polymorphism (SNP) in the gene encoding OATP1B1 (SLCO1B1) demonstrated that atorvastatin AUC was increased 2.45-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals. Other statin drugs impacted by this polymorphism include simvastatin, pitavastatin, rosuvastatin, and pravastatin. •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 reported volume of distribution of atorvastatin is of 380 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Atorvastatin is highly bound to plasma proteins and over 98% of the administered dose is found in a bound form. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Atorvastatin is highly metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products, primarily by Cytochrome P450 3A4 in the intestine and liver. Atorvastatin's metabolites undergo further lactonization via the formation of acyl glucuronide intermediates by the enzymes UGT1A1 and UGT1A3. These lactones can be hydrolyzed back to their corresponding acid forms and exist in equilibirum. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Atorvastatin and its metabolites are mainly eliminated in the bile without enterohepatic recirculation. The renal elimination of atorvastatin is very minimal and represents less than 1% of the eliminated 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 half-life of atorvastatin is 14 hours while the half-life of its metabolites can reach up to 30 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 registered total plasma clearance of atorvastatin is of 625 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 reported LD50 of oral atorvastatin in mice is higher than 5000 mg/kg. In cases of overdose with atorvastatin, there is reported symptoms of complicated breathing, jaundice, liver damage, dark urine, muscle pain, and seizures. In case of overdose, symptomatic treatment is recommended and due to the high plasma protein binding, hemodialysis is not expected to generate significant improvement. In carcinogenic studies with high doses of atorvastatin, evidence of rhabdomyosarcoma, fibrosarcoma, liver adenoma, and liver carcinoma were observed. In fertility studies with high doses of atorvastatin, there were events of aplasia, aspermia, low testis and epididymal weight, decreased sperm motility, decreased spermatid head concentration and increased abnormal sperm. Atorvastatin was shown to not be mutagenic in diverse mutagenic assays. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Atorvaliq, Caduet, Lipitor, Lypqozet •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): Atorvastatin is an HMG-CoA reductase inhibitor used to lower lipid levels and reduce the risk of cardiovascular disease including myocardial infarction and stroke. 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 Avacopan interact?

•Drug A: Abatacept •Drug B: Avacopan •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Avacopan. •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): Avacopan is indicated for the adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis; GPA/MPA) in combination with standard therapy including glucocorticoids. Avacopan does not eliminate the need for glucocorticoids. In Europe, avacopan is approved for the treatment of adults with severe, active granulomatosis polyangiitis (GPA) or microscopic polyangiitis (MPA) in combination with rituximab or cyclophosphamide. •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): Avacopan is a complement 5a receptor (C5aR) antagonist that blocks C5a-induced upregulation of C11b (integrin alpha M) on neutrophils and inhibits C5a-mediated neutrophil activation and migration. Avacopan has been associated with hypersensitivity reactions, including angioedema, and hepatotoxicity, as evidenced by elevated liver transaminases. Likely due to its effect on the complement pathway, avacopan has also been associated with hepatitis B virus reactivation and serious infections, which should be monitored for as appropriate. •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): Anti-neutrophil cytoplasmic (auto)antibody (ANCA)-associated vasculitis (AAV) is considered a "pauci-immune" form of systemic small-vessel vasculitis accompanied by the presence of ANCAs in the serum. The full spectrum of AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and drug-induced AAV. AAV may be associated with necrotizing and crescentic glomerulonephritis (NCGN). Of the various known ANCAs, the major antigens are myeloperoxidase (MPO) and proteinase 3 (PR3/myeloblastin). The pathophysiology giving rise to AAV is complex, though a working model has been proposed. An initial trigger, such as infection, causes differentiation of naive T cells into T H 17 helper T cells that induce the release from macrophages of pro-inflammatory cytokines (e.g., TNF-α and IL-1β), which prime neutrophils. Concurrently, the anaphylatoxin C5a is produced through activation of the alternative complement pathway, which also primes neutrophils through binding to the C5a receptor (C5aR; CD88). Primed neutrophils undergo physiological changes, including upregulating the display of ANCA antigens on their surface. Circulating ANCAs bind to displayed ANCA antigens on the surface of neutrophils; simultaneously, the Fc region of these ANCAs is recognized by Fcγ receptors on other neutrophils, resulting in excessive neutrophil activation. Activated neutrophils form NETs (neutrophil extracellular traps), which induce tissue damage and vasculitis. MPO/PR3 in NETs induces further ANCA production through dendritic cell- and CD4 T cell-mediated activation of B cells, further exacerbating the condition. A role for complement was not initially considered in AAV due to a lack of excessive complement or immunoglobulin deposition in AAV lesions. However, extensive molecular studies confirmed a significant role for the alternative complement pathway, acting through C3 and C5, in the pathogenesis of AAV. The C5a fragment, generated by C5 cleavage, can bind to both the C5aR and C5a-like receptor (C5L2) on the surface of neutrophils; C5aR binding is associated with AAV while C5L2 binding has a protective effect. As the alternative complement pathway is self-sustaining in the absence of down-regulation by specific proteins, it is likely a significant driver of AAV. Furthermore, neutrophils activated by C5a release reactive oxygen species, properdin, and other molecules that stimulate the complement pathway leading to the production of more C5a in a vicious cycle. Avacopan (CCX168) is a specific C5aR receptor allosteric antagonist that inhibits C5a-mediated neutrophil activation both in vitro and in vivo. By inhibiting the C5a/C5aR axis, avacopan should have minimal effects on the formation of the membrane attack complex (which includes C5b) and therefore little effect on the innate immune response in treated patients. •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 AAV patients receiving 30 mg avacopan twice daily, avacopan had a C max of 349 ± 169 ng/mL and an AUC 0-12hr of 3466 ± 1921 ng*h/mL. On this dosing scheme, steady-state plasma concentrations are reached by 13 weeks with a roughly 4-fold accumulation. Co-administration of 30 mg with a high-fat meal increased the C max by ~8%, the AUC by ~72%, and delayed the T max by four hours (from two 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): Avacopan has an apparent volume of distribution of 345 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Avacopan and its M1 metabolite are more than 99.9% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Avacopan is metabolized primarily by CYP3A4. The major circulating M1 metabolite, a mono-hydroxylated form of avacopan, represents ~12% of drug plasma levels and acts as a C5aR antagonist with similar efficacy to avacopan itself. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Avacopan is mainly eliminated in feces, with smaller amounts present in the urine. Following oral administration of the radiolabeled drug, roughly 77% (7% as unchanged avacopan) was recovered in feces while 10% (<0.1% unchanged) was recovered 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): A single 30 mg dose of avacopan given with food to healthy subjects resulted in mean elimination half-lives of 97.6 and 55.6 hours for avacopan and its M1 metabolite, 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): Avacopan has an estimated total apparent body clearance (CL/F) of 16.3 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): Animal studies have not revealed any mutagenic potential of avacopan and no impairment of fertility at doses up to 1000 mg/kg/day. Avacopan is not mutagenic based on the Ames test. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tavneos •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): Avacopan is an orally bioavailable complement 5a receptor (C5aR) antagonist for the treatment of severe anti-neutrophil cytoplasmic (auto)antibody (ANCA)-associated vasculitis.

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 Avacopan interact? Information: •Drug A: Abatacept •Drug B: Avacopan •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Avacopan. •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): Avacopan is indicated for the adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis; GPA/MPA) in combination with standard therapy including glucocorticoids. Avacopan does not eliminate the need for glucocorticoids. In Europe, avacopan is approved for the treatment of adults with severe, active granulomatosis polyangiitis (GPA) or microscopic polyangiitis (MPA) in combination with rituximab or cyclophosphamide. •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): Avacopan is a complement 5a receptor (C5aR) antagonist that blocks C5a-induced upregulation of C11b (integrin alpha M) on neutrophils and inhibits C5a-mediated neutrophil activation and migration. Avacopan has been associated with hypersensitivity reactions, including angioedema, and hepatotoxicity, as evidenced by elevated liver transaminases. Likely due to its effect on the complement pathway, avacopan has also been associated with hepatitis B virus reactivation and serious infections, which should be monitored for as appropriate. •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): Anti-neutrophil cytoplasmic (auto)antibody (ANCA)-associated vasculitis (AAV) is considered a "pauci-immune" form of systemic small-vessel vasculitis accompanied by the presence of ANCAs in the serum. The full spectrum of AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and drug-induced AAV. AAV may be associated with necrotizing and crescentic glomerulonephritis (NCGN). Of the various known ANCAs, the major antigens are myeloperoxidase (MPO) and proteinase 3 (PR3/myeloblastin). The pathophysiology giving rise to AAV is complex, though a working model has been proposed. An initial trigger, such as infection, causes differentiation of naive T cells into T H 17 helper T cells that induce the release from macrophages of pro-inflammatory cytokines (e.g., TNF-α and IL-1β), which prime neutrophils. Concurrently, the anaphylatoxin C5a is produced through activation of the alternative complement pathway, which also primes neutrophils through binding to the C5a receptor (C5aR; CD88). Primed neutrophils undergo physiological changes, including upregulating the display of ANCA antigens on their surface. Circulating ANCAs bind to displayed ANCA antigens on the surface of neutrophils; simultaneously, the Fc region of these ANCAs is recognized by Fcγ receptors on other neutrophils, resulting in excessive neutrophil activation. Activated neutrophils form NETs (neutrophil extracellular traps), which induce tissue damage and vasculitis. MPO/PR3 in NETs induces further ANCA production through dendritic cell- and CD4 T cell-mediated activation of B cells, further exacerbating the condition. A role for complement was not initially considered in AAV due to a lack of excessive complement or immunoglobulin deposition in AAV lesions. However, extensive molecular studies confirmed a significant role for the alternative complement pathway, acting through C3 and C5, in the pathogenesis of AAV. The C5a fragment, generated by C5 cleavage, can bind to both the C5aR and C5a-like receptor (C5L2) on the surface of neutrophils; C5aR binding is associated with AAV while C5L2 binding has a protective effect. As the alternative complement pathway is self-sustaining in the absence of down-regulation by specific proteins, it is likely a significant driver of AAV. Furthermore, neutrophils activated by C5a release reactive oxygen species, properdin, and other molecules that stimulate the complement pathway leading to the production of more C5a in a vicious cycle. Avacopan (CCX168) is a specific C5aR receptor allosteric antagonist that inhibits C5a-mediated neutrophil activation both in vitro and in vivo. By inhibiting the C5a/C5aR axis, avacopan should have minimal effects on the formation of the membrane attack complex (which includes C5b) and therefore little effect on the innate immune response in treated patients. •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 AAV patients receiving 30 mg avacopan twice daily, avacopan had a C max of 349 ± 169 ng/mL and an AUC 0-12hr of 3466 ± 1921 ng*h/mL. On this dosing scheme, steady-state plasma concentrations are reached by 13 weeks with a roughly 4-fold accumulation. Co-administration of 30 mg with a high-fat meal increased the C max by ~8%, the AUC by ~72%, and delayed the T max by four hours (from two 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): Avacopan has an apparent volume of distribution of 345 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Avacopan and its M1 metabolite are more than 99.9% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Avacopan is metabolized primarily by CYP3A4. The major circulating M1 metabolite, a mono-hydroxylated form of avacopan, represents ~12% of drug plasma levels and acts as a C5aR antagonist with similar efficacy to avacopan itself. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Avacopan is mainly eliminated in feces, with smaller amounts present in the urine. Following oral administration of the radiolabeled drug, roughly 77% (7% as unchanged avacopan) was recovered in feces while 10% (<0.1% unchanged) was recovered 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): A single 30 mg dose of avacopan given with food to healthy subjects resulted in mean elimination half-lives of 97.6 and 55.6 hours for avacopan and its M1 metabolite, 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): Avacopan has an estimated total apparent body clearance (CL/F) of 16.3 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): Animal studies have not revealed any mutagenic potential of avacopan and no impairment of fertility at doses up to 1000 mg/kg/day. Avacopan is not mutagenic based on the Ames test. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Tavneos •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): Avacopan is an orally bioavailable complement 5a receptor (C5aR) antagonist for the treatment of severe anti-neutrophil cytoplasmic (auto)antibody (ANCA)-associated vasculitis. 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 Avanafil interact?

•Drug A: Abatacept •Drug B: Avanafil •Severity: MODERATE •Description: The metabolism of Avanafil 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): Avanafil is indicated for the treatment of erectile dysfunction. •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): Avanafil is a strong competitive inhibitor of phosphodiesterase 5 (PDE5) with a demonstrated in vitro IC 50 of 5.2 nM. Its inhibitory effects on PDE5 are 100-fold more potent than on PDE6 and >1000-fold more potent than on other PDE enzymes, meaning it is less likely to cause visual disturbances and cardiovascular adverse effects when compared with less selective PDE5 inhibitors such as sildenafil and vardenafil. It has a relatively quick onset of action allowing for administration as early as 15 minutes prior to sexual activity. PDE5 inhibitors like avanafil can cause significant drug interactions when administered alongside certain antihypertensive agents (e.g. alpha blockers, substantial amounts of alcohol). PDE5 inhibitors have also been associated with the development of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition that typically presents as sudden loss of vision in one or both eyes and appears to be more common in patients with a "crowded" optic disc. Patients presenting with any degree of vision loss should immediately discontinue use of all PDE5 inhibitors and seek medical attention. In some jurisdictions, a history of NAION or other degenerative retinal disorders is considered a contraindication to avanafil 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): Avanafil inhibits the cGMP-specific phosphodiesterase type 5 (PDE5) which is responsible for the degradation of cGMP in the corpus cavernosum located around the penis. Sexual arousal results in the local release of nitric oxide, which in turn stimulates the enzyme guanylate cyclase to produce cGMP. Elevated levels of cGMP result in local smooth muscle relaxation and increased blood flow to the penis (i.e. an erection). As PDE5 inhibitors like avanafil require the endogenous release of nitric oxide in order to exert their pharmacologic effect, they have no effect on the user in the absence of sexual stimulation/arousal. •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): Avanafil is rapidly absorbed following oral administration (T max of 30-45 minutes) and appears to have low to moderate oral bioavailability, though formal studies have not been conducted. Administration with a meal results in a mean delay in T max of 1.12 to 1.25 hours, a 39% mean reduction in C max, and a negligible effect on AUC. •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 avanafil is 47 to 83 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Avanafil and its two major metabolites, M4 and M16, are highly protein-bound in plasma at approximately 99%, 97%, and 81%, respectively. Binding occurs primarily to albumin (99%), with smaller contributions from γ-globulin (43%) and α1-acid glycoprotein (66%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Avanafil is extensively metabolized, primarily by CYP3A4 and to a lesser extent by CYP2C9. There are two major metabolites formed, M4 and M16, which exist in the plasma at concentrations 23% and 29% that of the parent compound, respectively. The M16 metabolite lacks pharmacologic effect, but the M4 metabolite has an inhibitory potency for PDE5 18% that of avanafil and accounts for approximately 4% of the observed pharmacologic activity of avanafil. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration, avanafil is extensively metabolized. Approximately 62% of a given dose is excreted as metabolites in the feces and approximately 21% as metabolites 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): Studies have demonstrated variability in the terminal elimination half-life of avanafil, with estimates ranging between 5 - 17 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): Experience with avanafil overdose is limited. Single doses of up to 800mg and repeat doses of up to 300mg have been administered - these patients experienced adverse effects similar to those seen at therapeutic doses but with increased incidence and severity. Patients experiencing an overdosage of avanafil should be treated with standard symptomatic and supportive measures. Dialysis is unlikely to be of benefit in cases of overdose as avanafil is highly protein-bound in plasma. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Spedra, Stendra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Avanafil Avanafilo •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): Avanafil is a phosphodiesterase-5 (PDE5) inhibitor used to treat erectile dysfunction.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Avanafil interact? Information: •Drug A: Abatacept •Drug B: Avanafil •Severity: MODERATE •Description: The metabolism of Avanafil 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): Avanafil is indicated for the treatment of erectile dysfunction. •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): Avanafil is a strong competitive inhibitor of phosphodiesterase 5 (PDE5) with a demonstrated in vitro IC 50 of 5.2 nM. Its inhibitory effects on PDE5 are 100-fold more potent than on PDE6 and >1000-fold more potent than on other PDE enzymes, meaning it is less likely to cause visual disturbances and cardiovascular adverse effects when compared with less selective PDE5 inhibitors such as sildenafil and vardenafil. It has a relatively quick onset of action allowing for administration as early as 15 minutes prior to sexual activity. PDE5 inhibitors like avanafil can cause significant drug interactions when administered alongside certain antihypertensive agents (e.g. alpha blockers, substantial amounts of alcohol). PDE5 inhibitors have also been associated with the development of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition that typically presents as sudden loss of vision in one or both eyes and appears to be more common in patients with a "crowded" optic disc. Patients presenting with any degree of vision loss should immediately discontinue use of all PDE5 inhibitors and seek medical attention. In some jurisdictions, a history of NAION or other degenerative retinal disorders is considered a contraindication to avanafil 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): Avanafil inhibits the cGMP-specific phosphodiesterase type 5 (PDE5) which is responsible for the degradation of cGMP in the corpus cavernosum located around the penis. Sexual arousal results in the local release of nitric oxide, which in turn stimulates the enzyme guanylate cyclase to produce cGMP. Elevated levels of cGMP result in local smooth muscle relaxation and increased blood flow to the penis (i.e. an erection). As PDE5 inhibitors like avanafil require the endogenous release of nitric oxide in order to exert their pharmacologic effect, they have no effect on the user in the absence of sexual stimulation/arousal. •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): Avanafil is rapidly absorbed following oral administration (T max of 30-45 minutes) and appears to have low to moderate oral bioavailability, though formal studies have not been conducted. Administration with a meal results in a mean delay in T max of 1.12 to 1.25 hours, a 39% mean reduction in C max, and a negligible effect on AUC. •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 avanafil is 47 to 83 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Avanafil and its two major metabolites, M4 and M16, are highly protein-bound in plasma at approximately 99%, 97%, and 81%, respectively. Binding occurs primarily to albumin (99%), with smaller contributions from γ-globulin (43%) and α1-acid glycoprotein (66%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Avanafil is extensively metabolized, primarily by CYP3A4 and to a lesser extent by CYP2C9. There are two major metabolites formed, M4 and M16, which exist in the plasma at concentrations 23% and 29% that of the parent compound, respectively. The M16 metabolite lacks pharmacologic effect, but the M4 metabolite has an inhibitory potency for PDE5 18% that of avanafil and accounts for approximately 4% of the observed pharmacologic activity of avanafil. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following oral administration, avanafil is extensively metabolized. Approximately 62% of a given dose is excreted as metabolites in the feces and approximately 21% as metabolites 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): Studies have demonstrated variability in the terminal elimination half-life of avanafil, with estimates ranging between 5 - 17 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): Experience with avanafil overdose is limited. Single doses of up to 800mg and repeat doses of up to 300mg have been administered - these patients experienced adverse effects similar to those seen at therapeutic doses but with increased incidence and severity. Patients experiencing an overdosage of avanafil should be treated with standard symptomatic and supportive measures. Dialysis is unlikely to be of benefit in cases of overdose as avanafil is highly protein-bound in plasma. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Spedra, Stendra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Avanafil Avanafilo •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): Avanafil is a phosphodiesterase-5 (PDE5) inhibitor used to treat erectile dysfunction. 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 Avapritinib interact?

•Drug A: Abatacept •Drug B: Avapritinib •Severity: MODERATE •Description: The metabolism of Avapritinib 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): Avapritinib is indicated for the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. It is also used to treat adult patients with advanced systemic mastocytosis (AdvSM). AdvSM includes patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia. However, it is not recommended for the treatment of patients with AdvSM with platelet counts of less than 50 X 10 L. •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): Avapritinib is a selective kinase inhibitor that negatively modulates the action of cell transporters to resensitize them to other chemotherapies. It has a long duration of action as it is given once daily. Patients should be counselled regarding the risk of intracranial hemorrhage, CNS effects, 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): Avapritinib has a negative modulating effect on the transporters ABCB1 and ABCG2, which mediate the multidrug resistance phenotype of some cancers. This modulation may be due to interactions of avapritinib with the drug binding pocket of these transporters. Negative modulation of these transporters, resensitizes cancerous cells to treatment with chemotherapeutic agents like paclitaxel. •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): A 300mg oral dose of avapritinib reaches a C max of 813ng/mL with a T max of 2.0-4.1h and an AUC of 15400h*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 mean apparent volume of distribution is 1200L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Avapritinib is 98.8% protein bound in serum. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Avapritinib is metabolized mainly by CYP3A4 and CYP2C9 in vitro. A 310mg oral dose is recovered as 49% unchanged drug, 35% hydroxy glucuronide metabolite, and 14% oxidatively deaminated metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Avapritinib is 70% eliminated in the feces with 11% as the unchanged drug and 18% eliminated in the urine with 0.23% 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 half life of avapritinib is 32-57h. •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 apparent oral clearance of avapritinib is 19.5L/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 overdoses of avapritinib are not readily available. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ayvakit •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): Avapritinib is a selective tyrosine kinase inhibitor being investigated for the treatment of multidrug resistant gastrointestinal 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 CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Avapritinib interact? Information: •Drug A: Abatacept •Drug B: Avapritinib •Severity: MODERATE •Description: The metabolism of Avapritinib 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): Avapritinib is indicated for the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. It is also used to treat adult patients with advanced systemic mastocytosis (AdvSM). AdvSM includes patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia. However, it is not recommended for the treatment of patients with AdvSM with platelet counts of less than 50 X 10 L. •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): Avapritinib is a selective kinase inhibitor that negatively modulates the action of cell transporters to resensitize them to other chemotherapies. It has a long duration of action as it is given once daily. Patients should be counselled regarding the risk of intracranial hemorrhage, CNS effects, 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): Avapritinib has a negative modulating effect on the transporters ABCB1 and ABCG2, which mediate the multidrug resistance phenotype of some cancers. This modulation may be due to interactions of avapritinib with the drug binding pocket of these transporters. Negative modulation of these transporters, resensitizes cancerous cells to treatment with chemotherapeutic agents like paclitaxel. •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): A 300mg oral dose of avapritinib reaches a C max of 813ng/mL with a T max of 2.0-4.1h and an AUC of 15400h*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 mean apparent volume of distribution is 1200L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Avapritinib is 98.8% protein bound in serum. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Avapritinib is metabolized mainly by CYP3A4 and CYP2C9 in vitro. A 310mg oral dose is recovered as 49% unchanged drug, 35% hydroxy glucuronide metabolite, and 14% oxidatively deaminated metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Avapritinib is 70% eliminated in the feces with 11% as the unchanged drug and 18% eliminated in the urine with 0.23% 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 half life of avapritinib is 32-57h. •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 apparent oral clearance of avapritinib is 19.5L/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 overdoses of avapritinib are not readily available. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ayvakit •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): Avapritinib is a selective tyrosine kinase inhibitor being investigated for the treatment of multidrug resistant gastrointestinal 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 CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Avatrombopag interact?

•Drug A: Abatacept •Drug B: Avatrombopag •Severity: MODERATE •Description: The metabolism of Avatrombopag 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 for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. It is also indicated in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment. •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 a study of efficacy, avatrombopag resulted in dose and exposure-dependent elevations in platelet counts in adults. The onset of the platelet count increase was noted within 3 to 5 days of the start of a 5-day treatment course, with the highest level of effect measured after 10 to 13 days. Following this, platelet counts decreased gradually, returning to near baseline values at the 35-day point. Increased platelet activation leads to increased blood clotting, which may lead to various complications. Avatrombopag does not lead to increased platelet activation. •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): Avatrombopag is an orally bioavailable, small molecule thrombopoietin (TPO) receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells resulting in an increased production of platelets. Avatrombopag is not competitive with thrombopoietin for binding to the TPO receptor and has an additive pharmacological effect with TPO on platelet production. Avatrombopag is a thrombopoietin receptor (TPOR; MPL) agonist, with possible megakaryopoiesis stimulating activity. After administration, avatrombopag binds to and stimulates the platelet thrombopoeitin receptor (TPOR), which can lead to the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. This process increases the production of platelets and may serve to prevent chemotherapy-induced thrombocytopenia (CIT). TPOR is classified as a cytokine receptor and as a member of the hematopoietin receptor superfamily. •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 single dosing under fasted and fed conditions, mean peak concentrations occurred at 5-8 hours and declined with a half-life of 16-18 hours in Japanese and white subjects. Administration with food did not have an effect on the rate or extent of avatrombopag absorption, however, significantly reduced pharmacokinetic variability relative to the fasting state. Avatrombopag showed dose-proportional pharmacokinetics after single doses from 10 mg (0.25-times the lowest approved dosage) to 80 mg (1.3-times the highest recommended dosage). Healthy subjects administered 40 mg of avatrombopag showed a geometric mean (%CV) maximal concentration (Cmax) of 166 (84%) ng/mL and area under the time-concentration curve, extrapolated to infinity (AUC0-inf) of 4198 (83%) ng.hr/mL. The pharmacokinetics of avatrombopag are similar in both healthy subjects and the chronic liver disease population. •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): Avatrombopag has an estimated mean volume of distribution (%CV) of 180 L (25%). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Avatrombopag is greater than 96% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Avatrombopag is primarily metabolized by CYP2C9 and CYP3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Fecal excretion accounted for 88% of the administered dose, with 34% of the dose excreted as unchanged avatrombopag. Only 6% of the administered dose was found 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): The mean plasma elimination half-life (%CV) of avatrombopag is approximately 19 hours (19%). •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 (%CV) of the clearance of avatrombopag is estimated to be 6.9 L/hr (29%). •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 reported in at least 3% of patients were pyrexia, abdominal pain, nausea, headache, fatigue, and peripheral edema. Hyponatremia was also a rare serious adverse effect of this drug, seen in only 2 patients in the treatment group. Adverse reactions resulting in discontinuation of this drug have been anemia, pyrexia, and myalgia. Atrombopag is a thrombopoietin (TPO) receptor agonist, and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease. Portal venous thrombosis occurrence has been reported in patients with chronic liver disease who are treated with TPO receptor agonists. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Doptelet 60 Mg Daily Dose Carton •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): Avatrombopag is a thrombopoietin receptor agonist used pre-operatively to treat thrombocytopenia in patients with chronic liver disease and in patients with chronic refractory thrombocytopenia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Avatrombopag interact? Information: •Drug A: Abatacept •Drug B: Avatrombopag •Severity: MODERATE •Description: The metabolism of Avatrombopag 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 for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. It is also indicated in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment. •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 a study of efficacy, avatrombopag resulted in dose and exposure-dependent elevations in platelet counts in adults. The onset of the platelet count increase was noted within 3 to 5 days of the start of a 5-day treatment course, with the highest level of effect measured after 10 to 13 days. Following this, platelet counts decreased gradually, returning to near baseline values at the 35-day point. Increased platelet activation leads to increased blood clotting, which may lead to various complications. Avatrombopag does not lead to increased platelet activation. •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): Avatrombopag is an orally bioavailable, small molecule thrombopoietin (TPO) receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells resulting in an increased production of platelets. Avatrombopag is not competitive with thrombopoietin for binding to the TPO receptor and has an additive pharmacological effect with TPO on platelet production. Avatrombopag is a thrombopoietin receptor (TPOR; MPL) agonist, with possible megakaryopoiesis stimulating activity. After administration, avatrombopag binds to and stimulates the platelet thrombopoeitin receptor (TPOR), which can lead to the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. This process increases the production of platelets and may serve to prevent chemotherapy-induced thrombocytopenia (CIT). TPOR is classified as a cytokine receptor and as a member of the hematopoietin receptor superfamily. •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 single dosing under fasted and fed conditions, mean peak concentrations occurred at 5-8 hours and declined with a half-life of 16-18 hours in Japanese and white subjects. Administration with food did not have an effect on the rate or extent of avatrombopag absorption, however, significantly reduced pharmacokinetic variability relative to the fasting state. Avatrombopag showed dose-proportional pharmacokinetics after single doses from 10 mg (0.25-times the lowest approved dosage) to 80 mg (1.3-times the highest recommended dosage). Healthy subjects administered 40 mg of avatrombopag showed a geometric mean (%CV) maximal concentration (Cmax) of 166 (84%) ng/mL and area under the time-concentration curve, extrapolated to infinity (AUC0-inf) of 4198 (83%) ng.hr/mL. The pharmacokinetics of avatrombopag are similar in both healthy subjects and the chronic liver disease population. •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): Avatrombopag has an estimated mean volume of distribution (%CV) of 180 L (25%). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Avatrombopag is greater than 96% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Avatrombopag is primarily metabolized by CYP2C9 and CYP3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Fecal excretion accounted for 88% of the administered dose, with 34% of the dose excreted as unchanged avatrombopag. Only 6% of the administered dose was found 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): The mean plasma elimination half-life (%CV) of avatrombopag is approximately 19 hours (19%). •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 (%CV) of the clearance of avatrombopag is estimated to be 6.9 L/hr (29%). •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 reported in at least 3% of patients were pyrexia, abdominal pain, nausea, headache, fatigue, and peripheral edema. Hyponatremia was also a rare serious adverse effect of this drug, seen in only 2 patients in the treatment group. Adverse reactions resulting in discontinuation of this drug have been anemia, pyrexia, and myalgia. Atrombopag is a thrombopoietin (TPO) receptor agonist, and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease. Portal venous thrombosis occurrence has been reported in patients with chronic liver disease who are treated with TPO receptor agonists. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Doptelet 60 Mg Daily Dose Carton •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): Avatrombopag is a thrombopoietin receptor agonist used pre-operatively to treat thrombocytopenia in patients with chronic liver disease and in patients with chronic refractory thrombocytopenia. 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 Axitinib interact?

•Drug A: Abatacept •Drug B: Axitinib •Severity: MAJOR •Description: The metabolism of Axitinib 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): Used in kidney cell cancer and investigated for use/treatment in pancreatic and thyroid 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): Axitinib prevents the progression of cancer by inhibiting angiogenesis and blocking tumor growth. •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): Axitinib selectively blocks the tyrosine kinase receptors VEGFR-1 (vascular endothelial growth factor receptor), VEGFR-2, and VEGFR-3. •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 one 5 mg dose of axitinib, it takes about 2.5 to 4.1 hours to reach maximum plasma concentration. •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 160 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding for axitinib is high at over 99% with most protein binding to albumin followed by α1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Axitinib undergoes mainly hepatic metabolism. CYP3A4 and CYP3A5 are the main hepatic enzymes while CYP1A2, CYP2C19, and UGT1A1 enzymes are secondary. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Axitinib is mainly eliminated unchanged in the feces (41%) with 12% of the original dose as unchanged axitinib. There is also 23% eliminated in the urine, most of which are 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): Axitinib has a half life of 2.5 to 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): The average clearance of axitinib is 38 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): Some of the more serious toxic effects seen in patients taking axitinib include, but are not limited to, hypertension, thrombotic events, hemorrhage, and GI perforation. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Inlyta •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): Axitinib is an oral VEGFR and kinase inhibitor used for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Axitinib interact? Information: •Drug A: Abatacept •Drug B: Axitinib •Severity: MAJOR •Description: The metabolism of Axitinib 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): Used in kidney cell cancer and investigated for use/treatment in pancreatic and thyroid 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): Axitinib prevents the progression of cancer by inhibiting angiogenesis and blocking tumor growth. •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): Axitinib selectively blocks the tyrosine kinase receptors VEGFR-1 (vascular endothelial growth factor receptor), VEGFR-2, and VEGFR-3. •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 one 5 mg dose of axitinib, it takes about 2.5 to 4.1 hours to reach maximum plasma concentration. •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 160 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding for axitinib is high at over 99% with most protein binding to albumin followed by α1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Axitinib undergoes mainly hepatic metabolism. CYP3A4 and CYP3A5 are the main hepatic enzymes while CYP1A2, CYP2C19, and UGT1A1 enzymes are secondary. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Axitinib is mainly eliminated unchanged in the feces (41%) with 12% of the original dose as unchanged axitinib. There is also 23% eliminated in the urine, most of which are 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): Axitinib has a half life of 2.5 to 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): The average clearance of axitinib is 38 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): Some of the more serious toxic effects seen in patients taking axitinib include, but are not limited to, hypertension, thrombotic events, hemorrhage, and GI perforation. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Inlyta •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): Axitinib is an oral VEGFR and kinase inhibitor used for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy. 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 Azacitidine interact?

•Drug A: Abatacept •Drug B: Azacitidine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Azacitidine 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): Azacitidine (for subcutaneous or intravenous use) is indicated for the treatment of adult patients with the following French-American-British (FAB) myelodysplastic syndrome (MDS) subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). Azacitidine is also indicated for the treatment of pediatric patients aged 1 month and older with newly diagnosed Juvenile Myelomonocytic Leukemia (JMML). Azacitidine (for oral use) is indicated for continued treatment of adult patients with acute myeloid leukemia (AML) who achieved first complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative 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): The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis, and hypomethylation may restore normal function to genes critical for differentiation and proliferation. Genome-wide DNA methylation levels in bone marrow granulocytes were reduced in patients with juvenile myelomonocytic leukemia after the first treatment cycle of azacitidine (75 mg/m or 2.5 mg/kg), confirming the DNA-hypomethylating activity of azacitidine. The use of azacitidine causes anemia, neutropenia and thrombocytopenia in adult patients with myelodysplastic syndrome and pediatric patients with juvenile myelomonocytic leukemia. Azacitidine may cause renal toxicity, tumor lysis syndrome and embryo-fetal toxicity. It may also lead to the development of hepatotoxicity in patients with severe pre-existing hepatic impairment. •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): Azacitidine (5-azacytidine) is a chemical analogue of the cytosine nucleoside present in DNA and RNA. It induces antineoplastic activity by inhibiting DNA methyltransferase at low doses and inducing cytotoxicity by incorporating itself into RNA and DNA at high doses. Covalent binding to DNA methyltransferase results in DNA hypomethylation and prevents DNA synthesis. On the other hand, the incorporation of azacitidine into RNA and DNA leads to cytotoxicity as follows: Following cellular uptake, azacitidine is phosphorylated by uridine-cytidine kinase to form 5-azacytidine monophosphate. Afterwards, pyrimidine monophosphate and diphosphate kinases phosphorylate 5-azacytidine monophosphate to form 5-azacytidine diphosphate and triphosphate, respectively. Azacitidine triphosphate is able to incorporate into RNA, disrupting RNA metabolism and protein synthesis. The reduction of azacytidine diphosphate leads to the formation of 5-aza-deoxycytidine diphosphate, which is then phosphorylated to form 5-azadeoxycitidine triphosphate, a compound able to incorporate into DNA and inhibit DNA synthesis. As a ribonucleoside, azacitidine incorporates into RNA to a larger extent than into DNA. Incorporating into RNA leads to the disassembly of polyribosomes, defective methylation and acceptor function of transfer RNA, and the inhibition of protein production, resulting in cell death. During the S-phase of the cell cycle, azacitidine exhibits the highest toxicity; however, the predominant mechanism of cytotoxicity has not been elucidated. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine. It is believed that azacitidine exerts its antineoplastic effects through direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. •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): Azacitidine is rapidly absorbed after subcutaneous administration. In adult patients with myelodysplastic syndrome given a single subcutaneous dose of 75 mg/m of azacitidine, the C max and T max were 750 ng/ml and 0.5 hours, respectively. Based on the area under the curve, the bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%. In 21 patients with cancer given subcutaneous azacitidine, the AUC and C max were approximately dose-proportional between 25 and 100 mg/m. Multiple subcutaneous or intravenous doses of azacitidine are not expected to result in drug accumulation. •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 given an intravenous dose of azacitidine, the volume of distribution is 76 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Not available. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): An in vitro study of azacitidine incubation in human liver fractions indicated that cytochrome P450 (CYP) enzymes do not participate in the metabolism of azacitidine. Azacitidine is metabolized through spontaneous hydrolysis and deamination mediated by cytidine deaminase. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Azacitidine and its metabolites are mainly excreted through urine. In five cancer patients given radioactive azacitidine intravenously, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for less than 1% of administered radioactivity over three days. Following the subcutaneous administration of 14C-azacitidine, the mean excretion of radioactivity in urine was 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): The mean half-life of azacitidine after subcutaneous administration is 41 minutes. The mean elimination half-life of azacitidine and its metabolites was about 4 hours for intravenous and subcutaneous administrations. •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): Azacitidine has an apparent subcutaneous clearance of 167 L/hour in adults. In pediatric patients, the geometric mean clearance was 21.8 L/hour. •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): One case of overdose with azacitidine was reported during clinical trials. After receiving a single dose of 290 mg/m of azacitidine intravenously (almost 4 times the recommended starting dose), a patient experienced diarrhea, nausea, and vomiting. These adverse events resolved without sequelae, and the correct dose was resumed the following day. In case of overdose, patients should be monitored with appropriate blood counts and receive supportive treatment as necessary. There is no known specific antidote for azacitidine overdosage. In mice, the oral LD 50 of azacitidine is 572 mg/kg, while the intravenous LD 50 is approximately 117 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Onureg, Vidaza •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azacitidina Azacitidine Azacitidinum Azacytidine •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): Azacitidine is a pyrimidine nucleoside analogue used to treat certain subtypes of 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 Azacitidine interact? Information: •Drug A: Abatacept •Drug B: Azacitidine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Azacitidine 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): Azacitidine (for subcutaneous or intravenous use) is indicated for the treatment of adult patients with the following French-American-British (FAB) myelodysplastic syndrome (MDS) subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). Azacitidine is also indicated for the treatment of pediatric patients aged 1 month and older with newly diagnosed Juvenile Myelomonocytic Leukemia (JMML). Azacitidine (for oral use) is indicated for continued treatment of adult patients with acute myeloid leukemia (AML) who achieved first complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative 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): The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis, and hypomethylation may restore normal function to genes critical for differentiation and proliferation. Genome-wide DNA methylation levels in bone marrow granulocytes were reduced in patients with juvenile myelomonocytic leukemia after the first treatment cycle of azacitidine (75 mg/m or 2.5 mg/kg), confirming the DNA-hypomethylating activity of azacitidine. The use of azacitidine causes anemia, neutropenia and thrombocytopenia in adult patients with myelodysplastic syndrome and pediatric patients with juvenile myelomonocytic leukemia. Azacitidine may cause renal toxicity, tumor lysis syndrome and embryo-fetal toxicity. It may also lead to the development of hepatotoxicity in patients with severe pre-existing hepatic impairment. •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): Azacitidine (5-azacytidine) is a chemical analogue of the cytosine nucleoside present in DNA and RNA. It induces antineoplastic activity by inhibiting DNA methyltransferase at low doses and inducing cytotoxicity by incorporating itself into RNA and DNA at high doses. Covalent binding to DNA methyltransferase results in DNA hypomethylation and prevents DNA synthesis. On the other hand, the incorporation of azacitidine into RNA and DNA leads to cytotoxicity as follows: Following cellular uptake, azacitidine is phosphorylated by uridine-cytidine kinase to form 5-azacytidine monophosphate. Afterwards, pyrimidine monophosphate and diphosphate kinases phosphorylate 5-azacytidine monophosphate to form 5-azacytidine diphosphate and triphosphate, respectively. Azacitidine triphosphate is able to incorporate into RNA, disrupting RNA metabolism and protein synthesis. The reduction of azacytidine diphosphate leads to the formation of 5-aza-deoxycytidine diphosphate, which is then phosphorylated to form 5-azadeoxycitidine triphosphate, a compound able to incorporate into DNA and inhibit DNA synthesis. As a ribonucleoside, azacitidine incorporates into RNA to a larger extent than into DNA. Incorporating into RNA leads to the disassembly of polyribosomes, defective methylation and acceptor function of transfer RNA, and the inhibition of protein production, resulting in cell death. During the S-phase of the cell cycle, azacitidine exhibits the highest toxicity; however, the predominant mechanism of cytotoxicity has not been elucidated. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine. It is believed that azacitidine exerts its antineoplastic effects through direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. •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): Azacitidine is rapidly absorbed after subcutaneous administration. In adult patients with myelodysplastic syndrome given a single subcutaneous dose of 75 mg/m of azacitidine, the C max and T max were 750 ng/ml and 0.5 hours, respectively. Based on the area under the curve, the bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%. In 21 patients with cancer given subcutaneous azacitidine, the AUC and C max were approximately dose-proportional between 25 and 100 mg/m. Multiple subcutaneous or intravenous doses of azacitidine are not expected to result in drug accumulation. •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 given an intravenous dose of azacitidine, the volume of distribution is 76 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Not available. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): An in vitro study of azacitidine incubation in human liver fractions indicated that cytochrome P450 (CYP) enzymes do not participate in the metabolism of azacitidine. Azacitidine is metabolized through spontaneous hydrolysis and deamination mediated by cytidine deaminase. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Azacitidine and its metabolites are mainly excreted through urine. In five cancer patients given radioactive azacitidine intravenously, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for less than 1% of administered radioactivity over three days. Following the subcutaneous administration of 14C-azacitidine, the mean excretion of radioactivity in urine was 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): The mean half-life of azacitidine after subcutaneous administration is 41 minutes. The mean elimination half-life of azacitidine and its metabolites was about 4 hours for intravenous and subcutaneous administrations. •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): Azacitidine has an apparent subcutaneous clearance of 167 L/hour in adults. In pediatric patients, the geometric mean clearance was 21.8 L/hour. •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): One case of overdose with azacitidine was reported during clinical trials. After receiving a single dose of 290 mg/m of azacitidine intravenously (almost 4 times the recommended starting dose), a patient experienced diarrhea, nausea, and vomiting. These adverse events resolved without sequelae, and the correct dose was resumed the following day. In case of overdose, patients should be monitored with appropriate blood counts and receive supportive treatment as necessary. There is no known specific antidote for azacitidine overdosage. In mice, the oral LD 50 of azacitidine is 572 mg/kg, while the intravenous LD 50 is approximately 117 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Onureg, Vidaza •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azacitidina Azacitidine Azacitidinum Azacytidine •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): Azacitidine is a pyrimidine nucleoside analogue used to treat certain subtypes of 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 Azathioprine interact?

•Drug A: Abatacept •Drug B: Azathioprine •Severity: MODERATE •Description: The metabolism of Azathioprine 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): Azathioprine is indicated to treat rheumatoid arthritis and prevent renal transplant rejection. •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): Azathioprine is an immunosuppressive agent which functions through modulation of rac1 to induce T cell apoptosis, as well as other unknown immunosuppressive functions. It has a long duration of action as it is given daily, and has a narrow therapeutic index. Patients should be counselled regarding the risk of malignancies of the skin and lymphomas. •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): Azathioprine's mechanism of action is not entirely understood but it may be related to inhibition of purine synthesis, along with inhibition of B and T cells. 6-thioguanine triphosphate, a metabolite of azathioprine, modulates activation of rac1 when costimulated with CD28, inducing T cell apoptosis. This may be mediated through rac1's action on mitogen-activated protein kinase, NF-kappaB. •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 azathioprine is well absorbed, with a T max of 1-2h. Further data regarding the absorption of azathioprine is not readily 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): Data regarding the volume of distribution of azathioprine is not readily available. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Azathioprine is 30% bound to proteins such as human serum albumin in circulation. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Azathioprine is converted to 6-mercaptopurine nonenzymatically. 6-mercaptopurine is then metabolized to 6-methylmercaptopurine by thiopurine methyltransferase, 6-thiouric acid by xanthine oxidase, or 6-thiosine-5'-monophosphate by hypoxanthine phosphoribosyltransferase. 6-thiosine-5'-monophosphate is metabolized to 6-methylthiosine-5'-monophosphate by thiopurine methyltransferase or 6-thioxanthylic acid by inosine monophosphate dehydrogenase. 6-thioxanthylic acid is metabolized by guanosine monophosphate synthetase to 6-thioguanine monophosphate, the first of the 6-thioguanine nucleotides. 6-thioguanine monophosphate is phosphorylated to produce the remaining 6-thioguanine nucleotides, 6-thioguanine diphosphate and 6-thioguanine triphosphate. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Azathioprine and mercaptopurine are not detectable in urine after 8 hours. Further data regarding the route of elimination of azathioprine are not 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 half life of azathioprine is approximately 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): Data regarding the clearance of azathioprine is not readily 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 mice is 2500mg/kg and in rats is 400mg/kg. Patients experiencing an overdose may present with bone marrow hypoplasia, bleeding, and infection, which may progress to death. Patients should be treated with supportive and symptomatic treatments. 8 hour hemodialysis may remove 45% of a dose from serum. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Azasan, Imuran •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azamun Azathioprine Azathioprinum Azatioprina •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): Azathioprine is an immunosuppressant used to prevent renal transplant rejection, treat rheumatoid arthritis, Crohn's disease, 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 CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Azathioprine interact? Information: •Drug A: Abatacept •Drug B: Azathioprine •Severity: MODERATE •Description: The metabolism of Azathioprine 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): Azathioprine is indicated to treat rheumatoid arthritis and prevent renal transplant rejection. •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): Azathioprine is an immunosuppressive agent which functions through modulation of rac1 to induce T cell apoptosis, as well as other unknown immunosuppressive functions. It has a long duration of action as it is given daily, and has a narrow therapeutic index. Patients should be counselled regarding the risk of malignancies of the skin and lymphomas. •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): Azathioprine's mechanism of action is not entirely understood but it may be related to inhibition of purine synthesis, along with inhibition of B and T cells. 6-thioguanine triphosphate, a metabolite of azathioprine, modulates activation of rac1 when costimulated with CD28, inducing T cell apoptosis. This may be mediated through rac1's action on mitogen-activated protein kinase, NF-kappaB. •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 azathioprine is well absorbed, with a T max of 1-2h. Further data regarding the absorption of azathioprine is not readily 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): Data regarding the volume of distribution of azathioprine is not readily available. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Azathioprine is 30% bound to proteins such as human serum albumin in circulation. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Azathioprine is converted to 6-mercaptopurine nonenzymatically. 6-mercaptopurine is then metabolized to 6-methylmercaptopurine by thiopurine methyltransferase, 6-thiouric acid by xanthine oxidase, or 6-thiosine-5'-monophosphate by hypoxanthine phosphoribosyltransferase. 6-thiosine-5'-monophosphate is metabolized to 6-methylthiosine-5'-monophosphate by thiopurine methyltransferase or 6-thioxanthylic acid by inosine monophosphate dehydrogenase. 6-thioxanthylic acid is metabolized by guanosine monophosphate synthetase to 6-thioguanine monophosphate, the first of the 6-thioguanine nucleotides. 6-thioguanine monophosphate is phosphorylated to produce the remaining 6-thioguanine nucleotides, 6-thioguanine diphosphate and 6-thioguanine triphosphate. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Azathioprine and mercaptopurine are not detectable in urine after 8 hours. Further data regarding the route of elimination of azathioprine are not 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 half life of azathioprine is approximately 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): Data regarding the clearance of azathioprine is not readily 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 mice is 2500mg/kg and in rats is 400mg/kg. Patients experiencing an overdose may present with bone marrow hypoplasia, bleeding, and infection, which may progress to death. Patients should be treated with supportive and symptomatic treatments. 8 hour hemodialysis may remove 45% of a dose from serum. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Azasan, Imuran •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azamun Azathioprine Azathioprinum Azatioprina •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): Azathioprine is an immunosuppressant used to prevent renal transplant rejection, treat rheumatoid arthritis, Crohn's disease, 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 CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Azelastine interact?

•Drug A: Abatacept •Drug B: Azelastine •Severity: MODERATE •Description: The metabolism of Azelastine 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): Intranasal azelastine is indicated for the symptomatic treatment of seasonal allergic rhinitis in patients 5 years and older and for the symptomatic treatment of vasomotor rhinitis in patients 12 years and older. Ophthalmic azelastine solution is indicated for the treatment of itchy eyes associated with allergic conjunctivitis. As a 0.15% nasal spray, azelastine hydrochloride is also indicated for over-the-counter treatment of allergies in patients aged six years 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): Azelastine antagonizes the actions of histamine, resulting in the relief of histamine-mediated allergy symptoms. Onset of action occurs within 15 minutes with intranasal formulations and as quickly as 3 minutes with ophthalmic solutions. Intranasal formulations have a relatively long-duration of action, with peak effects observed 4-6 hours after the initial dose and efficacy maintained over the entirety of the standard 12 hour dosing 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): Azelastine is primarily a selective antagonist of histamine H1-receptors, with a lesser affinity for H2-receptors, used for the symptomatic treatment of allergies. Histamine H1-receptors are G-protein-coupled receptors with 7 transmembrane spanning domains that are found on nerve endings, smooth muscle cells, and glandular cells. Following allergen exposure in sensitized individuals, IgE-receptor cross-linking on mast cells results in the release of histamine, which binds to H1-receptors and contributes to typical allergic symptoms such as itching, sneezing, and congestion. Though its primary mode of action is thought to be via H1-receptor antagonism, azelastine (like other second-generation antihistamines) appears to affect other mediators of allergic symptomatology. Azelastine has mast cell-stabilizing properties that prevent the release of interleukin-6, tryptase, histamine, and TNF-alpha from mast cells, and has been shown to reduce mediators of mast cell degranulation such as leukotrienes in the nasal lavage of patients with rhinitis, as well as inhibiting their production and release from eosinophils (potentially via inhibition of phospholipase A 2 and leukotriene C 4 synthase). Additionally, patients using oral azelastine were observed to have significantly reduced concentrations of substance P and bradykinin in nasal secretions, both of which may play a role in nasal itching and sneezing in patients with allergic rhinitis. •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): Systemic bioavailability of azelastine hydrochloride following intranasal administration is approximately 40%, reaching Cmax within 2-3 hours. When administered at doses greater than the recommended maximum, greater than proportional increases in both Cmax and AUC were observed. •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 intravenous and oral administration, the steady-state volume of distribution is 14.5 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In-vitro studies in human plasma indicate that the plasma protein binding of azelastine and desmethylazelastine are approximately 88% and 97%, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Azelastine hydrochloride is oxidatively metabolized to its main, and biologically active, metabolite desmethylazelastine by the cytochrome P450 enzyme system. Though labels for azelastine state that specific CYP enzyme involvement has not been elucidated, it has been suggested that the N-demethylation of azelastine is primarily catalyzed by CYP3A4, CYP2D6, and CYP1A2. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After an oral dose of radio-labeled azelastine hydrochloride, approximately 75% was excreted in the feces, with less than 10% as unchanged azelastine hydrochloride. •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 intravenous and oral administration, azelastine demonstrated an elimination half-life of 22 hours. Its primary active metabolite, desmethylazelastine, has an elimination half-life of 54 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): Based on intravenous and oral administration, azelastine demonstrated a plasma clearance of 0.5 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): Overdosage of intranasal or ophthalmic azelastine is unlikely to result in clinically significant adverse effects aside from increased drowsiness. If overdose does occur, employ general supportive measures. Oral ingestion of antihistamines, including non-oral formulations of azelastine, can cause serious adverse effects in children - for this reason, these products should be kept out of the reach of children. The oral LD 50 in rats is 580 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Astelin, Astepro, Astepro Allergy, Dymista •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azelastina Azelastine Azélastine Azelastinum •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): Azelastine is a histamine H1-receptor antagonist used intranasally to treat allergic and vasomotor rhinitis and in an ophthalmic solution to treat allergic conjunctivitis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Azelastine interact? Information: •Drug A: Abatacept •Drug B: Azelastine •Severity: MODERATE •Description: The metabolism of Azelastine 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): Intranasal azelastine is indicated for the symptomatic treatment of seasonal allergic rhinitis in patients 5 years and older and for the symptomatic treatment of vasomotor rhinitis in patients 12 years and older. Ophthalmic azelastine solution is indicated for the treatment of itchy eyes associated with allergic conjunctivitis. As a 0.15% nasal spray, azelastine hydrochloride is also indicated for over-the-counter treatment of allergies in patients aged six years 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): Azelastine antagonizes the actions of histamine, resulting in the relief of histamine-mediated allergy symptoms. Onset of action occurs within 15 minutes with intranasal formulations and as quickly as 3 minutes with ophthalmic solutions. Intranasal formulations have a relatively long-duration of action, with peak effects observed 4-6 hours after the initial dose and efficacy maintained over the entirety of the standard 12 hour dosing 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): Azelastine is primarily a selective antagonist of histamine H1-receptors, with a lesser affinity for H2-receptors, used for the symptomatic treatment of allergies. Histamine H1-receptors are G-protein-coupled receptors with 7 transmembrane spanning domains that are found on nerve endings, smooth muscle cells, and glandular cells. Following allergen exposure in sensitized individuals, IgE-receptor cross-linking on mast cells results in the release of histamine, which binds to H1-receptors and contributes to typical allergic symptoms such as itching, sneezing, and congestion. Though its primary mode of action is thought to be via H1-receptor antagonism, azelastine (like other second-generation antihistamines) appears to affect other mediators of allergic symptomatology. Azelastine has mast cell-stabilizing properties that prevent the release of interleukin-6, tryptase, histamine, and TNF-alpha from mast cells, and has been shown to reduce mediators of mast cell degranulation such as leukotrienes in the nasal lavage of patients with rhinitis, as well as inhibiting their production and release from eosinophils (potentially via inhibition of phospholipase A 2 and leukotriene C 4 synthase). Additionally, patients using oral azelastine were observed to have significantly reduced concentrations of substance P and bradykinin in nasal secretions, both of which may play a role in nasal itching and sneezing in patients with allergic rhinitis. •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): Systemic bioavailability of azelastine hydrochloride following intranasal administration is approximately 40%, reaching Cmax within 2-3 hours. When administered at doses greater than the recommended maximum, greater than proportional increases in both Cmax and AUC were observed. •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 intravenous and oral administration, the steady-state volume of distribution is 14.5 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In-vitro studies in human plasma indicate that the plasma protein binding of azelastine and desmethylazelastine are approximately 88% and 97%, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Azelastine hydrochloride is oxidatively metabolized to its main, and biologically active, metabolite desmethylazelastine by the cytochrome P450 enzyme system. Though labels for azelastine state that specific CYP enzyme involvement has not been elucidated, it has been suggested that the N-demethylation of azelastine is primarily catalyzed by CYP3A4, CYP2D6, and CYP1A2. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After an oral dose of radio-labeled azelastine hydrochloride, approximately 75% was excreted in the feces, with less than 10% as unchanged azelastine hydrochloride. •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 intravenous and oral administration, azelastine demonstrated an elimination half-life of 22 hours. Its primary active metabolite, desmethylazelastine, has an elimination half-life of 54 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): Based on intravenous and oral administration, azelastine demonstrated a plasma clearance of 0.5 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): Overdosage of intranasal or ophthalmic azelastine is unlikely to result in clinically significant adverse effects aside from increased drowsiness. If overdose does occur, employ general supportive measures. Oral ingestion of antihistamines, including non-oral formulations of azelastine, can cause serious adverse effects in children - for this reason, these products should be kept out of the reach of children. The oral LD 50 in rats is 580 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Astelin, Astepro, Astepro Allergy, Dymista •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azelastina Azelastine Azélastine Azelastinum •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): Azelastine is a histamine H1-receptor antagonist used intranasally to treat allergic and vasomotor rhinitis and in an ophthalmic solution to treat allergic conjunctivitis. 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 Azithromycin interact?

•Drug A: Abatacept •Drug B: Azithromycin •Severity: MODERATE •Description: The metabolism of Azithromycin 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): Azithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria in order to prevent the development antimicrobial resistance and maintain the efficacy of azithromycin. Azithromycin is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the microorganisms listed in the specific conditions below. Recommended dosages, duration of therapy and considerations for various patient populations may vary among these infections. Refer to the FDA label and "Indications" section of this drug entry for detailed information. Adults: Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy. Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae. Abscesses usually require surgical drainage. Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae. Genital ulcer disease in men due to Haemophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established. Pediatric Patients Acute otitis media caused by Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy. Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line 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): Macrolides stop bacterial growth by inhibiting protein synthesis and translation, treating bacterial infections. Azithromycin has additional immunomodulatory effects and has been used in chronic respiratory inflammatory diseases for this purpose. •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): In order to replicate, bacteria require a specific process of protein synthesis, enabled by ribosomal proteins. Azithromycin binds to the 23S rRNA of the bacterial 50S ribosomal subunit. It stops bacterial protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit,. This results in the control of various bacterial infections,. The strong affinity of macrolides, including azithromycin, for bacterial ribosomes, is consistent with their broad‐spectrum antibacterial activities. Azithromycin is highly stable at a low pH, giving it a longer serum half-life and increasing its concentrations in tissues compared to erythromycin. •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): Bioavailability of azithromycin is 37% following oral administration. Absorption is not affected by food. Macrolide absorption in the intestines is believed to be mediated by P-glycoprotein (ABCB1) efflux transporters, which are known to be encoded by the ABCB1 gene. •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, azithromycin is widely distributed in tissues with an apparent steady-state volume of distribution of 31.1 L/kg. Significantly greater azithromycin concentrations have been measured in the tissues rather than in plasma or serum,. The lung, tonsils and prostate are organs have shown a particularly high rate of azithromycin uptake. This drug is concentrated within macrophages and polymorphonucleocytes, allowing for effective activity against Chlamydia trachomatis. In addition, azithromycin is found to be concentrated in phagocytes and fibroblasts, shown by in vitro incubation techniques. In vivo studies demonstrate that concentration in phagocytes may contribute to azithromycin distribution to inflamed tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The serum protein binding of azithromycin varies in humans, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed, however, this drug is eliminated by the liver,. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Biliary excretion of azithromycin, primarily as unchanged drug, is a major route of elimination. Over a 1 week period, approximately 6% of the administered dose is found as unchanged drug 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): Terminal elimination half-life: 68 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): Mean apparent plasma cl=630 mL/min (following single 500 mg oral and i.v. 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): Rat Oral LD50: >2000 mk/kg Possible major adverse effects include cardiovascular arrhythmias and hearing loss. Macrolide resistance is also an ongoing issue. Hepatotoxicity has been observed in rare cases. A note on the risk of liver toxicity: Due to the act that azithromycin is mainly eliminated by the liver, caution should be observed when azithromycin is given to patients with decreased hepatic function. A note on potential renal toxicity: Because limited data in patients with renal GFR <10 mL/min, caution should be exercised when prescribing azithromycin to these patients. Use in Pregnancy: This drug is categorized as a pregnancy category B drug. Reproduction studies have been done in rats and mice at doses up to moderately maternally toxic doses (for example, 200 mg/kg/day). These doses, based on a mg/m2 basis, are approximately 4 and 2 times, respectively, the human daily dose of 500 mg. In the animal studies, no harmful effects to the fetus due to azithromycin were observed. There are, at this time, no conclusive and well-controlled studies that have been done in pregnant women. Because animal reproduction studies do not always predict human response, azithromycin should be used during pregnancy only if clearly needed. Nursing Mothers: It is unknown at this time whether azithromycin is excreted in human milk. Because many other drugs are excreted in human milk, caution should be observed when azithromycin is given to a nursing woman. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to study carcinogenic potential. Azithromycin has demonstrated no potential to be mutagenic in standard laboratory tests. No evidence of negative effects on fertility due to azithromycin was found. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Azasite, Zithromax, Zmax •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): Azithromycin is a macrolide antibiotic used to treat a variety of bacterial infections.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Azithromycin interact? Information: •Drug A: Abatacept •Drug B: Azithromycin •Severity: MODERATE •Description: The metabolism of Azithromycin 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): Azithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria in order to prevent the development antimicrobial resistance and maintain the efficacy of azithromycin. Azithromycin is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the microorganisms listed in the specific conditions below. Recommended dosages, duration of therapy and considerations for various patient populations may vary among these infections. Refer to the FDA label and "Indications" section of this drug entry for detailed information. Adults: Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy. Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae. Abscesses usually require surgical drainage. Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae. Genital ulcer disease in men due to Haemophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established. Pediatric Patients Acute otitis media caused by Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy. Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line 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): Macrolides stop bacterial growth by inhibiting protein synthesis and translation, treating bacterial infections. Azithromycin has additional immunomodulatory effects and has been used in chronic respiratory inflammatory diseases for this purpose. •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): In order to replicate, bacteria require a specific process of protein synthesis, enabled by ribosomal proteins. Azithromycin binds to the 23S rRNA of the bacterial 50S ribosomal subunit. It stops bacterial protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit,. This results in the control of various bacterial infections,. The strong affinity of macrolides, including azithromycin, for bacterial ribosomes, is consistent with their broad‐spectrum antibacterial activities. Azithromycin is highly stable at a low pH, giving it a longer serum half-life and increasing its concentrations in tissues compared to erythromycin. •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): Bioavailability of azithromycin is 37% following oral administration. Absorption is not affected by food. Macrolide absorption in the intestines is believed to be mediated by P-glycoprotein (ABCB1) efflux transporters, which are known to be encoded by the ABCB1 gene. •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, azithromycin is widely distributed in tissues with an apparent steady-state volume of distribution of 31.1 L/kg. Significantly greater azithromycin concentrations have been measured in the tissues rather than in plasma or serum,. The lung, tonsils and prostate are organs have shown a particularly high rate of azithromycin uptake. This drug is concentrated within macrophages and polymorphonucleocytes, allowing for effective activity against Chlamydia trachomatis. In addition, azithromycin is found to be concentrated in phagocytes and fibroblasts, shown by in vitro incubation techniques. In vivo studies demonstrate that concentration in phagocytes may contribute to azithromycin distribution to inflamed tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The serum protein binding of azithromycin varies in humans, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed, however, this drug is eliminated by the liver,. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Biliary excretion of azithromycin, primarily as unchanged drug, is a major route of elimination. Over a 1 week period, approximately 6% of the administered dose is found as unchanged drug 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): Terminal elimination half-life: 68 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): Mean apparent plasma cl=630 mL/min (following single 500 mg oral and i.v. 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): Rat Oral LD50: >2000 mk/kg Possible major adverse effects include cardiovascular arrhythmias and hearing loss. Macrolide resistance is also an ongoing issue. Hepatotoxicity has been observed in rare cases. A note on the risk of liver toxicity: Due to the act that azithromycin is mainly eliminated by the liver, caution should be observed when azithromycin is given to patients with decreased hepatic function. A note on potential renal toxicity: Because limited data in patients with renal GFR <10 mL/min, caution should be exercised when prescribing azithromycin to these patients. Use in Pregnancy: This drug is categorized as a pregnancy category B drug. Reproduction studies have been done in rats and mice at doses up to moderately maternally toxic doses (for example, 200 mg/kg/day). These doses, based on a mg/m2 basis, are approximately 4 and 2 times, respectively, the human daily dose of 500 mg. In the animal studies, no harmful effects to the fetus due to azithromycin were observed. There are, at this time, no conclusive and well-controlled studies that have been done in pregnant women. Because animal reproduction studies do not always predict human response, azithromycin should be used during pregnancy only if clearly needed. Nursing Mothers: It is unknown at this time whether azithromycin is excreted in human milk. Because many other drugs are excreted in human milk, caution should be observed when azithromycin is given to a nursing woman. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to study carcinogenic potential. Azithromycin has demonstrated no potential to be mutagenic in standard laboratory tests. No evidence of negative effects on fertility due to azithromycin was found. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Azasite, Zithromax, Zmax •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): Azithromycin is a macrolide antibiotic used to treat a variety of bacterial infections. 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 Bacillus calmette-guerin substrain russian BCG-I live antigen interact?

•Drug A: Abatacept •Drug B: Bacillus calmette-guerin substrain russian BCG-I live antigen •Severity: MAJOR •Description: The therapeutic efficacy of Bacillus calmette-guerin substrain russian BCG-I live antigen can be decreased when used in combination with Abatacept. •Extended Description: VERITY-BCG is a live BCG vaccine used in the treatment of bladder cancer. In order to exert its therapeutic effect, intravesically-administered live BCG vaccines require the development of an immune response - its coadministration with immunosuppressive agents, such as the subject drug, may therefore interfere with anti-tumor efficacy by dampening the desired immune response. •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

VERITY-BCG is a live BCG vaccine used in the treatment of bladder cancer. In order to exert its therapeutic effect, intravesically-administered live BCG vaccines require the development of an immune response - its coadministration with immunosuppressive agents, such as the subject drug, may therefore interfere with anti-tumor efficacy by dampening the desired immune response. The severity of the interaction is major.

Question: Does Abatacept and Bacillus calmette-guerin substrain russian BCG-I live antigen interact? Information: •Drug A: Abatacept •Drug B: Bacillus calmette-guerin substrain russian BCG-I live antigen •Severity: MAJOR •Description: The therapeutic efficacy of Bacillus calmette-guerin substrain russian BCG-I live antigen can be decreased when used in combination with Abatacept. •Extended Description: VERITY-BCG is a live BCG vaccine used in the treatment of bladder cancer. In order to exert its therapeutic effect, intravesically-administered live BCG vaccines require the development of an immune response - its coadministration with immunosuppressive agents, such as the subject drug, may therefore interfere with anti-tumor efficacy by dampening the desired immune response. •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: VERITY-BCG is a live BCG vaccine used in the treatment of bladder cancer. In order to exert its therapeutic effect, intravesically-administered live BCG vaccines require the development of an immune response - its coadministration with immunosuppressive agents, such as the subject drug, may therefore interfere with anti-tumor efficacy by dampening the desired immune response. The severity of the interaction is major.

Does Abatacept and Bacillus calmette-guerin substrain tice live antigen interact?

•Drug A: Abatacept •Drug B: Bacillus calmette-guerin substrain tice live antigen •Severity: MAJOR •Description: The risk or severity of infection can be increased when Bacillus calmette-guerin substrain tice live antigen is combined with Abatacept. •Extended Description: In most cases, the coadministration of live vaccines and immunosuppressive agents is contraindicated due to the risk of uncontrolled replication of the virus and subsequent infection. Drugs capable of causing clinically significant immunosuppression include chemotherapeutic agents (e.g. alkylating agents, antimetabolites), high-dose corticosteroids, and immune mediators/modulators (e.g. TNF-alpha inhibitors). •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

In most cases, the coadministration of live vaccines and immunosuppressive agents is contraindicated due to the risk of uncontrolled replication of the virus and subsequent infection. Drugs capable of causing clinically significant immunosuppression include chemotherapeutic agents (e.g. alkylating agents, antimetabolites), high-dose corticosteroids, and immune mediators/modulators (e.g. TNF-alpha inhibitors). The severity of the interaction is major.

Question: Does Abatacept and Bacillus calmette-guerin substrain tice live antigen interact? Information: •Drug A: Abatacept •Drug B: Bacillus calmette-guerin substrain tice live antigen •Severity: MAJOR •Description: The risk or severity of infection can be increased when Bacillus calmette-guerin substrain tice live antigen is combined with Abatacept. •Extended Description: In most cases, the coadministration of live vaccines and immunosuppressive agents is contraindicated due to the risk of uncontrolled replication of the virus and subsequent infection. Drugs capable of causing clinically significant immunosuppression include chemotherapeutic agents (e.g. alkylating agents, antimetabolites), high-dose corticosteroids, and immune mediators/modulators (e.g. TNF-alpha inhibitors). •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: In most cases, the coadministration of live vaccines and immunosuppressive agents is contraindicated due to the risk of uncontrolled replication of the virus and subsequent infection. Drugs capable of causing clinically significant immunosuppression include chemotherapeutic agents (e.g. alkylating agents, antimetabolites), high-dose corticosteroids, and immune mediators/modulators (e.g. TNF-alpha inhibitors). The severity of the interaction is major.

Does Abatacept and Baricitinib interact?

•Drug A: Abatacept •Drug B: Baricitinib •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Baricitinib. •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 US and Europe, baricitinib is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF blockers. Baricitinib may be used as monotherapy or in combination with methotrexate or other DMARDs. In Europe, baricitinib is indicated for the treatment of moderate to severe atopic dermatitis in adult patients who are candidates for systemic therapy. In the US, baricitinib is also indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation. Recently, it is also approved as the treatment for severe alopecia areata 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): Baricitinib is a disease-modifying antirheumatic drug (DMARD) used to ameliorate symptoms and slow down the progression of rheumatoid arthritis. In animal models of inflammatory arthritis, baricitinib was shown to have significant anti-inflammatory effects but also led to the preservation of cartilage and bone, with no detectable suppression of humoral immunity or adverse hematologic effects. Baricitinib decreased the levels of immunoglobulins and serum C-reactive protein in patients with rheumatoid arthritis. •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 members of the tyrosine kinase family, Janus kinases (JAKs) are intracellular enzymes that modulate signals from cytokines and growth factor receptors involved in hematopoiesis, inflammation, and immune cell function. Upon binding of extracellular cytokines and growth factors, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs). STATs modulate intracellular activity, including gene transcription of inflammatory mediators that promote an autoimmune response, such as IL-2, IL-6, IL-12, IL-15, IL-23, IFN-γ, GM-CSF, and interferons. The JAK-STAT pathway has been implicated in the pathophysiology of rheumatoid arthritis, as it is associated with an overproduction of inflammatory mediators. There are four JAK proteins: JAK 1, JAK 2, JAK 3 and TYK2. JAKs form homodimers or heterodimers and pair differently in different cell receptors to transmit cytokine signaling. Baricitinib is a selective and reversible inhibitor of JAK1 and JAK2 with less affinity for JAK3 and TYK2; however, the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. Baricitinib inhibits the activity of JAK proteins and modulates the signaling pathway of various interleukins, interferons, and growth factors. It was also shown to decrease the proliferation of JAK1/JAK2 expression in mutated cells and induce cell apoptosis. •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 baricitinib is approximately 80%. The C max was reached after one hour of oral drug administration. A high-fat meal decreased the mean AUC and C max of baricitinib by approximately 11% and 18%, respectively, and delayed T max by 0.5 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): Following intravenous administration, the volume of distribution was 76 L, indicating distribution into tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Baricitinib is approximately 50% bound to plasma proteins and 45% bound to serum proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Baricitinib is metabolized by CYP3A4. Approximately 6% of the orally administered dose was identified as metabolites in urine and feces; however, no metabolites of baricitinib were quantifiable in plasma. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Baricitinib is predominantly excreted via renal elimination. It is cleared via filtration and active secretion. Approximately 75% of the administered dose was eliminated in the urine, with 20% of that dose being the unchanged drug. About 20% of the dose was eliminated in the feces, with 15% of that dose being an 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 elimination half-life in patients with rheumatoid arthritis is approximately 12 hours. The elimination half-life was 10.8 hours in intubated patients with COVID-19 who received baricitinib via nasogastric (NG) or orogastric (OG) tube. •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 baricitinib was 8.9 L/h in patients with rheumatoid arthritis. The total body clearance and half-life of baricitinib was 14.2 L/h in intubated patients with COVID-19 who received baricitinib via nasogastric (NG) or orogastric (OG) tube. •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 lowest published toxic dose (TDLo) is 1820 g/kg in mice and 5096 g/kg in rats. In clinical trials, single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days did not result in any dose-limiting toxicity. Pharmacokinetic data of a single dose of 40 mg in healthy volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 24 hours. In case of an overdose, it is recommended that patients are monitored for signs and symptoms of drug-related adverse reactions, which should be responded with appropriate treatment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Olumiant •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): Baricitinib is a Janus kinase inhibitor used to treat moderate to severe rheumatoid arthritis that has responded poorly to at least one TNF antagonist.

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 Baricitinib interact? Information: •Drug A: Abatacept •Drug B: Baricitinib •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Baricitinib. •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 US and Europe, baricitinib is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF blockers. Baricitinib may be used as monotherapy or in combination with methotrexate or other DMARDs. In Europe, baricitinib is indicated for the treatment of moderate to severe atopic dermatitis in adult patients who are candidates for systemic therapy. In the US, baricitinib is also indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation. Recently, it is also approved as the treatment for severe alopecia areata 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): Baricitinib is a disease-modifying antirheumatic drug (DMARD) used to ameliorate symptoms and slow down the progression of rheumatoid arthritis. In animal models of inflammatory arthritis, baricitinib was shown to have significant anti-inflammatory effects but also led to the preservation of cartilage and bone, with no detectable suppression of humoral immunity or adverse hematologic effects. Baricitinib decreased the levels of immunoglobulins and serum C-reactive protein in patients with rheumatoid arthritis. •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 members of the tyrosine kinase family, Janus kinases (JAKs) are intracellular enzymes that modulate signals from cytokines and growth factor receptors involved in hematopoiesis, inflammation, and immune cell function. Upon binding of extracellular cytokines and growth factors, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs). STATs modulate intracellular activity, including gene transcription of inflammatory mediators that promote an autoimmune response, such as IL-2, IL-6, IL-12, IL-15, IL-23, IFN-γ, GM-CSF, and interferons. The JAK-STAT pathway has been implicated in the pathophysiology of rheumatoid arthritis, as it is associated with an overproduction of inflammatory mediators. There are four JAK proteins: JAK 1, JAK 2, JAK 3 and TYK2. JAKs form homodimers or heterodimers and pair differently in different cell receptors to transmit cytokine signaling. Baricitinib is a selective and reversible inhibitor of JAK1 and JAK2 with less affinity for JAK3 and TYK2; however, the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. Baricitinib inhibits the activity of JAK proteins and modulates the signaling pathway of various interleukins, interferons, and growth factors. It was also shown to decrease the proliferation of JAK1/JAK2 expression in mutated cells and induce cell apoptosis. •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 baricitinib is approximately 80%. The C max was reached after one hour of oral drug administration. A high-fat meal decreased the mean AUC and C max of baricitinib by approximately 11% and 18%, respectively, and delayed T max by 0.5 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): Following intravenous administration, the volume of distribution was 76 L, indicating distribution into tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Baricitinib is approximately 50% bound to plasma proteins and 45% bound to serum proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Baricitinib is metabolized by CYP3A4. Approximately 6% of the orally administered dose was identified as metabolites in urine and feces; however, no metabolites of baricitinib were quantifiable in plasma. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Baricitinib is predominantly excreted via renal elimination. It is cleared via filtration and active secretion. Approximately 75% of the administered dose was eliminated in the urine, with 20% of that dose being the unchanged drug. About 20% of the dose was eliminated in the feces, with 15% of that dose being an 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 elimination half-life in patients with rheumatoid arthritis is approximately 12 hours. The elimination half-life was 10.8 hours in intubated patients with COVID-19 who received baricitinib via nasogastric (NG) or orogastric (OG) tube. •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 baricitinib was 8.9 L/h in patients with rheumatoid arthritis. The total body clearance and half-life of baricitinib was 14.2 L/h in intubated patients with COVID-19 who received baricitinib via nasogastric (NG) or orogastric (OG) tube. •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 lowest published toxic dose (TDLo) is 1820 g/kg in mice and 5096 g/kg in rats. In clinical trials, single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days did not result in any dose-limiting toxicity. Pharmacokinetic data of a single dose of 40 mg in healthy volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 24 hours. In case of an overdose, it is recommended that patients are monitored for signs and symptoms of drug-related adverse reactions, which should be responded with appropriate treatment. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Olumiant •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): Baricitinib is a Janus kinase inhibitor used to treat moderate to severe rheumatoid arthritis that has responded poorly to at least one TNF antagonist. 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 Basiliximab interact?

•Drug A: Abatacept •Drug B: Basiliximab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Basiliximab 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 prophylactic treatment of kidney transplant rejection •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): Basiliximab functions as an IL-2 receptor antagonist. Specifically it inhibits IL-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection. •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): Basiliximab binds with high-affinity to the alpha-subunit (CD25) of the high-affinity IL-2 receptor. This inhibits IL-2 binding, which inhibits T-cell activation and prevents the body from mounting an immune response against the foreign kidney. •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): 7.8 ± 5.1 L [Pediatric] 4.8 ± 2.1 L [Adult] •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 lymphocytes, 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): 7.2 +/- 3.2 days (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): 41 +/- 19 mL/h [Adult patients undergoing first kidney transplantation] 17 +/- 6 mL/h [pediatric patients undergoing renal transplantation] 31 +/- 19 mL/h [adolescent patients undergoing renal transplantation] •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): Simulect •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): Basiliximab is a monoclonal anti-C25 antibody (interleukin-2 receptor alpha subunit) used as immunosuppressive therapy in kidney transplant 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 Basiliximab interact? Information: •Drug A: Abatacept •Drug B: Basiliximab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Basiliximab 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 prophylactic treatment of kidney transplant rejection •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): Basiliximab functions as an IL-2 receptor antagonist. Specifically it inhibits IL-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection. •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): Basiliximab binds with high-affinity to the alpha-subunit (CD25) of the high-affinity IL-2 receptor. This inhibits IL-2 binding, which inhibits T-cell activation and prevents the body from mounting an immune response against the foreign kidney. •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): 7.8 ± 5.1 L [Pediatric] 4.8 ± 2.1 L [Adult] •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 lymphocytes, 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): 7.2 +/- 3.2 days (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): 41 +/- 19 mL/h [Adult patients undergoing first kidney transplantation] 17 +/- 6 mL/h [pediatric patients undergoing renal transplantation] 31 +/- 19 mL/h [adolescent patients undergoing renal transplantation] •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): Simulect •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): Basiliximab is a monoclonal anti-C25 antibody (interleukin-2 receptor alpha subunit) used as immunosuppressive therapy in kidney transplant 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 BCG vaccine interact?

•Drug A: Abatacept •Drug B: BCG vaccine •Severity: MAJOR •Description: The risk or severity of infection can be increased when BCG vaccine is combined with Abatacept. •Extended Description: In most cases, the coadministration of live vaccines and immunosuppressive agents is contraindicated due to the risk of uncontrolled replication of the virus and subsequent infection. Drugs capable of causing clinically significant immunosuppression include chemotherapeutic agents (e.g. alkylating agents, antimetabolites), high-dose corticosteroids, and immune mediators/modulators (e.g. TNF-alpha inhibitors). •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

In most cases, the coadministration of live vaccines and immunosuppressive agents is contraindicated due to the risk of uncontrolled replication of the virus and subsequent infection. Drugs capable of causing clinically significant immunosuppression include chemotherapeutic agents (e.g. alkylating agents, antimetabolites), high-dose corticosteroids, and immune mediators/modulators (e.g. TNF-alpha inhibitors). The severity of the interaction is major.

Question: Does Abatacept and BCG vaccine interact? Information: •Drug A: Abatacept •Drug B: BCG vaccine •Severity: MAJOR •Description: The risk or severity of infection can be increased when BCG vaccine is combined with Abatacept. •Extended Description: In most cases, the coadministration of live vaccines and immunosuppressive agents is contraindicated due to the risk of uncontrolled replication of the virus and subsequent infection. Drugs capable of causing clinically significant immunosuppression include chemotherapeutic agents (e.g. alkylating agents, antimetabolites), high-dose corticosteroids, and immune mediators/modulators (e.g. TNF-alpha inhibitors). •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: In most cases, the coadministration of live vaccines and immunosuppressive agents is contraindicated due to the risk of uncontrolled replication of the virus and subsequent infection. Drugs capable of causing clinically significant immunosuppression include chemotherapeutic agents (e.g. alkylating agents, antimetabolites), high-dose corticosteroids, and immune mediators/modulators (e.g. TNF-alpha inhibitors). The severity of the interaction is major.

Does Abatacept and Beclomethasone dipropionate interact?

•Drug A: Abatacept •Drug B: Beclomethasone dipropionate •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Beclomethasone dipropionate 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 oral inhalation use in the maintenance treatment of asthma as prophylactic therapy in patients 5 years of age and older. The aerosol form of beclomethasone diproprionate is not indicated for the relief of acute bronchospasm. Indicated for intranasal use to relieve the symptoms of seasonal or perennial allergic and nonallergic (vasomotor) rhinitis and prevent the recurrence of nasal polyps following surgical removal. Indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 13 years of age and older. Corticosteroid-responsive dermatoses include psoriasis, contact dermatitis (dermatitis venenata), atopic dermatitis (infantile eczema, allergic dermatitis), neurodermatitis (lichen simplex chronicus, lichen planus, eczema, eczematous dermatitis), intertrigo, dyshidroses (pompholyx), seborrheic dermatitis, exfoliative dermatitis, solar dermatitis, stasis dermatitis, and anogenital and senile pruritus. •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): Inflammatory conditions, including asthma, dermatoses, and allergic rhinitis, involve the activation of cascades by inflammatory mediators. Inflammation is a primary defense mechanism and the homeostatic response of the immune system; however, a prolonged inflammatory response in certain disorders may lead to tissue damage, pain, and swelling. Beclomethasone dipropionate works by attenuating the inflammatory responses associated with asthma, allergic rhinitis, nasal polyps, and corticosteroid-responsive dermatoses. It suppresses the actions of inflammatory cells, such as mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils. It also inhibits the release of inflammatory mediators, such as histamine, eicosanoids, leukotrienes, and cytokines. Beclomethasone dipropionate is reported to exhibit potent topical activity while possessing low systemic effects. Beclomethasone dipropionate is a corticosteroid drug with anti-inflammatory and vasoconstrictive effects used to treat chronic inflammatory processes such as asthma, allergic rhinitis, corticosteroid-responsive dermatoses. When inhaled, it improves lung function, decreases airway hyper-reactivity, and reduces the severity of asthmatic symptoms. Although inhaled corticosteroids, including beclomethasone dipropionate, are reported to mainly act locally in the lungs, systemic effects such as disruption of hypothalamic-pituitary-adrenal (HPA) axis function, bone turnover, osteoporosis, and growth suppression may still be observed with chronic use or high dose administration. There were varying findings from clinical studies examining the effect of beclomethasone dipropionate on growth suppression in pediatric patients. It was shown to suppress the hypothalamo-pituitary-adrenal (HPA) axis in a dose-dependent manner. HPA axis is a central hormonal response system to stress and activation of HPA axis leads to the production of endogenous steroid hormone production. Long-term use of high-dose systemic corticosteroids, including those inhaled, was often associated with signs and symptoms of adrenal insufficiency when exposed to stress conditions, such as trauma, surgery, or infections. As corticosteroids work by suppressing the immune system, there may be an increased risk for developing infections. Cases of Candida albicans infection of the mouth and throat have been reported with inhaled beclomethasone dipropionate 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): Beclomethasone dipropionate is a corticosteroid and prodrug that is rapidly activated by hydrolysis to the active monoester, 17 monopropionate (17-BMP), which mediates anti-inflammatory actions. 17-BMP has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 13 times that of dexamethasone and 25 times that of beclomethasone dipropionate. Upon binding of the ligand, the glucocorticoid receptors dimerize and translocate into the nucleus, where they subsequently bind to glucocorticoid response elements (GRE) on glucocorticoid-responsive genes, leading to changes in transcription. There are several proposed mechanisms for the anti-inflammatory action of corticosteroids. Corticosteroids may work by increasing the transcription of genes coding for anti-inflammatory proteins, including lipocortin-1 and interleukin-10. Corticosteroids were also shown to inhibit the expression of multiple genes that encode pro-inflammatory factors, such as cytokines, chemokines, and adhesion molecules, that are activated during the chronic inflammatory process. This is thought to be due to the direct inhibitory interaction between activated glucocorticoid receptors and activated pro-inflammatory transcription factors, such as nuclear factor-kappa B and activator protein-1. Chronic inflammation is often characterized by enhanced expression of these transcription factors that bind to and activate coactivator molecules, which then acetylate core histones to switch on gene transcription to further amplify the inflammatory process. Corticosteroids suppress the multiple inflammatory gene expression by promoting histone deacetylation, resulting in tighter coiling of DNA and reduced access of transcription factors to their binding sites. •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 inhalation of 320 mcg of beclomethasone dipropionate (BDP), the Cmax was 88 pg/mL and it was reached after 0.5 at post-administration. The mean Cmax of the major and most active metabolite, beclomethasone-17-monopropionate (17-BMP), was 1419 pg/mL at 0.7 hour post-dosing. In another pharmacokinetic study, the AUC of BDP and 17-BMP were 6660 and 6185 pgxh/mL, respectively. The Cmax was 35356 pg/mL for BDP and 2633 pg/mL for 17-BMP, and and the median time to reach these concentrations (Tmax) was 0.2 hours. In the same study, the AUC of 17-BMP following oral and intranasal administration were 10158 and 3660 pgxh/mL, respectively. The Cmax of 17-BMP following oral and intranasal administration were 703 and 310 pg/mL, respectively, and the Tmax was 4 hours. The total bioavailability of 17-BMP following oral and intranasal administration were 41% and 44%, 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): Following intravenous administration, the steady-state volume of distribution was 20 L for beclomethasone dipropionate and 424 L for the active metabolite, beclomethasone-17-monopropionate. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Based on the findings of in vitro studies, the protein binding of the main active metabolite, beclomethasone-17-monopropionate (17-BMP), was 94-96% over the concentration range of 1000 to 5000 pg/mL. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): During absorption, beclomethasone dipropionate is undergoes rapid and extensive hydrolysis mediated by esterases CYP3A to form beclomethasone-17-monopropionate (17-BMP), beclomethasone-21-monopropionate (21-BMP), and beclomethasone (BOH). 17-BMP is the major active metabolite with the most potent anti-inflammatory activity. About 95% of the total beclomethasone dipropionate administered via oral inhalation undergoes presystemic conversion to form 17-BMP in the lung. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Regardless of the route of administration, beclomethasone dipropionate and its metabolites are predominantly excreted in the feces, with less than 10% of the drug and its metabolites being 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): Following intravenous administration, the half life of beclomethasone dipropionate was 0.5 hours while the half life of the active metabolite 17-BMP was 2.7 hours. Following oral and intranasal administration, the half life of 17-BMP was 8.8 and 5.7 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): Following intravenous administration, the clearance of beclomethasone dipropionate and 17-BMP were 150 L/h and 120 L/h, respectively. •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 >3750 mg/kg. The acute toxicity of beclometasone dipropionate is low. The only harmful effect that follows inhalation of large amounts of the drug over a short period of time is suppression of hypothalamic-pituitary-adrenal (HPA) function. Chronic: The excessive use of beclometasone dipropionate over a long period could lead to adrenal suppression. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alanase, Beconase, Propaderm, Qnasl, Qvar, Rivanase AQ •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Beclometasone dipropionate Beclometasone dipropionato Beclomethasone dipropionate •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): Beclomethasone dipropionate is an inhaled corticosteroid used as maintenance treatment in the prophylaxis of asthma attacks.

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 Beclomethasone dipropionate interact? Information: •Drug A: Abatacept •Drug B: Beclomethasone dipropionate •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Beclomethasone dipropionate 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 oral inhalation use in the maintenance treatment of asthma as prophylactic therapy in patients 5 years of age and older. The aerosol form of beclomethasone diproprionate is not indicated for the relief of acute bronchospasm. Indicated for intranasal use to relieve the symptoms of seasonal or perennial allergic and nonallergic (vasomotor) rhinitis and prevent the recurrence of nasal polyps following surgical removal. Indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in patients 13 years of age and older. Corticosteroid-responsive dermatoses include psoriasis, contact dermatitis (dermatitis venenata), atopic dermatitis (infantile eczema, allergic dermatitis), neurodermatitis (lichen simplex chronicus, lichen planus, eczema, eczematous dermatitis), intertrigo, dyshidroses (pompholyx), seborrheic dermatitis, exfoliative dermatitis, solar dermatitis, stasis dermatitis, and anogenital and senile pruritus. •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): Inflammatory conditions, including asthma, dermatoses, and allergic rhinitis, involve the activation of cascades by inflammatory mediators. Inflammation is a primary defense mechanism and the homeostatic response of the immune system; however, a prolonged inflammatory response in certain disorders may lead to tissue damage, pain, and swelling. Beclomethasone dipropionate works by attenuating the inflammatory responses associated with asthma, allergic rhinitis, nasal polyps, and corticosteroid-responsive dermatoses. It suppresses the actions of inflammatory cells, such as mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils. It also inhibits the release of inflammatory mediators, such as histamine, eicosanoids, leukotrienes, and cytokines. Beclomethasone dipropionate is reported to exhibit potent topical activity while possessing low systemic effects. Beclomethasone dipropionate is a corticosteroid drug with anti-inflammatory and vasoconstrictive effects used to treat chronic inflammatory processes such as asthma, allergic rhinitis, corticosteroid-responsive dermatoses. When inhaled, it improves lung function, decreases airway hyper-reactivity, and reduces the severity of asthmatic symptoms. Although inhaled corticosteroids, including beclomethasone dipropionate, are reported to mainly act locally in the lungs, systemic effects such as disruption of hypothalamic-pituitary-adrenal (HPA) axis function, bone turnover, osteoporosis, and growth suppression may still be observed with chronic use or high dose administration. There were varying findings from clinical studies examining the effect of beclomethasone dipropionate on growth suppression in pediatric patients. It was shown to suppress the hypothalamo-pituitary-adrenal (HPA) axis in a dose-dependent manner. HPA axis is a central hormonal response system to stress and activation of HPA axis leads to the production of endogenous steroid hormone production. Long-term use of high-dose systemic corticosteroids, including those inhaled, was often associated with signs and symptoms of adrenal insufficiency when exposed to stress conditions, such as trauma, surgery, or infections. As corticosteroids work by suppressing the immune system, there may be an increased risk for developing infections. Cases of Candida albicans infection of the mouth and throat have been reported with inhaled beclomethasone dipropionate 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): Beclomethasone dipropionate is a corticosteroid and prodrug that is rapidly activated by hydrolysis to the active monoester, 17 monopropionate (17-BMP), which mediates anti-inflammatory actions. 17-BMP has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 13 times that of dexamethasone and 25 times that of beclomethasone dipropionate. Upon binding of the ligand, the glucocorticoid receptors dimerize and translocate into the nucleus, where they subsequently bind to glucocorticoid response elements (GRE) on glucocorticoid-responsive genes, leading to changes in transcription. There are several proposed mechanisms for the anti-inflammatory action of corticosteroids. Corticosteroids may work by increasing the transcription of genes coding for anti-inflammatory proteins, including lipocortin-1 and interleukin-10. Corticosteroids were also shown to inhibit the expression of multiple genes that encode pro-inflammatory factors, such as cytokines, chemokines, and adhesion molecules, that are activated during the chronic inflammatory process. This is thought to be due to the direct inhibitory interaction between activated glucocorticoid receptors and activated pro-inflammatory transcription factors, such as nuclear factor-kappa B and activator protein-1. Chronic inflammation is often characterized by enhanced expression of these transcription factors that bind to and activate coactivator molecules, which then acetylate core histones to switch on gene transcription to further amplify the inflammatory process. Corticosteroids suppress the multiple inflammatory gene expression by promoting histone deacetylation, resulting in tighter coiling of DNA and reduced access of transcription factors to their binding sites. •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 inhalation of 320 mcg of beclomethasone dipropionate (BDP), the Cmax was 88 pg/mL and it was reached after 0.5 at post-administration. The mean Cmax of the major and most active metabolite, beclomethasone-17-monopropionate (17-BMP), was 1419 pg/mL at 0.7 hour post-dosing. In another pharmacokinetic study, the AUC of BDP and 17-BMP were 6660 and 6185 pgxh/mL, respectively. The Cmax was 35356 pg/mL for BDP and 2633 pg/mL for 17-BMP, and and the median time to reach these concentrations (Tmax) was 0.2 hours. In the same study, the AUC of 17-BMP following oral and intranasal administration were 10158 and 3660 pgxh/mL, respectively. The Cmax of 17-BMP following oral and intranasal administration were 703 and 310 pg/mL, respectively, and the Tmax was 4 hours. The total bioavailability of 17-BMP following oral and intranasal administration were 41% and 44%, 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): Following intravenous administration, the steady-state volume of distribution was 20 L for beclomethasone dipropionate and 424 L for the active metabolite, beclomethasone-17-monopropionate. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Based on the findings of in vitro studies, the protein binding of the main active metabolite, beclomethasone-17-monopropionate (17-BMP), was 94-96% over the concentration range of 1000 to 5000 pg/mL. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): During absorption, beclomethasone dipropionate is undergoes rapid and extensive hydrolysis mediated by esterases CYP3A to form beclomethasone-17-monopropionate (17-BMP), beclomethasone-21-monopropionate (21-BMP), and beclomethasone (BOH). 17-BMP is the major active metabolite with the most potent anti-inflammatory activity. About 95% of the total beclomethasone dipropionate administered via oral inhalation undergoes presystemic conversion to form 17-BMP in the lung. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Regardless of the route of administration, beclomethasone dipropionate and its metabolites are predominantly excreted in the feces, with less than 10% of the drug and its metabolites being 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): Following intravenous administration, the half life of beclomethasone dipropionate was 0.5 hours while the half life of the active metabolite 17-BMP was 2.7 hours. Following oral and intranasal administration, the half life of 17-BMP was 8.8 and 5.7 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): Following intravenous administration, the clearance of beclomethasone dipropionate and 17-BMP were 150 L/h and 120 L/h, respectively. •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 >3750 mg/kg. The acute toxicity of beclometasone dipropionate is low. The only harmful effect that follows inhalation of large amounts of the drug over a short period of time is suppression of hypothalamic-pituitary-adrenal (HPA) function. Chronic: The excessive use of beclometasone dipropionate over a long period could lead to adrenal suppression. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alanase, Beconase, Propaderm, Qnasl, Qvar, Rivanase AQ •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Beclometasone dipropionate Beclometasone dipropionato Beclomethasone dipropionate •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): Beclomethasone dipropionate is an inhaled corticosteroid used as maintenance treatment in the prophylaxis of asthma attacks. 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 Belatacept interact?

•Drug A: Abatacept •Drug B: Belatacept •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Belatacept. •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 prophylaxis of organ rejection. It is also used concomitantly with basiliximumab for induction therapy, mycophenolate, and corticosteriods in kidney transplant recepients that are seropositive for the Epstein-Barr virus. •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): Belatacept binds to CD86 with a 4-fold higher affinity than abatacept. It also binds to CD80 with a 2-fold higher affinity than abatacept. It was observed in non-human primates that belatacept prolongs graft survival due to a decrease in antibody production against the donor organ. Furthermore, belatacept also inhibits the primary humoral immune response which is indicated by the decrease in post-transplant levels of IgG, IgM, and IgA. The magnitude of this effect is more significant in belatacept than it is in cyclosporine. •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): Belatacept is a fusion protein in which the Fc portion of human IgG1 is attached onto the extracellular portion of human CTLA-4 (CD152). Belatacept specifically binds to CD80 and CD86 receptors that are found on the antigen-presenting cell (B cells, macrophages, dendritic cells) to block selective T-cell lymphocyte costimulation. CD80 and CD86 would normally act as the ligands to the CD28 receptor T-cells in which this interaction triggers the activation of T lymphocytes. However in the presence of belatacept, because the extracellular CTLA-4 component binds to CD28 with higher affinity than CD80 or CD86, T lymphyocyte anergy, a state of antigen specific tolerance, occurs instead. The T cell is also no longer able to respond to their antigen. •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 multiple intravenous doses of an initial 10 mg/kg dose and followed by a maintenance dose of 5 mg/kg in kidney transplant recipients, these are the following pharmacokinetic parameters: Cmax, 10 mg/kg = 247 µg/mL; Cmax, 5 mg/kg = 139 µg/mL; AUC, 10 mg/kg = 22,252 µg · h/mL; AUC, 5 mg/kg = 14,090 µg · h/mL; Belatacept had linear and dose-dependent 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): Vd, steady state, transplant patients, 10 mg/kg = 0.11 L/kg; Vd, steady state, transplant patients, 5 mg/kg = 0.12 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): The cytochrome P450 enzyme system or uridine diphosphate-glucuronosyltransferases are not expected to be involved with the metabolism of belatacept. Because the drug is a protein, belatacept is degraded into smaller peptides and amino acids by proteolytic enzymes. •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): Mean terminal elimination half-life: 10 mg/kg, kidney transplant recipients= 9.8 days; 5 mg/kg, kidney transplant recipient = 8.2 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): Increased body weight may increase the clearance rate of belatacept. Mean systemic clearance: 10 mg/kg, kidney transplant recipients= 0.49 mL/h/kg; 5 mg/kg, kidney transplant recipient = 0.51 mL/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): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Nulojix •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): Belatacept is a selective T-cell costimulation blocker used in the prophylaxis of organ rejection in adult patients receiving a kidney transplant.

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 Belatacept interact? Information: •Drug A: Abatacept •Drug B: Belatacept •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Belatacept. •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 prophylaxis of organ rejection. It is also used concomitantly with basiliximumab for induction therapy, mycophenolate, and corticosteriods in kidney transplant recepients that are seropositive for the Epstein-Barr virus. •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): Belatacept binds to CD86 with a 4-fold higher affinity than abatacept. It also binds to CD80 with a 2-fold higher affinity than abatacept. It was observed in non-human primates that belatacept prolongs graft survival due to a decrease in antibody production against the donor organ. Furthermore, belatacept also inhibits the primary humoral immune response which is indicated by the decrease in post-transplant levels of IgG, IgM, and IgA. The magnitude of this effect is more significant in belatacept than it is in cyclosporine. •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): Belatacept is a fusion protein in which the Fc portion of human IgG1 is attached onto the extracellular portion of human CTLA-4 (CD152). Belatacept specifically binds to CD80 and CD86 receptors that are found on the antigen-presenting cell (B cells, macrophages, dendritic cells) to block selective T-cell lymphocyte costimulation. CD80 and CD86 would normally act as the ligands to the CD28 receptor T-cells in which this interaction triggers the activation of T lymphocytes. However in the presence of belatacept, because the extracellular CTLA-4 component binds to CD28 with higher affinity than CD80 or CD86, T lymphyocyte anergy, a state of antigen specific tolerance, occurs instead. The T cell is also no longer able to respond to their antigen. •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 multiple intravenous doses of an initial 10 mg/kg dose and followed by a maintenance dose of 5 mg/kg in kidney transplant recipients, these are the following pharmacokinetic parameters: Cmax, 10 mg/kg = 247 µg/mL; Cmax, 5 mg/kg = 139 µg/mL; AUC, 10 mg/kg = 22,252 µg · h/mL; AUC, 5 mg/kg = 14,090 µg · h/mL; Belatacept had linear and dose-dependent 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): Vd, steady state, transplant patients, 10 mg/kg = 0.11 L/kg; Vd, steady state, transplant patients, 5 mg/kg = 0.12 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): The cytochrome P450 enzyme system or uridine diphosphate-glucuronosyltransferases are not expected to be involved with the metabolism of belatacept. Because the drug is a protein, belatacept is degraded into smaller peptides and amino acids by proteolytic enzymes. •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): Mean terminal elimination half-life: 10 mg/kg, kidney transplant recipients= 9.8 days; 5 mg/kg, kidney transplant recipient = 8.2 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): Increased body weight may increase the clearance rate of belatacept. Mean systemic clearance: 10 mg/kg, kidney transplant recipients= 0.49 mL/h/kg; 5 mg/kg, kidney transplant recipient = 0.51 mL/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): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Nulojix •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): Belatacept is a selective T-cell costimulation blocker used in the prophylaxis of organ rejection in adult patients receiving a kidney transplant. 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 Belimumab interact?

•Drug A: Abatacept •Drug B: Belimumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Belimumab. •Extended Description: Belimumab is a biologic treatment used for individuals with lupus 2, abatacept is also a biological treatment 1. While being studied, it was found that the use of abatacept with other biologic agents is not safe . The concurrent use of abatacept with another biologic agent may result in an increased incidence of serious infection and neoplasm, and the coadministration is therefore not advised . •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, belimumab is indicated to treat active systemic lupus erythematosus (SLE) and active lupus nephritis in patients aged five years and older who are receiving standard therapy. In Europe, belimumab is also used to treat SLE and lupus nephritis but only in adults. The efficacy of belimumab has not been evaluated in patients with severe active central nervous system lupus. Use of belimumab is not recommended in this situation. •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): Belimumab works to inhibit the actions of autoreactive, pro-inflammatory B cells that cause chronic inflammation and tissue damage. In patients with SLE, belimumab significantly reduced levels of circulating B (CD20+) 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): Systemic lupus erythematosus (SLE) and lupus nephritis, a common and serious manifestation of SLE, are autoimmune disorders characterized by the presence of autoreactive B lymphocytes (B cells), which promotes the production of autoantibodies that cause inflammation and progressive and irreversible tissue damage. One of the key cytokines involved in B cell homeostasis and survival is B lymphocyte stimulator protein (BLyS), which is a member of tumour necrosis factor (TNF) superfamily of cytokines. While the contribution of BLyS to the pathophysiology of autoimmune diseases is not fully understood, BLyS has been identified as a key therapeutic target for the treatment of SLE as BLyS levels are elevated in patients with SLE along with other autoimmune diseases. Belimumab is an antibody directed against BLyS: it selectively binds BLyS with high affinity, neutralizes it, and blocks its interaction with B cell receptors - transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), B-cell maturation antigen (BCMA), and BLyS receptor 3 (BR3). Belimumab ultimately inhibits the survival of B cells, promotes apoptosis, and reduces the differentiation and maturation of B cells into immunoglobulin-producing plasma 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 absolute bioavailability was 74-82% following single belimumab SC doses in healthy adults. Following administration of 10 mg/kg belimumab via intravenous infusion in adults with SLE, the C max was 313 mcg/mL and the AUC 0-∞ was 3,083 day x mcg/mL. Following subcutaneous administration of 200 mg belimumab once-weekly in adults with SLE, the C max was 108 mcg/mL and the AUC 0-∞ was 726 day x mcg/mL. In healthy Japanese volunteers, the T max was 6.5 days after administration of a single subcutaneous dose of 200 mg/mL belimumab. Steady-state exposure was reached after approximately 11 weeks of subcutaneous administration in healthy subjects of patients with SLE. •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 administration of 10 mg/kg belimumab via intravenous infusion or 200 mg belimumab once-weekly in adults with SLE, the volume of distribution (V ss ) was 5 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): There is no information available. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No formal metabolism studies have been conducted. As belimumab is an antibody, it is expected to undergo degradation mediated by proteolytic enzymes to form small peptides and individual amino acids. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): There is no information 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): Following administration of 10 mg/kg belimumab via intravenous infusion in adults with SLE, the distribution and terminal half-lives were 1.8 days and 19.4 days, respectively. Following subcutaneous administration of 200 mg belimumab once-weekly in adults with SLE, the distribution and terminal half-lives were 1.1 days and 18.3 days, 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): Following administration of 10 mg/kg belimumab via intravenous infusion in adults with SLE, systemic clearance was 215 mL/day. Following subcutaneous administration of 200 mg belimumab once-weekly in adults with SLE, systemic clearance was 204 mL/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): There is no LD 50 data available for belimumab. There is limited experience with overdosage of belimumab. Two doses of up to 20 mg/kg have been given intravenously to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg. In the case of inadvertent overdose, patients should be carefully observed and supportive care administered, as appropriate •Brand Names (Drug A): Orencia •Brand Names (Drug B): Benlysta •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): Belimumab is a B-lymphocyte stimulator (BLyS)-specific inhibitor used to treat systemic lupus erythematosus and active lupus nephritis as an add-on therapy.

Belimumab is a biologic treatment used for individuals with lupus 2, abatacept is also a biological treatment 1. While being studied, it was found that the use of abatacept with other biologic agents is not safe . The concurrent use of abatacept with another biologic agent may result in an increased incidence of serious infection and neoplasm, and the coadministration is therefore not advised . The severity of the interaction is major.

Question: Does Abatacept and Belimumab interact? Information: •Drug A: Abatacept •Drug B: Belimumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Belimumab. •Extended Description: Belimumab is a biologic treatment used for individuals with lupus 2, abatacept is also a biological treatment 1. While being studied, it was found that the use of abatacept with other biologic agents is not safe . The concurrent use of abatacept with another biologic agent may result in an increased incidence of serious infection and neoplasm, and the coadministration is therefore not advised . •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, belimumab is indicated to treat active systemic lupus erythematosus (SLE) and active lupus nephritis in patients aged five years and older who are receiving standard therapy. In Europe, belimumab is also used to treat SLE and lupus nephritis but only in adults. The efficacy of belimumab has not been evaluated in patients with severe active central nervous system lupus. Use of belimumab is not recommended in this situation. •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): Belimumab works to inhibit the actions of autoreactive, pro-inflammatory B cells that cause chronic inflammation and tissue damage. In patients with SLE, belimumab significantly reduced levels of circulating B (CD20+) 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): Systemic lupus erythematosus (SLE) and lupus nephritis, a common and serious manifestation of SLE, are autoimmune disorders characterized by the presence of autoreactive B lymphocytes (B cells), which promotes the production of autoantibodies that cause inflammation and progressive and irreversible tissue damage. One of the key cytokines involved in B cell homeostasis and survival is B lymphocyte stimulator protein (BLyS), which is a member of tumour necrosis factor (TNF) superfamily of cytokines. While the contribution of BLyS to the pathophysiology of autoimmune diseases is not fully understood, BLyS has been identified as a key therapeutic target for the treatment of SLE as BLyS levels are elevated in patients with SLE along with other autoimmune diseases. Belimumab is an antibody directed against BLyS: it selectively binds BLyS with high affinity, neutralizes it, and blocks its interaction with B cell receptors - transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), B-cell maturation antigen (BCMA), and BLyS receptor 3 (BR3). Belimumab ultimately inhibits the survival of B cells, promotes apoptosis, and reduces the differentiation and maturation of B cells into immunoglobulin-producing plasma 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 absolute bioavailability was 74-82% following single belimumab SC doses in healthy adults. Following administration of 10 mg/kg belimumab via intravenous infusion in adults with SLE, the C max was 313 mcg/mL and the AUC 0-∞ was 3,083 day x mcg/mL. Following subcutaneous administration of 200 mg belimumab once-weekly in adults with SLE, the C max was 108 mcg/mL and the AUC 0-∞ was 726 day x mcg/mL. In healthy Japanese volunteers, the T max was 6.5 days after administration of a single subcutaneous dose of 200 mg/mL belimumab. Steady-state exposure was reached after approximately 11 weeks of subcutaneous administration in healthy subjects of patients with SLE. •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 administration of 10 mg/kg belimumab via intravenous infusion or 200 mg belimumab once-weekly in adults with SLE, the volume of distribution (V ss ) was 5 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): There is no information available. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No formal metabolism studies have been conducted. As belimumab is an antibody, it is expected to undergo degradation mediated by proteolytic enzymes to form small peptides and individual amino acids. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): There is no information 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): Following administration of 10 mg/kg belimumab via intravenous infusion in adults with SLE, the distribution and terminal half-lives were 1.8 days and 19.4 days, respectively. Following subcutaneous administration of 200 mg belimumab once-weekly in adults with SLE, the distribution and terminal half-lives were 1.1 days and 18.3 days, 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): Following administration of 10 mg/kg belimumab via intravenous infusion in adults with SLE, systemic clearance was 215 mL/day. Following subcutaneous administration of 200 mg belimumab once-weekly in adults with SLE, systemic clearance was 204 mL/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): There is no LD 50 data available for belimumab. There is limited experience with overdosage of belimumab. Two doses of up to 20 mg/kg have been given intravenously to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg. In the case of inadvertent overdose, patients should be carefully observed and supportive care administered, as appropriate •Brand Names (Drug A): Orencia •Brand Names (Drug B): Benlysta •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): Belimumab is a B-lymphocyte stimulator (BLyS)-specific inhibitor used to treat systemic lupus erythematosus and active lupus nephritis as an add-on therapy. Output: Belimumab is a biologic treatment used for individuals with lupus 2, abatacept is also a biological treatment 1. While being studied, it was found that the use of abatacept with other biologic agents is not safe . The concurrent use of abatacept with another biologic agent may result in an increased incidence of serious infection and neoplasm, and the coadministration is therefore not advised . The severity of the interaction is major.

Does Abatacept and Belinostat interact?

•Drug A: Abatacept •Drug B: Belinostat •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Belinostat. •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): Belinostat is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) with manageable safety profile. It is a potential alternative therapy for patients who did not experience adequate response to first-line drugs for PTCL. It can be used in patients with baseline thrombocytopenia. •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): Beleodaq is a histone deacetylase (HDAC) inhibitor that exhibits pan-HDAC inhibition and potent growth inhibitory and pro-apoptotic activities in a variety of tumor cells, including PTCL cells, at nanomolar concentrations. None of the trials show any clinically relevant changes caused by Beleodaq on heart rate, PR duration or QRS duration as measures of autonomic state, atrio-ventricular conduction or depolarization; there were no cases of Torsades de Pointes. •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): Belinostat inhibits the activity of histone deacetylase (HDAC) thus prevents the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, increased the expression of tumor-suppressor genes. It ultimately induces cell cycle arrest, inhibition of angiogenesis and/or apoptosis of some transformed 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): 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): The volume of distribution is 409 ± 76.7 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 92.9% and 95.8% of belinostat is bound to protein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily metabolized by hepatic UGT1A1. Strong UGT1A1 inhibitors are expected to increase exposure to belinostat. Belinostat also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes to form belinostat amide and belinostat acid. The enzymes responsible for the formation of methyl belinostat and 3-(anilinosulfonyl)-benzenecarboxylic acid, (3-ASBA) are not known •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 40% of the belinostat dose is excreted renally, primarily as metabolites and less than 2% of total dose recovered as unchanged parent 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): Displays a three-compartment pharmacokinetic property with elimination half life of 1.1 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): 1240 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): Belinostat is genotoxic according to Ames test and may impair male fertility. Weekly complete blood count should be monitored during treatment to adjust the dosage as intravenous infusion of belinostat is frequently associated with hematologic toxicity such as leukopenia and thrombocytopenia. Incidences of infections such as sepsis, hepatotoxicity, tumor lysis syndrome, gastrointestinal toxicity, and embryo-fetal toxicity may occur. No specific information is available on the treatment of overdosage of Beleodaq. There is no antidote for Beleodaq and it is not known if Beleodaq is dialyzable. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Beleodaq •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): Belinostat is a histone deacetylase (HDAC) inhibitor used for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

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 Belinostat interact? Information: •Drug A: Abatacept •Drug B: Belinostat •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Belinostat. •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): Belinostat is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) with manageable safety profile. It is a potential alternative therapy for patients who did not experience adequate response to first-line drugs for PTCL. It can be used in patients with baseline thrombocytopenia. •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): Beleodaq is a histone deacetylase (HDAC) inhibitor that exhibits pan-HDAC inhibition and potent growth inhibitory and pro-apoptotic activities in a variety of tumor cells, including PTCL cells, at nanomolar concentrations. None of the trials show any clinically relevant changes caused by Beleodaq on heart rate, PR duration or QRS duration as measures of autonomic state, atrio-ventricular conduction or depolarization; there were no cases of Torsades de Pointes. •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): Belinostat inhibits the activity of histone deacetylase (HDAC) thus prevents the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, increased the expression of tumor-suppressor genes. It ultimately induces cell cycle arrest, inhibition of angiogenesis and/or apoptosis of some transformed 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): 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): The volume of distribution is 409 ± 76.7 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 92.9% and 95.8% of belinostat is bound to protein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily metabolized by hepatic UGT1A1. Strong UGT1A1 inhibitors are expected to increase exposure to belinostat. Belinostat also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes to form belinostat amide and belinostat acid. The enzymes responsible for the formation of methyl belinostat and 3-(anilinosulfonyl)-benzenecarboxylic acid, (3-ASBA) are not known •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 40% of the belinostat dose is excreted renally, primarily as metabolites and less than 2% of total dose recovered as unchanged parent 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): Displays a three-compartment pharmacokinetic property with elimination half life of 1.1 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): 1240 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): Belinostat is genotoxic according to Ames test and may impair male fertility. Weekly complete blood count should be monitored during treatment to adjust the dosage as intravenous infusion of belinostat is frequently associated with hematologic toxicity such as leukopenia and thrombocytopenia. Incidences of infections such as sepsis, hepatotoxicity, tumor lysis syndrome, gastrointestinal toxicity, and embryo-fetal toxicity may occur. No specific information is available on the treatment of overdosage of Beleodaq. There is no antidote for Beleodaq and it is not known if Beleodaq is dialyzable. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Beleodaq •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): Belinostat is a histone deacetylase (HDAC) inhibitor used for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). 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 Belumosudil interact?

•Drug A: Abatacept •Drug B: Belumosudil •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Belumosudil. •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): Belumosudil is indicated for the treatment of chronic graft-versus-host disease (GVHD) in adult and pediatric patients 12 years of age and older following failure of at least two other lines of systemic 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): Belumosudil appears to inhibit several pro-fibrotic and pro-inflammatory processes in order to prevent and treat the damage incurred by graft-versus-host disease. Given its mechanism of action and findings in animal trials, belumosudil is considered to carry embryo-fetal toxicity and may cause significant harm to a developing fetus should a pregnant mother be exposed. Female patients of reproductive potential, or male patients with female partners of reproductive potential, should be advised to use effective contraception during treatment with belumosudil and for one week after the last dose. •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): Chronic graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation in which the transplanted donor T-cells recognize the recipient's tissues as foreign and mount an immune response. During the conditioning regimen prior to stem cell transplantation (e.g. involving irradiation or chemotherapy) the host tissues can become damaged which results in downstream inflammatory responses and the generation of inflammatory mediators like TNF-alpha and IL-1. These cytokines increase the expression of host major histocompatibility (MHC) antigens and adhesion molecules which enhances the ability of mature donor T-cells to recognize these molecules. The activation of these donor T-cells results in the activation of mononuclear phagocytes, whose effector functions are triggered by stimulatory molecules generated by the damage incurred during the conditioning phase of treatment. Activated macrophages and cytotoxic T-lymphocytes begin to directly lyse target cells and/or cause their apoptosis, which eventually leads to local tissue damage and further inflammatory responses. Belumosudil is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2), a protein that plays a vital role in the pathogenesis of immune and fibrotic diseases. The inhibition of ROCK2 has been shown to resolve immune dysregulation by down-regulating pro-inflammatory Th17 cells and up-regulating regulatory T-cells by manipulating the phosphorylation of STAT3 and STAT5. •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 mean bioavailability of belumosudil is 64% and the median T max at steady-state is 1.26 to 2.53 hours. As compared to administration in a fasted state, belumosudil C max and AUC increased by 2.2 and 2 times, respectively, when administered with 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): Following a single oral dose of belumosudil in healthy subjects, the mean geometric volume of distribution was 184 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Belumosudil appears to be extensively protein-bound in plasma - in vitro protein binding to serum albumin and alpha-1-acid glycoprotein was found to be 99.9% and 98.6%, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The in vitro metabolism of belumosudil occurs primarily via CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and UGT1A9. The specific metabolites generated by belumosudil metabolism remain unclear. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Belumosudil is eliminated primarily in the feces. Following the administration of a radiolabeled oral dose of belumosudil in healthy subjects, approximately 85% of the radioactivity was recovered in the feces, 30% of which was unchanged parent drug, with less than 5% recovered 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 mean elimination half-life of belumosudil following oral administration is 19 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 clearance of belumosudil is 9.83 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): There are no data regarding overdosage with belumosudil. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Rezurock •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): Belumosudil is an oral inhibitor of rho-associated coiled-coil-containing protein kinases (ROCK) used in the treatment of chronic graft-versus-host disease (GVHD).

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 Belumosudil interact? Information: •Drug A: Abatacept •Drug B: Belumosudil •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Belumosudil. •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): Belumosudil is indicated for the treatment of chronic graft-versus-host disease (GVHD) in adult and pediatric patients 12 years of age and older following failure of at least two other lines of systemic 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): Belumosudil appears to inhibit several pro-fibrotic and pro-inflammatory processes in order to prevent and treat the damage incurred by graft-versus-host disease. Given its mechanism of action and findings in animal trials, belumosudil is considered to carry embryo-fetal toxicity and may cause significant harm to a developing fetus should a pregnant mother be exposed. Female patients of reproductive potential, or male patients with female partners of reproductive potential, should be advised to use effective contraception during treatment with belumosudil and for one week after the last dose. •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): Chronic graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation in which the transplanted donor T-cells recognize the recipient's tissues as foreign and mount an immune response. During the conditioning regimen prior to stem cell transplantation (e.g. involving irradiation or chemotherapy) the host tissues can become damaged which results in downstream inflammatory responses and the generation of inflammatory mediators like TNF-alpha and IL-1. These cytokines increase the expression of host major histocompatibility (MHC) antigens and adhesion molecules which enhances the ability of mature donor T-cells to recognize these molecules. The activation of these donor T-cells results in the activation of mononuclear phagocytes, whose effector functions are triggered by stimulatory molecules generated by the damage incurred during the conditioning phase of treatment. Activated macrophages and cytotoxic T-lymphocytes begin to directly lyse target cells and/or cause their apoptosis, which eventually leads to local tissue damage and further inflammatory responses. Belumosudil is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2), a protein that plays a vital role in the pathogenesis of immune and fibrotic diseases. The inhibition of ROCK2 has been shown to resolve immune dysregulation by down-regulating pro-inflammatory Th17 cells and up-regulating regulatory T-cells by manipulating the phosphorylation of STAT3 and STAT5. •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 mean bioavailability of belumosudil is 64% and the median T max at steady-state is 1.26 to 2.53 hours. As compared to administration in a fasted state, belumosudil C max and AUC increased by 2.2 and 2 times, respectively, when administered with 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): Following a single oral dose of belumosudil in healthy subjects, the mean geometric volume of distribution was 184 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Belumosudil appears to be extensively protein-bound in plasma - in vitro protein binding to serum albumin and alpha-1-acid glycoprotein was found to be 99.9% and 98.6%, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The in vitro metabolism of belumosudil occurs primarily via CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and UGT1A9. The specific metabolites generated by belumosudil metabolism remain unclear. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Belumosudil is eliminated primarily in the feces. Following the administration of a radiolabeled oral dose of belumosudil in healthy subjects, approximately 85% of the radioactivity was recovered in the feces, 30% of which was unchanged parent drug, with less than 5% recovered 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 mean elimination half-life of belumosudil following oral administration is 19 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 clearance of belumosudil is 9.83 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): There are no data regarding overdosage with belumosudil. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Rezurock •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): Belumosudil is an oral inhibitor of rho-associated coiled-coil-containing protein kinases (ROCK) used in the treatment of chronic graft-versus-host disease (GVHD). 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 Belzutifan interact?

•Drug A: Abatacept •Drug B: Belzutifan •Severity: MODERATE •Description: The metabolism of Belzutifan 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): Belzutifan is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), who do not require immediate surgery. •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): Belzutifan exerts its therapeutic effects by inhibiting a transcription factor necessary for the growth of solid tumors associated with VHL disease. It is taken once daily at approximately the same time each day, with or without food. Both severe anemia and hypoxia have been observed following therapy with belzutifan, and patients should be monitored closely before and during therapy to ensure patients can be managed as clinically indicated. There are no data regarding the use of erythropoiesis-stimulating agents for the treatment of belzutifan-induced anemia, and as such these therapies should be avoided. Belzutifan may cause embryo-fetal toxicity when administered to pregnant women. Female patients and male patients with female partners of reproductive potential should ensure that an effective form of contraception is used throughout therapy and for one week after the last dose - as belzutifan appears to decrease the efficacy of systemic hormonal contraceptives, patients should be advised to use an additional method of contraception (e.g. condoms) to eliminate the possibility of pregnancy during 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): Hypoxia-inducible factor 2α (HIF-2α) is a transcription factor which aids in oxygen sensing by regulating genes that promote adaptation to hypoxia. In healthy patients, when oxygen levels are normal, HIF-2α is broken down via ubiquitin-proteasomal degradation by von-Hippel Lindau (VHL) proteins. In the presence of hypoxia, HIF-2α translocates into cell nuclei and forms a transcriptional complex with hypoxia-inducible factor 1β (HIF-1β) - this complex then induces the expression of downstream genes associated with cellular proliferation and angiogenesis. Patients with von-Hippel Lindau (VHL) disease lack functional VHL proteins, leading to an accumulation of HIF-2α, and this accumulation is what drives the growth of VHL-associated tumors. Belzutifan is an inhibitor of HIF-2α that prevents its complexation with HIF-1β in conditions of hypoxia or impaired VHL protein function, thereby reducing the expression of HIF-2α target genes and slowing/stopping the growth of VHL-associated tumors. •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 patients with VHL disease-associated renal cell carcinoma, the mean C max and AUC 0-24h at steady-state - which was achieved after approximately three days of therapy - were 1.3 µg/mL and 16.7 μg•hr/mL, respectively. The median T max is one to two hours following oral administration. The administration of belzutifan with food has a negligible effect on drug disposition - when given alongside a high-calorie, high-fat meal, the T max was delayed by approximately 2 hours with no other clinically meaningful effects observed. •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 of belzutifan following oral administration is approximately 130 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein-binding is approximately 45%, although data regarding the specific proteins to which belzutifan binds are unavailable. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Belzutifan is primarily metabolized by UGT2B17 and CYP2C19, and to a lesser extent by CYP3A4. •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 elimination half-life of belzutifan is 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 mean clearance of belzutifan following oral administration is 7.3 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): Data regarding overdosage with belzutifan is lacking. There is no specific treatment available for belzutifan overdose - if a patient is suspected to have overdosed, immediately withhold belzutifan and institute standard supportive care. Grade 3 hypoxia has been observed at doses of 120mg twice daily and Grade 4 thrombocytopenia has been observed at doses of 240mg once daily (twice the recommended dose). •Brand Names (Drug A): Orencia •Brand Names (Drug B): Welireg •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): Belzutifan is an inhibitor of hypoxia-inducible factor 2α used as an antineoplastic in the treatment of certain cancers associated with von Hippel-Lindau (VHL) 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 CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Belzutifan interact? Information: •Drug A: Abatacept •Drug B: Belzutifan •Severity: MODERATE •Description: The metabolism of Belzutifan 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): Belzutifan is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), who do not require immediate surgery. •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): Belzutifan exerts its therapeutic effects by inhibiting a transcription factor necessary for the growth of solid tumors associated with VHL disease. It is taken once daily at approximately the same time each day, with or without food. Both severe anemia and hypoxia have been observed following therapy with belzutifan, and patients should be monitored closely before and during therapy to ensure patients can be managed as clinically indicated. There are no data regarding the use of erythropoiesis-stimulating agents for the treatment of belzutifan-induced anemia, and as such these therapies should be avoided. Belzutifan may cause embryo-fetal toxicity when administered to pregnant women. Female patients and male patients with female partners of reproductive potential should ensure that an effective form of contraception is used throughout therapy and for one week after the last dose - as belzutifan appears to decrease the efficacy of systemic hormonal contraceptives, patients should be advised to use an additional method of contraception (e.g. condoms) to eliminate the possibility of pregnancy during 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): Hypoxia-inducible factor 2α (HIF-2α) is a transcription factor which aids in oxygen sensing by regulating genes that promote adaptation to hypoxia. In healthy patients, when oxygen levels are normal, HIF-2α is broken down via ubiquitin-proteasomal degradation by von-Hippel Lindau (VHL) proteins. In the presence of hypoxia, HIF-2α translocates into cell nuclei and forms a transcriptional complex with hypoxia-inducible factor 1β (HIF-1β) - this complex then induces the expression of downstream genes associated with cellular proliferation and angiogenesis. Patients with von-Hippel Lindau (VHL) disease lack functional VHL proteins, leading to an accumulation of HIF-2α, and this accumulation is what drives the growth of VHL-associated tumors. Belzutifan is an inhibitor of HIF-2α that prevents its complexation with HIF-1β in conditions of hypoxia or impaired VHL protein function, thereby reducing the expression of HIF-2α target genes and slowing/stopping the growth of VHL-associated tumors. •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 patients with VHL disease-associated renal cell carcinoma, the mean C max and AUC 0-24h at steady-state - which was achieved after approximately three days of therapy - were 1.3 µg/mL and 16.7 μg•hr/mL, respectively. The median T max is one to two hours following oral administration. The administration of belzutifan with food has a negligible effect on drug disposition - when given alongside a high-calorie, high-fat meal, the T max was delayed by approximately 2 hours with no other clinically meaningful effects observed. •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 of belzutifan following oral administration is approximately 130 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein-binding is approximately 45%, although data regarding the specific proteins to which belzutifan binds are unavailable. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Belzutifan is primarily metabolized by UGT2B17 and CYP2C19, and to a lesser extent by CYP3A4. •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 elimination half-life of belzutifan is 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 mean clearance of belzutifan following oral administration is 7.3 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): Data regarding overdosage with belzutifan is lacking. There is no specific treatment available for belzutifan overdose - if a patient is suspected to have overdosed, immediately withhold belzutifan and institute standard supportive care. Grade 3 hypoxia has been observed at doses of 120mg twice daily and Grade 4 thrombocytopenia has been observed at doses of 240mg once daily (twice the recommended dose). •Brand Names (Drug A): Orencia •Brand Names (Drug B): Welireg •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): Belzutifan is an inhibitor of hypoxia-inducible factor 2α used as an antineoplastic in the treatment of certain cancers associated with von Hippel-Lindau (VHL) 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 CYP2C19 substrates. The severity of the interaction is moderate.

Does Abatacept and Bendamustine interact?

•Drug A: Abatacept •Drug B: Bendamustine •Severity: MAJOR •Description: The metabolism of Bendamustine 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): Bendamustine is indicated for use in the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. •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 mean changes in QTc interval greater than 20 milliseconds were detected up to one hour post-infusion. •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): Bendamustine is a bifunctional mechlorethamine derivative capable of forming electrophilic alkyl groups that covalently bond to other molecules. Through this function as an alkylating agent, bendamustine causes intra- and inter-strand crosslinks between DNA bases resulting in cell death. It is active against both active and quiescent cells, although the exact mechanism of action 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): Following a single IV dose of bendamustine hydrochloride Cmax typically occurred at the end of infusion. The dose proportionality of bendamustine has not been studied. •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) of bendamustine was approximately 20-25 L. Steady-state volume of distribution for total radioactivity was approximately 50 L, indicating that neither bendamustine nor total radioactivity are extensively distributed into the tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, the binding of bendamustine to human serum plasma proteins ranged from 94-96% and data suggest that bendamustine is not likely to displace or to be displaced by highly protein-bound drugs. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro data indicate that bendamustine is primarily metabolized via hydrolysis to monohydroxy (HP1) and dihydroxy-bendamustine (HP2) metabolites with low cytotoxic activity. Two active minor metabolites, M3 and M4, are primarily formed via CYP1A2. However, concentrations of these metabolites in plasma are 1/10th and 1/100th that of the parent compound, respectively, suggesting that the cytotoxic activity is primarily due to bendamustine. Results of a human mass balance study confirm that bendamustine is extensively metabolized via hydrolytic, oxidative, and conjugative pathways. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Mean recovery of total radioactivity in cancer patients following IV infusion of [14C] bendamustine hydrochloride was approximately 76% of the dose. Approximately 50% of the dose was recovered in the urine and approximately 25% of the dose was recovered in the feces. Urinary excretion was confirmed as a relatively minor pathway of elimination of bendamustine, with approximately 3.3% of the dose recovered in the urine as parent. Less than 1% of the dose was recovered in the urine as M3 and M4, and less than 5% of the dose was recovered in the urine as HP2. •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): 40 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): 700 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): Risk for tumor-lysis syndrome. Discontinue use in the event of severe/progressive skin reactions. Hematologic malignancies of different forms reported. Discontinue use in the case of severe infusion reactions. May cause extravasation. Mild to moderate renal impairment. Mild hepatic impairment. Sepsis (infections) may occur. Avoid use if pregnant. Possibility of anaphylaxis or infusion reactions- severe in rare cases. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Belrapzo, Bendeka, Treanda, Vivimusta •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): Bendamustine is an antineoplastic agent used for the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed following rituximab therapy.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Bendamustine interact? Information: •Drug A: Abatacept •Drug B: Bendamustine •Severity: MAJOR •Description: The metabolism of Bendamustine 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): Bendamustine is indicated for use in the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. •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 mean changes in QTc interval greater than 20 milliseconds were detected up to one hour post-infusion. •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): Bendamustine is a bifunctional mechlorethamine derivative capable of forming electrophilic alkyl groups that covalently bond to other molecules. Through this function as an alkylating agent, bendamustine causes intra- and inter-strand crosslinks between DNA bases resulting in cell death. It is active against both active and quiescent cells, although the exact mechanism of action 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): Following a single IV dose of bendamustine hydrochloride Cmax typically occurred at the end of infusion. The dose proportionality of bendamustine has not been studied. •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) of bendamustine was approximately 20-25 L. Steady-state volume of distribution for total radioactivity was approximately 50 L, indicating that neither bendamustine nor total radioactivity are extensively distributed into the tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, the binding of bendamustine to human serum plasma proteins ranged from 94-96% and data suggest that bendamustine is not likely to displace or to be displaced by highly protein-bound drugs. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro data indicate that bendamustine is primarily metabolized via hydrolysis to monohydroxy (HP1) and dihydroxy-bendamustine (HP2) metabolites with low cytotoxic activity. Two active minor metabolites, M3 and M4, are primarily formed via CYP1A2. However, concentrations of these metabolites in plasma are 1/10th and 1/100th that of the parent compound, respectively, suggesting that the cytotoxic activity is primarily due to bendamustine. Results of a human mass balance study confirm that bendamustine is extensively metabolized via hydrolytic, oxidative, and conjugative pathways. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Mean recovery of total radioactivity in cancer patients following IV infusion of [14C] bendamustine hydrochloride was approximately 76% of the dose. Approximately 50% of the dose was recovered in the urine and approximately 25% of the dose was recovered in the feces. Urinary excretion was confirmed as a relatively minor pathway of elimination of bendamustine, with approximately 3.3% of the dose recovered in the urine as parent. Less than 1% of the dose was recovered in the urine as M3 and M4, and less than 5% of the dose was recovered in the urine as HP2. •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): 40 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): 700 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): Risk for tumor-lysis syndrome. Discontinue use in the event of severe/progressive skin reactions. Hematologic malignancies of different forms reported. Discontinue use in the case of severe infusion reactions. May cause extravasation. Mild to moderate renal impairment. Mild hepatic impairment. Sepsis (infections) may occur. Avoid use if pregnant. Possibility of anaphylaxis or infusion reactions- severe in rare cases. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Belrapzo, Bendeka, Treanda, Vivimusta •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): Bendamustine is an antineoplastic agent used for the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed following rituximab therapy. 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 Benzatropine interact?

•Drug A: Abatacept •Drug B: Benzatropine •Severity: MODERATE •Description: The metabolism of Benzatropine 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): Benztropine is indicated to be used as an adjunct in the therapy of all forms of parkinsonism. It can also be used for the control of extrapyramidal disorders due to neuroleptic drugs. The extrapyramidal symptoms are defined as drug-induced disorders that include symptoms of dystonia, akathisia, parkinsonism, bradykinesia, tremors, and dyskinesia. Parkinsonism is a general term that refers to the group of neurological disorders that produce symptoms similar to Parkinson's disease such as tremors, slow movement, and stiffness. The parkinsonism includes a large number of disorders and some of them have not been clearly defined. •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 inhibition of dopamine reuptake by benztropine produces a dose-dependent increase of dopamine in the nerve terminal of the dopaminergic system. Clinically the activity of benztropine is observed after 1-2 hours of oral administration and after a few minutes of intramuscular administration with a last-longing effect of about 24 hours. Reports have indicated that benztropine has a very large sedative effect. The antihistaminic effect of benztropine is very similar to the effect found in pyrilamine and the anticholinergic activity was found to be equal to atropine ex vivo and of about 50% activity in vivo. •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): Benztropine is an agent with anti-muscarinic and antihistaminic effects. Its main mechanism of action is presented by the selective inhibition of dopamine transporters but it also presents affinity for histamine and muscarine receptors. It is widely known that benztropine is a potent inhibitor of presynaptic carrier-mediated dopamine transport. As well, it is known to be an analog of atropine and hence, it has a large affinity for muscarinic receptors M1 in the human brain. Once bound, benztropine blocks the activity of the muscarinic receptors mainly in the striatum. The increased advantage of benztropine lays on the antagonism of acetylcholine activity which corrects the imbalance between dopamine and acetylcholine in Parkinson patients. •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 administration of 1.5 mg of benztropine is slowly absorbed in the gastrointestinal tract and it reaches a peak concentration of 2.5 ng/ml in about 7 hours. It has an approximate oral bioavailability of 29%. •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): Benztropine is expected to present a large volume of distribution between 12-30 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): About 95% of the administered dose of benztropine is found bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Benztropine has been shown to undergo metabolism mainly marked by N-oxidation, N-dealkylation and ring hydroxylation. The extensive metabolism of benztropine produces eight phase-I metabolites plus four glucuronide conjugates. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Benztropine is mainly excreted in the urine but it is also found in the feces 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 elimination half-life of benztropine is very variable and it is reported to be of around 36 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): Extensive pharmacodynamic or pharmacokinetic studies have not been performed. •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 of benztropine is reported to be of 940 mg/kg in rats. In the presence of overdose with benztropine, it has been observed symptoms of circulatory collapse, cardiac arrest, respiratory depression, respiratory arrest, psychosis, shock, coma, seizure, ataxia, combativeness, anhidrosis, hyperthermia, fever, dysphagia, decreased bowel sounds and sluggish pupils. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cogentin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Benzatropina Benzatropine Benzatropinum Benztropine Tropine benzohydryl ether •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): Benzatropine is an anticholinergic drug used to treat Parkinson's disease (PD) and extrapyramidal symptoms, except tardive dyskinesia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Benzatropine interact? Information: •Drug A: Abatacept •Drug B: Benzatropine •Severity: MODERATE •Description: The metabolism of Benzatropine 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): Benztropine is indicated to be used as an adjunct in the therapy of all forms of parkinsonism. It can also be used for the control of extrapyramidal disorders due to neuroleptic drugs. The extrapyramidal symptoms are defined as drug-induced disorders that include symptoms of dystonia, akathisia, parkinsonism, bradykinesia, tremors, and dyskinesia. Parkinsonism is a general term that refers to the group of neurological disorders that produce symptoms similar to Parkinson's disease such as tremors, slow movement, and stiffness. The parkinsonism includes a large number of disorders and some of them have not been clearly defined. •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 inhibition of dopamine reuptake by benztropine produces a dose-dependent increase of dopamine in the nerve terminal of the dopaminergic system. Clinically the activity of benztropine is observed after 1-2 hours of oral administration and after a few minutes of intramuscular administration with a last-longing effect of about 24 hours. Reports have indicated that benztropine has a very large sedative effect. The antihistaminic effect of benztropine is very similar to the effect found in pyrilamine and the anticholinergic activity was found to be equal to atropine ex vivo and of about 50% activity in vivo. •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): Benztropine is an agent with anti-muscarinic and antihistaminic effects. Its main mechanism of action is presented by the selective inhibition of dopamine transporters but it also presents affinity for histamine and muscarine receptors. It is widely known that benztropine is a potent inhibitor of presynaptic carrier-mediated dopamine transport. As well, it is known to be an analog of atropine and hence, it has a large affinity for muscarinic receptors M1 in the human brain. Once bound, benztropine blocks the activity of the muscarinic receptors mainly in the striatum. The increased advantage of benztropine lays on the antagonism of acetylcholine activity which corrects the imbalance between dopamine and acetylcholine in Parkinson patients. •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 administration of 1.5 mg of benztropine is slowly absorbed in the gastrointestinal tract and it reaches a peak concentration of 2.5 ng/ml in about 7 hours. It has an approximate oral bioavailability of 29%. •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): Benztropine is expected to present a large volume of distribution between 12-30 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): About 95% of the administered dose of benztropine is found bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Benztropine has been shown to undergo metabolism mainly marked by N-oxidation, N-dealkylation and ring hydroxylation. The extensive metabolism of benztropine produces eight phase-I metabolites plus four glucuronide conjugates. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Benztropine is mainly excreted in the urine but it is also found in the feces 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 elimination half-life of benztropine is very variable and it is reported to be of around 36 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): Extensive pharmacodynamic or pharmacokinetic studies have not been performed. •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 of benztropine is reported to be of 940 mg/kg in rats. In the presence of overdose with benztropine, it has been observed symptoms of circulatory collapse, cardiac arrest, respiratory depression, respiratory arrest, psychosis, shock, coma, seizure, ataxia, combativeness, anhidrosis, hyperthermia, fever, dysphagia, decreased bowel sounds and sluggish pupils. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cogentin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Benzatropina Benzatropine Benzatropinum Benztropine Tropine benzohydryl ether •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): Benzatropine is an anticholinergic drug used to treat Parkinson's disease (PD) and extrapyramidal symptoms, except tardive dyskinesia. 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 Benzocaine interact?

•Drug A: Abatacept •Drug B: Benzocaine •Severity: MODERATE •Description: The metabolism of Benzocaine 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): Benzocaine is indicated for local anesthesia in dentistry, minor trauma, and as preparation for infiltrative anesthesia. Benzocaine products are indicated for topical anesthesia in a wide variety of conditions including skin irritation, oral pain, and hemorrhoids. •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): Benzocaine is indicated for use as a topical anesthetic. It has a duration of action of approximately 10 minutes and a wide therapeutic window. Patients should be counselled regarding the risks of methemoglobinemia. •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): Benzocaine diffuses into nerve cells where it binds to sodium channels, preventing the channels from opening, and blocking the influx of sodium ions. Nerve cells unable to allow sodium into cells cannot depolarize and conduct nerve impulses. •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): Benzocaine binds to both serum albumin and alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Benzocaine undergoes ester hydrolysis to form 4-aminobenzoic acid, acetylation to form acetylbenzocaine, or N-hydroxylation to form benzocaine hydroxide. 4-aminobenzoic acid can be acetylated or acetylbenzocaine can undergo ester hydrolysis to form 4-acetaminobenzoic acid. •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): Patients experiencing an overdose may present with local anesthetic systemic toxicity syndrome, decreased cardiovascular function, decreased central nervous system function, cardiac arrest, bradycardia, hypotension, cardiac arrhythmias, syncope, and seizures. Patients should be treated with symptomatic and supportive measures which include airway maintenance, controlling seizures, and hemodynamic stabilization. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Anbesol Cold Sore Therapy, Cepacol Sore Throat Plus Cough, Cetacaine, Chloraseptic Sore Throat, Chloraseptic Sore Throat + Cough, Diphen, Docusol Plus, Enemeez Plus, Medicaine Sting and Bite, One Touch Reformulated Apr 2009, Orasep Reformulated Dec 2013, Rectogel, Salinocaine, Topex, Vagisil Original Formula, Zap, Zilactin-B •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amben ethyl ester Benzocaina Benzocaine Benzocainum Ethyl aminobenzoate Ethyl p-aminobenzoate Ethyl p-aminophenylcarboxylate p-(Ethoxycarbonyl)aniline p-Carbethoxyaniline p-Ethoxycarboxylic aniline •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): Benzocaine is a topical local anesthetic used for the temporary relief of pain and itching associated with minor burns, sunburn, scrapes and insect bites or minor skin irritations.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Benzocaine interact? Information: •Drug A: Abatacept •Drug B: Benzocaine •Severity: MODERATE •Description: The metabolism of Benzocaine 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): Benzocaine is indicated for local anesthesia in dentistry, minor trauma, and as preparation for infiltrative anesthesia. Benzocaine products are indicated for topical anesthesia in a wide variety of conditions including skin irritation, oral pain, and hemorrhoids. •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): Benzocaine is indicated for use as a topical anesthetic. It has a duration of action of approximately 10 minutes and a wide therapeutic window. Patients should be counselled regarding the risks of methemoglobinemia. •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): Benzocaine diffuses into nerve cells where it binds to sodium channels, preventing the channels from opening, and blocking the influx of sodium ions. Nerve cells unable to allow sodium into cells cannot depolarize and conduct nerve impulses. •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): Benzocaine binds to both serum albumin and alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Benzocaine undergoes ester hydrolysis to form 4-aminobenzoic acid, acetylation to form acetylbenzocaine, or N-hydroxylation to form benzocaine hydroxide. 4-aminobenzoic acid can be acetylated or acetylbenzocaine can undergo ester hydrolysis to form 4-acetaminobenzoic acid. •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): Patients experiencing an overdose may present with local anesthetic systemic toxicity syndrome, decreased cardiovascular function, decreased central nervous system function, cardiac arrest, bradycardia, hypotension, cardiac arrhythmias, syncope, and seizures. Patients should be treated with symptomatic and supportive measures which include airway maintenance, controlling seizures, and hemodynamic stabilization. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Anbesol Cold Sore Therapy, Cepacol Sore Throat Plus Cough, Cetacaine, Chloraseptic Sore Throat, Chloraseptic Sore Throat + Cough, Diphen, Docusol Plus, Enemeez Plus, Medicaine Sting and Bite, One Touch Reformulated Apr 2009, Orasep Reformulated Dec 2013, Rectogel, Salinocaine, Topex, Vagisil Original Formula, Zap, Zilactin-B •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amben ethyl ester Benzocaina Benzocaine Benzocainum Ethyl aminobenzoate Ethyl p-aminobenzoate Ethyl p-aminophenylcarboxylate p-(Ethoxycarbonyl)aniline p-Carbethoxyaniline p-Ethoxycarboxylic aniline •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): Benzocaine is a topical local anesthetic used for the temporary relief of pain and itching associated with minor burns, sunburn, scrapes and insect bites or minor skin irritations. 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 Benzphetamine interact?

•Drug A: Abatacept •Drug B: Benzphetamine •Severity: MODERATE •Description: The metabolism of Benzphetamine 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 the management of exogenous obesity as a short term adjunct (a few weeks) in a regimen of weight reduction based on caloric restriction •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): Benzphetamine, a phenylalkylamin, is related to amphetamine both chemically and pharmacologically. It is an anorectic agent indicated in the management of exogenous obesity as a short term adjunct (a few weeks) in a regimen of weight reduction based on caloric restriction. Benzphetamine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, the amphetamines. Actions include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for. •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 these drugs is not fully understood, however it may be similar to that of amphetamines. Amphetamines stimulate noepinephrine and dopamine release in nerve endings in the lateral hypothalamic feeding centre, decreasing appetite. This release is mediated by the binding of benzphetamine to centrally located adrenergic 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): Readily absorbed from the gastro-intestinal tract and buccal mucosa. It Is resistant to metabolism by monoamine oxidase. •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): 75-99% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Benzphetamine's metabolites include amphetamine and methamphetamine. •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): 16 to 31 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 =160 mg/kg (orally in rats). Acute overdosage may result in restlessness, tremor, tachypnea, confusion, assaultiveness, and panic states. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Didrex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-benzphetamine Benzaphetamine Benzfetamina Benzfetamine Benzfetaminum Benzphetamine Benzylamphetamine •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): Benzphetamine is a sympathomimetic used to manage exogenous obesity short term.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Benzphetamine interact? Information: •Drug A: Abatacept •Drug B: Benzphetamine •Severity: MODERATE •Description: The metabolism of Benzphetamine 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 the management of exogenous obesity as a short term adjunct (a few weeks) in a regimen of weight reduction based on caloric restriction •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): Benzphetamine, a phenylalkylamin, is related to amphetamine both chemically and pharmacologically. It is an anorectic agent indicated in the management of exogenous obesity as a short term adjunct (a few weeks) in a regimen of weight reduction based on caloric restriction. Benzphetamine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, the amphetamines. Actions include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for. •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 these drugs is not fully understood, however it may be similar to that of amphetamines. Amphetamines stimulate noepinephrine and dopamine release in nerve endings in the lateral hypothalamic feeding centre, decreasing appetite. This release is mediated by the binding of benzphetamine to centrally located adrenergic 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): Readily absorbed from the gastro-intestinal tract and buccal mucosa. It Is resistant to metabolism by monoamine oxidase. •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): 75-99% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Benzphetamine's metabolites include amphetamine and methamphetamine. •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): 16 to 31 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 =160 mg/kg (orally in rats). Acute overdosage may result in restlessness, tremor, tachypnea, confusion, assaultiveness, and panic states. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Didrex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-benzphetamine Benzaphetamine Benzfetamina Benzfetamine Benzfetaminum Benzphetamine Benzylamphetamine •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): Benzphetamine is a sympathomimetic used to manage exogenous obesity short term. 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 Benzyl alcohol interact?

•Drug A: Abatacept •Drug B: Benzyl alcohol •Severity: MODERATE •Description: The metabolism of Benzyl alcohol 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): Ulesfia (benzyl alcohol) lotion is indicated for the topical treatment of head lice infestation in patients 6 months of age and older. Ulesfia Lotion does not have ovicidal activity. •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): Benzyl alcohol inhibits lice from closing their respiratory spiracles, allowing the vehicle to obstruct the spiracles and causing the lice to asphyxiate. •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): 1250 mg/kg (rat, oral) LD50 400 mg/kg IPR-RAT LD50 2000 mg/kg SKN-RBT LD50 53 mg/kg IVN-RAT LD50 2500 mg/kg ORL-GPG LD50 •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cipro, Cipro HC, Itch-X, Ivy-dry Cream, Ulesfia, Zilactin Cold Sore •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (hydroxymethyl)benzene Alcoholum benzylicum Alcool benzylique Alcoolbenzylique alpha-Hydroxytoluene Aromatic alcohol Bentalol Benzalalcohol Benzalcohol Benzenecarbinol Benzenemethanol Benzoyl alcohol Benzyl alcohol Benzylalkohol Benzylic alcohol Hydroxymethylbenzene Phenylcarbinol Phenylmethanol Phenylmethyl alcohol •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): Benzyl alcohol is an antiparasitic agent used for the topical treatment of head lice infestation in patients 6 months of age and older.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Benzyl alcohol interact? Information: •Drug A: Abatacept •Drug B: Benzyl alcohol •Severity: MODERATE •Description: The metabolism of Benzyl alcohol 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): Ulesfia (benzyl alcohol) lotion is indicated for the topical treatment of head lice infestation in patients 6 months of age and older. Ulesfia Lotion does not have ovicidal activity. •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): Benzyl alcohol inhibits lice from closing their respiratory spiracles, allowing the vehicle to obstruct the spiracles and causing the lice to asphyxiate. •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): 1250 mg/kg (rat, oral) LD50 400 mg/kg IPR-RAT LD50 2000 mg/kg SKN-RBT LD50 53 mg/kg IVN-RAT LD50 2500 mg/kg ORL-GPG LD50 •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cipro, Cipro HC, Itch-X, Ivy-dry Cream, Ulesfia, Zilactin Cold Sore •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (hydroxymethyl)benzene Alcoholum benzylicum Alcool benzylique Alcoolbenzylique alpha-Hydroxytoluene Aromatic alcohol Bentalol Benzalalcohol Benzalcohol Benzenecarbinol Benzenemethanol Benzoyl alcohol Benzyl alcohol Benzylalkohol Benzylic alcohol Hydroxymethylbenzene Phenylcarbinol Phenylmethanol Phenylmethyl alcohol •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): Benzyl alcohol is an antiparasitic agent used for the topical treatment of head lice infestation in patients 6 months of age and older. 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 Betamethasone interact?

•Drug A: Abatacept •Drug B: Betamethasone •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Betamethasone 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): As a member of the corticosteroid family, betamethasone is indicated for the treatment of several inflammatory conditions. As topical monotherapy, betamethasone is indicated to relieve pruritic and inflammatory symptoms of corticosteroid-responsive-dermatoses. Betamethasone can be used topically in combination with a vitamin D analog such as calcipotriene to treat plaque psoriasis. The corticosteroid is also available as an injectable suspension and can be used to manage a range of inflammatory conditions including endocrine disorders, gastrointestinal disorders, and rheumatic disorders among other conditions. •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): Corticosteroids bind to the glucocorticoid receptor inhibiting pro-inflammatory signals, while promoting anti-inflammatory signals. Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces. Patients who require long-term treatment with a corticosteroid should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections. •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): Glucocorticoids inhibit neutrophil apoptosis and demargination, and inhibit NF-Kappa B and other inflammatory transcription factors. They also inhibit phospholipase A2, leading to decreased formation of arachidonic acid derivatives. In addition, glucocorticoids promote anti-inflammatory genes like interleukin-10. Corticosteroids like betamethasone can act through nongenomic and genomic pathways. The genomic pathway is slower and occurs when glucocorticoids activate glucocorticoid receptors and initiate downstream effects that promote transcription of anti-inflammatory genes including phosphoenolpyruvate carboxykinase (PEPCK), IL-1-receptor antagonist, and tyrosine amino transferase (TAT). On the other hand, the nongenomic pathway is able to elicit a quicker response by modulating T-cell, platelet and monocyte activity through the use of existing membrane-bound receptors and second messengers. •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 potency of any topical corticosteroid including betamethasone depends on the vehicle in which the steroid is delivered. For example, betamethasone dipropionate 0.05% ointment is classified as a highly potent topical steroid, while betamethasone dipropionate 0.05% cream or lotion is considered to be moderately potent. There are several structural modifications that can determine the potency of a topical corticosteroid. For example, corticosteroids containing a halogen at specific carbons, or that contain esters are more potent due to enhanced lipophilicity. As such, there is a marked difference between topical products containing betamethasone dipropionate vs. betamethasone valerate. Betamethasone dipropionate contains 2 esters which enhances its potency, while betamethasone valerate has only one ester and is less potent. It should be noted that the use of occlusive dressings with topical steroids significantly increases the absorption, increasing the risk for adverse effects. •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 a study that included Indian women of reproductive age, the volume of distribution following a single intramuscular dose of betamethasone phosphate was 94,584±23,539 mL(s). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Betamethasone valerate binds to serum albumin and corticosteroid-binding globulin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of betamethasone yields 6 metabolites. The metabolic processes include 6β hydroxylation, 11β-hydroxyl oxidation, and reduction of the C-20 carbonyl group followed by removal of the side chain. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Corticosteroids are eliminated predominantly 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): In a study that included Indian women of reproductive age, the half-life following a single intramuscular dose of betamethasone phosphate was 10.2 ± 2.5 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): In a study that included Indian women of reproductive age, the CL/F following a single intramuscular dose of betamethasone phosphate was 6,466 ± 805 mL/hour. •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): Chronic high doses of glucocorticoids can lead to the development of cataracts, 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): Betaderm, Betaloan Suik, Beteflam, Celestoderm, Celestone Soluspan, Dermacinrx Therazole Pak, Diprolene, Diprosalic, Diprosone, Dovobet, Enstilar, Fucibet, Lotriderm, Lotrisone, Luxiq, Marbeta, Rivasone, Rolene, Rosone, Sernivo, Taclonex, Valisone-G, Wynzora •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): beta-Methasone alcohol Betadexamethasone Betametasona Betamethasone Bétaméthasone Betamethasonum •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): Betamethasone is a systemic corticosteroid used to relieve inflammation in various conditions, including but not limited to allergic states, dermatologic disorders, gastrointestinal diseases, and hematological 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 Betamethasone interact? Information: •Drug A: Abatacept •Drug B: Betamethasone •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Betamethasone 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): As a member of the corticosteroid family, betamethasone is indicated for the treatment of several inflammatory conditions. As topical monotherapy, betamethasone is indicated to relieve pruritic and inflammatory symptoms of corticosteroid-responsive-dermatoses. Betamethasone can be used topically in combination with a vitamin D analog such as calcipotriene to treat plaque psoriasis. The corticosteroid is also available as an injectable suspension and can be used to manage a range of inflammatory conditions including endocrine disorders, gastrointestinal disorders, and rheumatic disorders among other conditions. •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): Corticosteroids bind to the glucocorticoid receptor inhibiting pro-inflammatory signals, while promoting anti-inflammatory signals. Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces. Patients who require long-term treatment with a corticosteroid should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections. •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): Glucocorticoids inhibit neutrophil apoptosis and demargination, and inhibit NF-Kappa B and other inflammatory transcription factors. They also inhibit phospholipase A2, leading to decreased formation of arachidonic acid derivatives. In addition, glucocorticoids promote anti-inflammatory genes like interleukin-10. Corticosteroids like betamethasone can act through nongenomic and genomic pathways. The genomic pathway is slower and occurs when glucocorticoids activate glucocorticoid receptors and initiate downstream effects that promote transcription of anti-inflammatory genes including phosphoenolpyruvate carboxykinase (PEPCK), IL-1-receptor antagonist, and tyrosine amino transferase (TAT). On the other hand, the nongenomic pathway is able to elicit a quicker response by modulating T-cell, platelet and monocyte activity through the use of existing membrane-bound receptors and second messengers. •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 potency of any topical corticosteroid including betamethasone depends on the vehicle in which the steroid is delivered. For example, betamethasone dipropionate 0.05% ointment is classified as a highly potent topical steroid, while betamethasone dipropionate 0.05% cream or lotion is considered to be moderately potent. There are several structural modifications that can determine the potency of a topical corticosteroid. For example, corticosteroids containing a halogen at specific carbons, or that contain esters are more potent due to enhanced lipophilicity. As such, there is a marked difference between topical products containing betamethasone dipropionate vs. betamethasone valerate. Betamethasone dipropionate contains 2 esters which enhances its potency, while betamethasone valerate has only one ester and is less potent. It should be noted that the use of occlusive dressings with topical steroids significantly increases the absorption, increasing the risk for adverse effects. •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 a study that included Indian women of reproductive age, the volume of distribution following a single intramuscular dose of betamethasone phosphate was 94,584±23,539 mL(s). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Betamethasone valerate binds to serum albumin and corticosteroid-binding globulin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of betamethasone yields 6 metabolites. The metabolic processes include 6β hydroxylation, 11β-hydroxyl oxidation, and reduction of the C-20 carbonyl group followed by removal of the side chain. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Corticosteroids are eliminated predominantly 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): In a study that included Indian women of reproductive age, the half-life following a single intramuscular dose of betamethasone phosphate was 10.2 ± 2.5 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): In a study that included Indian women of reproductive age, the CL/F following a single intramuscular dose of betamethasone phosphate was 6,466 ± 805 mL/hour. •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): Chronic high doses of glucocorticoids can lead to the development of cataracts, 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): Betaderm, Betaloan Suik, Beteflam, Celestoderm, Celestone Soluspan, Dermacinrx Therazole Pak, Diprolene, Diprosalic, Diprosone, Dovobet, Enstilar, Fucibet, Lotriderm, Lotrisone, Luxiq, Marbeta, Rivasone, Rolene, Rosone, Sernivo, Taclonex, Valisone-G, Wynzora •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): beta-Methasone alcohol Betadexamethasone Betametasona Betamethasone Bétaméthasone Betamethasonum •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): Betamethasone is a systemic corticosteroid used to relieve inflammation in various conditions, including but not limited to allergic states, dermatologic disorders, gastrointestinal diseases, and hematological 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 Betaxolol interact?

•Drug A: Abatacept •Drug B: Betaxolol •Severity: MODERATE •Description: The metabolism of Betaxolol 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 management of 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): Betaxolol is a competitive, beta(1)-selective (cardioselective) adrenergic antagonist. Betaxolol is used to treat hypertension, arrhythmias, coronary heart disease, glaucoma, and is also used to reduce non-fatal cardiac events in patients with heart failure. Activation of beta(1)-receptors (located mainly in the heart) by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Drugs such as betaxolol that block these receptors therefore have the reverse effect: they lower the heart rate and blood pressure and hence are used in conditions when the heart itself is deprived of oxygen. They are routinely prescribed in patients with ischemic heart disease. In addition, beta(1)-selective blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. Betaxolol is lipophilic and exhibits no intrinsic sympathomimetic activity (ISA) or membrane stabilizing 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): Betaxolol selectively blocks catecholamine stimulation of beta(1)-adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension. Betaxolol can also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles, causing bronchospasm. •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 an oral dose is complete. There is a small and consistent first-pass effect resulting in an absolute bioavailability of 89% ± 5% that is unaffected by the concomitant ingestion of food or alcohol. •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): 50% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic. Approximately 15% of the dose administered is excreted as unchanged drug, the remainder being metabolites whose contribution to the clinical effect is negligible. •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): 14-22 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): Oral LD 50 s are 350 to 400 mg betaxolol/kg in mice and 860 to 980 mg/kg in rats. Predicted symptoms of overdose include bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Betoptic, Betoptic Pilo, Betoptic S •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Betaxolol Bétaxolol Betaxololum •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): Betaxolol is a cardioselective beta blocking agent commonly used to treat hypertension and elevated intraocular pressure (when administered ophthalmically).

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Betaxolol interact? Information: •Drug A: Abatacept •Drug B: Betaxolol •Severity: MODERATE •Description: The metabolism of Betaxolol 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 management of 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): Betaxolol is a competitive, beta(1)-selective (cardioselective) adrenergic antagonist. Betaxolol is used to treat hypertension, arrhythmias, coronary heart disease, glaucoma, and is also used to reduce non-fatal cardiac events in patients with heart failure. Activation of beta(1)-receptors (located mainly in the heart) by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Drugs such as betaxolol that block these receptors therefore have the reverse effect: they lower the heart rate and blood pressure and hence are used in conditions when the heart itself is deprived of oxygen. They are routinely prescribed in patients with ischemic heart disease. In addition, beta(1)-selective blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. Betaxolol is lipophilic and exhibits no intrinsic sympathomimetic activity (ISA) or membrane stabilizing 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): Betaxolol selectively blocks catecholamine stimulation of beta(1)-adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension. Betaxolol can also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles, causing bronchospasm. •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 an oral dose is complete. There is a small and consistent first-pass effect resulting in an absolute bioavailability of 89% ± 5% that is unaffected by the concomitant ingestion of food or alcohol. •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): 50% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic. Approximately 15% of the dose administered is excreted as unchanged drug, the remainder being metabolites whose contribution to the clinical effect is negligible. •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): 14-22 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): Oral LD 50 s are 350 to 400 mg betaxolol/kg in mice and 860 to 980 mg/kg in rats. Predicted symptoms of overdose include bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Betoptic, Betoptic Pilo, Betoptic S •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Betaxolol Bétaxolol Betaxololum •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): Betaxolol is a cardioselective beta blocking agent commonly used to treat hypertension and elevated intraocular pressure (when administered ophthalmically). 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 Bexarotene interact?

•Drug A: Abatacept •Drug B: Bexarotene •Severity: MODERATE •Description: The metabolism of Bexarotene 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 orally for the treatment of skin manifestations of cutaneous T-cell lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy. Also used topically for the treatment of skin lesions in early (stage IA and IB) CTCL in patients who experience refractory or persistent disease with the use of other therapies or are intolerant of other 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): Bexarotene is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs). Bexarotene is indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. Bexarotene selectively binds and activates retinoid X receptor subtypes (RXR α, RXR β, RXR γ ). RXRs can form heterodimers with various receptor partners such as retinoic acid receptors (RARs), vitamin D receptor, thyroid receptor, and peroxisome proliferator activator receptors (PPARs). Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. Bexarotene inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin. It also induces tumor regression in vivo in some animal models. •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): Bexarotene selectively binds with and activates retinoid X receptor subtypes. There are three subtypes in total: RXR α, RXR β, RXR γ. The exact mechanism of action of bexarotene in the treatment of CTCL is unknown but the drug has activity in all clinical stages of CTCL. •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): >99% •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): Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway (<1% of 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): 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): 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): Targretin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bexaroten Bexarotène Bexarotene Bexaroteno Bexarotenum •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): Bexarotene is a retinoid drug used for cutaneous manifestations of T-cell lymphoma in patients who have not responded well to previous systemic therapy.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Bexarotene interact? Information: •Drug A: Abatacept •Drug B: Bexarotene •Severity: MODERATE •Description: The metabolism of Bexarotene 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 orally for the treatment of skin manifestations of cutaneous T-cell lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy. Also used topically for the treatment of skin lesions in early (stage IA and IB) CTCL in patients who experience refractory or persistent disease with the use of other therapies or are intolerant of other 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): Bexarotene is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs). Bexarotene is indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. Bexarotene selectively binds and activates retinoid X receptor subtypes (RXR α, RXR β, RXR γ ). RXRs can form heterodimers with various receptor partners such as retinoic acid receptors (RARs), vitamin D receptor, thyroid receptor, and peroxisome proliferator activator receptors (PPARs). Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. Bexarotene inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin. It also induces tumor regression in vivo in some animal models. •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): Bexarotene selectively binds with and activates retinoid X receptor subtypes. There are three subtypes in total: RXR α, RXR β, RXR γ. The exact mechanism of action of bexarotene in the treatment of CTCL is unknown but the drug has activity in all clinical stages of CTCL. •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): >99% •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): Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway (<1% of 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): 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): 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): Targretin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bexaroten Bexarotène Bexarotene Bexaroteno Bexarotenum •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): Bexarotene is a retinoid drug used for cutaneous manifestations of T-cell lymphoma in patients who have not responded well to previous systemic therapy. 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 Bicalutamide interact?

•Drug A: Abatacept •Drug B: Bicalutamide •Severity: MAJOR •Description: The metabolism of Bicalutamide 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): Bicalutamide is indicated in combination with a luteinizing hormone-releasing hormone (LHRH) agonist for the treatment of Stage D2 metastatic carcinoma of the prostate. •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): Bicalutamide is an antineoplastic hormonal agent primarily used in the treatment of prostate cancer. Bicalutamide is a pure, nonsteroidal anti-androgen with affinity for androgen receptors (but not for progestogen, estrogen, or glucocorticoid receptors). Consequently, Bicalutamide blocks the action of androgens of adrenal and testicular origin which stimulate the growth of normal and malignant prostatic tissue. Prostate cancer is mostly androgen-dependent and can be treated with surgical or chemical castration. To date, antiandrogen monotherapy has not consistently been shown to be equivalent to castration. •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): Bicalutamide competes with androgen for the binding of androgen receptors, consequently blocking the action of androgens of adrenal and testicular origin which stimulate the growth of normal and malignant prostatic tissue. •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): Bicalutamide is well-absorbed following oral administration, although the absolute bioavailability 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): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 96% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Bicalutamide undergoes stereo specific metabolism. The S (inactive) isomer is metabolized primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation. •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): 5.9 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): Apparent oral cl=0.32 L/h [Normal Males] •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): Casodex •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): Bicalutamide is an androgen receptor inhibitor used to treat Stage D2 metastatic carcinoma of the prostate.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Bicalutamide interact? Information: •Drug A: Abatacept •Drug B: Bicalutamide •Severity: MAJOR •Description: The metabolism of Bicalutamide 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): Bicalutamide is indicated in combination with a luteinizing hormone-releasing hormone (LHRH) agonist for the treatment of Stage D2 metastatic carcinoma of the prostate. •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): Bicalutamide is an antineoplastic hormonal agent primarily used in the treatment of prostate cancer. Bicalutamide is a pure, nonsteroidal anti-androgen with affinity for androgen receptors (but not for progestogen, estrogen, or glucocorticoid receptors). Consequently, Bicalutamide blocks the action of androgens of adrenal and testicular origin which stimulate the growth of normal and malignant prostatic tissue. Prostate cancer is mostly androgen-dependent and can be treated with surgical or chemical castration. To date, antiandrogen monotherapy has not consistently been shown to be equivalent to castration. •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): Bicalutamide competes with androgen for the binding of androgen receptors, consequently blocking the action of androgens of adrenal and testicular origin which stimulate the growth of normal and malignant prostatic tissue. •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): Bicalutamide is well-absorbed following oral administration, although the absolute bioavailability 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): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 96% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Bicalutamide undergoes stereo specific metabolism. The S (inactive) isomer is metabolized primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation. •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): 5.9 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): Apparent oral cl=0.32 L/h [Normal Males] •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): Casodex •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): Bicalutamide is an androgen receptor inhibitor used to treat Stage D2 metastatic carcinoma of the prostate. 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 Bimekizumab interact?

•Drug A: Abatacept •Drug B: Bimekizumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Bimekizumab. •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): Bimekizumab is indicated for the treatment of moderate-to-severe plaque psoriasis in adults 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): Bimekizumab exerts its pharmacologic effects by binding to and inhibiting one of the pro-inflammatory cytokines involved in psoriasis pathogenesis. It is administered once-monthly as a subcutaneous injection. Bimekizumab may increased the risk of infection, including upper respiratory tract infections and oral candidiasis. Any clinically important active infections should be resolved prior to therapy. In addition, the use of live vaccines during bimekizumab therapy is not recommended - ensure patients beginning therapy have completed all age appropriate immunizations prior to initiation. •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 pathophysiology of psoriasis involves a dysregulation of the immune system and is facilitated by a variety of cytokines released by dendritic cells and T-helper cells. Plaque psoriasis, the most common subtype of psoriasis, is driven primarily by tumor necrosis factor-alpha (TNF-α) and interleukins 17 and 23 (IL-17 and IL-23), with the axis between these three cytokines integral to the maintenance phase of psoriasis. IL-17 acts through two separate mechanisms: the first, dependent on the cytoplasmic adaptor protein ACT1, involves the activation of NF-κB and the transcription of inflammatory genes. The second, independent of ACT1, involves the activation of the JAK/STAT signaling cascade, which leads to further transcription of pro-inflammatory proteins and continued psoriasis pathogenicity. Bimekizumab is a monoclonal antibody targeted against IL-17A, IL-17F, and a heterodimer of the two called IL-17AF. It blocks the interaction of these interleukins with their respective receptors, thus reducing psoriatic inflammation. •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 volunteers, the absolute bioavailability of bimekizumab following subcutaneous injection was 70.1%. •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 plaque psoriasis, the median volume of distribution at steady-state was 11.2 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): As a monoclonal antibody, bimekizumab is likely degraded into smaller peptides and amino acids via catabolic processes. •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 elimination half-life of bimekizumab in patients with plaque psoriasis was 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): The median apparent clearance of bimekuzmab in patients with plaque psoriasis was 0.337 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): Single doses of up to 640mg given both intravenously and subcutaneously have been administered in clinical studies without evidence of dose-limiting toxicities. If overdosage of bimekizumab is suspected, monitor the patient for adverse reactions and institute symptomatic treatment as clinically indicated. •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): Bimekizumab is an anti-IL-17A, IL-17F, and IL-17AF monoclonal antibody used in the treatment 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 Bimekizumab interact? Information: •Drug A: Abatacept •Drug B: Bimekizumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Bimekizumab. •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): Bimekizumab is indicated for the treatment of moderate-to-severe plaque psoriasis in adults 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): Bimekizumab exerts its pharmacologic effects by binding to and inhibiting one of the pro-inflammatory cytokines involved in psoriasis pathogenesis. It is administered once-monthly as a subcutaneous injection. Bimekizumab may increased the risk of infection, including upper respiratory tract infections and oral candidiasis. Any clinically important active infections should be resolved prior to therapy. In addition, the use of live vaccines during bimekizumab therapy is not recommended - ensure patients beginning therapy have completed all age appropriate immunizations prior to initiation. •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 pathophysiology of psoriasis involves a dysregulation of the immune system and is facilitated by a variety of cytokines released by dendritic cells and T-helper cells. Plaque psoriasis, the most common subtype of psoriasis, is driven primarily by tumor necrosis factor-alpha (TNF-α) and interleukins 17 and 23 (IL-17 and IL-23), with the axis between these three cytokines integral to the maintenance phase of psoriasis. IL-17 acts through two separate mechanisms: the first, dependent on the cytoplasmic adaptor protein ACT1, involves the activation of NF-κB and the transcription of inflammatory genes. The second, independent of ACT1, involves the activation of the JAK/STAT signaling cascade, which leads to further transcription of pro-inflammatory proteins and continued psoriasis pathogenicity. Bimekizumab is a monoclonal antibody targeted against IL-17A, IL-17F, and a heterodimer of the two called IL-17AF. It blocks the interaction of these interleukins with their respective receptors, thus reducing psoriatic inflammation. •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 volunteers, the absolute bioavailability of bimekizumab following subcutaneous injection was 70.1%. •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 plaque psoriasis, the median volume of distribution at steady-state was 11.2 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): As a monoclonal antibody, bimekizumab is likely degraded into smaller peptides and amino acids via catabolic processes. •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 elimination half-life of bimekizumab in patients with plaque psoriasis was 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): The median apparent clearance of bimekuzmab in patients with plaque psoriasis was 0.337 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): Single doses of up to 640mg given both intravenously and subcutaneously have been administered in clinical studies without evidence of dose-limiting toxicities. If overdosage of bimekizumab is suspected, monitor the patient for adverse reactions and institute symptomatic treatment as clinically indicated. •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): Bimekizumab is an anti-IL-17A, IL-17F, and IL-17AF monoclonal antibody used in the treatment 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 Binimetinib interact?

•Drug A: Abatacept •Drug B: Binimetinib •Severity: MAJOR •Description: The metabolism of Binimetinib 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): Binimetinib, in conjunction with encorafenib, is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation and metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation. •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, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cell-free assays as well as viability and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. Binimetinib also inhibited in vivo ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models. MEK is an enzyme that regulates the biosynthesis of inflammatory cytokines such as TNF, IL-6 and IL-1; therefore, binimetinib anti-tumor activity can be mediated through the interference of cytokines biosynthesis. Binimetinib and encorafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of binimetinib and encorafenib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In a BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the coadministration compared to either drug alone. Following MEKTOVI 45 mg twice daily, no clinically meaningful QT prolongation was observed. •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): Binimetinib, noncompetitive with ATP, binds reversibly to and inhibits the activity of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and 2. The inhibition of MEK1/2 prevents the activation of MEK1/2-dependent effector proteins and transcription factors, resulting in the inhibition of growth factor-mediated cell signaling such as the downstream extracellular signal-related kinase (ERK) pathway. This may lead to the inhibition of tumor cell proliferation and an inhibition in the production of various inflammatory cytokines including interleukin-1, -6, and tumor necrosis factor. MEK1/2 are themselves threonine and tyrosine kinases that possess a dual specificity. They subsequently contribute critically to the activation of the RAS/RAF/MEK/ERK pathway and are typically upregulated in a number of different tumor cell types. •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 pharmacokinetics of binimetinib was studied in healthy subjects and patients with solid tumors. After twice-daily dosing, the accumulation is 1.5-fold and the coefficient of variation (CV%) of the area under the concentration-time curve (AUC) is <40% at steady state. The systemic exposure of binimetinib is approximately dose proportional. After oral administration, at least 50% of the binimetinib dose was absorbed with a median time to maximum concentration (T max ) of 1.6 hours. The administration of a single dose of binimetinib 45 mg with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib 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 geometric mean (CV%) of the apparent volume of distribution of binimetinib is 92 L (45%). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is 0.72. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinib metabolism. Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 produced by CYP1A2 and CYP2C19 represents 8.6% of the binimetinib exposure. Following a single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single oral dose of 45 mg radiolabeled binimetinib in healthy subjects, 62% (32% unchanged) of the administered dose was recovered in the feces while 31% (6.5% unchanged) was recovered 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 mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%). •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 (CL/F) of binimetinib is is 20.2 L/h (24%). •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 reproduction studies and its mechanism of action, binimetinib can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of binimetinib during pregnancy. In animal reproduction studies, oral administration of binimetinib during the period of organogenesis was embryotoxic and an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the clinical dose of 45 mg twice daily. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. No overall differences in the safety or effectiveness of MEKTOVI plus encorafenib were observed in older patients as compared to younger patients. Since binimetinib is 97% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with binimetinib. Carcinogenicity studies with binimetinib have not been conducted. Binimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in the bone marrow of rats. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Mektovi •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): Binimetinib is a medication used to treat metastatic melanoma with specific mutations.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Binimetinib interact? Information: •Drug A: Abatacept •Drug B: Binimetinib •Severity: MAJOR •Description: The metabolism of Binimetinib 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): Binimetinib, in conjunction with encorafenib, is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation and metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation. •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, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cell-free assays as well as viability and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. Binimetinib also inhibited in vivo ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models. MEK is an enzyme that regulates the biosynthesis of inflammatory cytokines such as TNF, IL-6 and IL-1; therefore, binimetinib anti-tumor activity can be mediated through the interference of cytokines biosynthesis. Binimetinib and encorafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of binimetinib and encorafenib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In a BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the coadministration compared to either drug alone. Following MEKTOVI 45 mg twice daily, no clinically meaningful QT prolongation was observed. •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): Binimetinib, noncompetitive with ATP, binds reversibly to and inhibits the activity of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and 2. The inhibition of MEK1/2 prevents the activation of MEK1/2-dependent effector proteins and transcription factors, resulting in the inhibition of growth factor-mediated cell signaling such as the downstream extracellular signal-related kinase (ERK) pathway. This may lead to the inhibition of tumor cell proliferation and an inhibition in the production of various inflammatory cytokines including interleukin-1, -6, and tumor necrosis factor. MEK1/2 are themselves threonine and tyrosine kinases that possess a dual specificity. They subsequently contribute critically to the activation of the RAS/RAF/MEK/ERK pathway and are typically upregulated in a number of different tumor cell types. •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 pharmacokinetics of binimetinib was studied in healthy subjects and patients with solid tumors. After twice-daily dosing, the accumulation is 1.5-fold and the coefficient of variation (CV%) of the area under the concentration-time curve (AUC) is <40% at steady state. The systemic exposure of binimetinib is approximately dose proportional. After oral administration, at least 50% of the binimetinib dose was absorbed with a median time to maximum concentration (T max ) of 1.6 hours. The administration of a single dose of binimetinib 45 mg with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib 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 geometric mean (CV%) of the apparent volume of distribution of binimetinib is 92 L (45%). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is 0.72. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinib metabolism. Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 produced by CYP1A2 and CYP2C19 represents 8.6% of the binimetinib exposure. Following a single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single oral dose of 45 mg radiolabeled binimetinib in healthy subjects, 62% (32% unchanged) of the administered dose was recovered in the feces while 31% (6.5% unchanged) was recovered 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 mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%). •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 (CL/F) of binimetinib is is 20.2 L/h (24%). •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 reproduction studies and its mechanism of action, binimetinib can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of binimetinib during pregnancy. In animal reproduction studies, oral administration of binimetinib during the period of organogenesis was embryotoxic and an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the clinical dose of 45 mg twice daily. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. No overall differences in the safety or effectiveness of MEKTOVI plus encorafenib were observed in older patients as compared to younger patients. Since binimetinib is 97% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with binimetinib. Carcinogenicity studies with binimetinib have not been conducted. Binimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in the bone marrow of rats. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Mektovi •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): Binimetinib is a medication used to treat metastatic melanoma with specific mutations. 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 Bleomycin interact?

•Drug A: Abatacept •Drug B: Bleomycin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Bleomycin 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 palliative treatment in the management malignant neoplasm (trachea, bronchus, lung), squamous cell carcinoma, and lymphomas. •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): Bleomycin is an antibiotic which has been shown to have antitumor activity. Bleomycin selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of mitomycin-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed. Bleomycin has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFa, and IL-2. The antibiotic antitumor drugs are cell cycle-nonspecific except for Bleomycin (which has major effects in G2 and M phases). •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): Although the exact mechanism of action of bleomycin is unknown, available evidence would seem to indicate that the main mode of action is the inhibition of DNA synthesis with some evidence of lesser inhibition of RNA and protein synthesis. As evident in in vitro studies, the DNA-cleaving actions of bleomycin is dependent on oxygen and metal ions. It is believed that bleomycin chelates metal ions (primarily iron) producing a pseudoenzyme that reacts with oxygen to produce superoxide and hydroxide free radicals that cleave DNA. •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): Systemic absorption is approximately 45%. •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): 1% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): It was reported that patients with moderately severe renal failure excreted less than 20% of the dose 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): 115 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): Excessive exposure may cause fever, chills, nausea, vomiting, mental, confusion, and wheezing. Bleomycin may cause irritation to eyes, skin and respiratory tract. It may also cause a darkening or thickening of the skin. It may cause an allergic reaction. •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): Bleomycin is a chemotherapy agent used to treat various malignancies, including head and neck malignancy, lymphoma, and testicular tumors, among others.

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 Bleomycin interact? Information: •Drug A: Abatacept •Drug B: Bleomycin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Bleomycin 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 palliative treatment in the management malignant neoplasm (trachea, bronchus, lung), squamous cell carcinoma, and lymphomas. •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): Bleomycin is an antibiotic which has been shown to have antitumor activity. Bleomycin selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of mitomycin-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed. Bleomycin has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFa, and IL-2. The antibiotic antitumor drugs are cell cycle-nonspecific except for Bleomycin (which has major effects in G2 and M phases). •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): Although the exact mechanism of action of bleomycin is unknown, available evidence would seem to indicate that the main mode of action is the inhibition of DNA synthesis with some evidence of lesser inhibition of RNA and protein synthesis. As evident in in vitro studies, the DNA-cleaving actions of bleomycin is dependent on oxygen and metal ions. It is believed that bleomycin chelates metal ions (primarily iron) producing a pseudoenzyme that reacts with oxygen to produce superoxide and hydroxide free radicals that cleave DNA. •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): Systemic absorption is approximately 45%. •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): 1% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): It was reported that patients with moderately severe renal failure excreted less than 20% of the dose 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): 115 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): Excessive exposure may cause fever, chills, nausea, vomiting, mental, confusion, and wheezing. Bleomycin may cause irritation to eyes, skin and respiratory tract. It may also cause a darkening or thickening of the skin. It may cause an allergic reaction. •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): Bleomycin is a chemotherapy agent used to treat various malignancies, including head and neck malignancy, lymphoma, and testicular tumors, among others. 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 Blinatumomab interact?

•Drug A: Abatacept •Drug B: Blinatumomab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Blinatumomab. •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): Blinatumomab is indicated for the treatment of adults and children with relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL). It is also indicated in adults and children for the treatment of CD19-positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. •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): Blinatumomab promoted peripheral T-cell redistribution at the start of infusion or dose escalation. In most patients, T-cell counts were lower in the first 1-2 days of treatment and returned to baseline levels within 7-14 days. An increase in T-cell levels, also known as T-cell expansion, was observed in a few patients. In the first treatment cycle, blinatumomab doses higher than ≥ 5 mcg/m2/day or ≥ 9 mcg/day decreased peripheral B-cell counts to 10 cells/microliter or less. During the blinatumomab-free period between treatment cycles (2 weeks), peripheral B-cell counts did not recover. The use of blinatumomab may lead to an elevation of IL-6, IL-10, and IFN-γ; however, cytokine levels return to baseline within 24 to 48 hours. Blinatumomab may lead to the development of cytokine release syndrome, neurological toxicities, infections, tumor lysis syndrome, neutropenia and febrile neutropenia, pancreatitis, leukoencephalopathy and transient elevations in liver enzymes. The use of blinatumomab can also affect a patient’s ability to drive and use machines. •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): Blinatumomab is a bispecific T-cell engager (BiTE) that targets CD19, an antigen expressed on the surface of B-cells, and CD3, an antigen expressed on the surface of T-cells. B-cell malignancies, such as acute lymphoblastic leukemia (ALL), express high levels of CD19, making it a therapeutic target for the treatment of these conditions. Blinatumomab recruits and activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on both benign and malignant B cells. By bringing T-cells and tumor cells together, blinatumomab induces an immune response that leads to T-cell activation and proliferation. It promotes the release of cytokines such as TNF-α, IFN-γ, IL-6, and IL-10 by T-cells, the induction of activation markers, such as CD69 and CD25, and the expression of adhesion molecules on the T-cell surface. Altogether, blinatumomab promotes the lysis of CD19+ 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): In adult patients, the pharmacokinetic profile of blinatumomab appears to be linear between 5 to 90 mcg/m /day (equivalent to 9 to 162 mcg/day). The steady-state serum concentration (C ss ) of blinatumomab was achieved within a day of continuous intravenous infusion, and in the range tested, the mean C ss was approximately dose-proportional. At the clinical doses for the treatment of relapsed or refractory acute lymphoblastic leukemia (9 mcg/day and 28 mcg/day), the C ss was 228 (356) pg/mL and 616 (537) pg/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): Blinatumomab has a volume of distribution based on terminal phase of 4.35 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): The metabolic pathway of blinatumomab has not been characterized. As a monoclonal antibody, blinatumomab is expected to be metabolized into small peptides and amino acids via catabolic pathways. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): At clinical doses, negligible amounts of blinatumomab were 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): Blinatumomab has a half-life of 2.10 hours. In pediatric patients, the half-life was 2.19 hours in the first cycle of blinatumomab at the recommended 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): Blinatumomab has an estimated systemic clearance of 3.11 L/hour in patients receiving blinatumomab with continuous intravenous infusion. There is a 2-fold difference in clearance values between patients with normal renal function and those with moderate renal impairment. Pediatric patients had an estimated clearance of 1.88 L/hour/m in the first cycle of blinatumomab at the recommended 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): Blinatumomab overdose cases have been reported, including a patient that received 133-fold the recommended therapeutic dose over a short period of time. In a study that included pediatric and adolescent patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), a patient receiving 30 mcg/m2/day of blinatumomab (higher than the maximum tolerated dose) experienced a fatal cardiac failure event in the setting of life-threatening cytokine release syndrome (CRS). The adverse reactions observed during blinatumomab overdoses included fever, tremors, and headache, consistent with those observed at the recommended dose. If a patient is experiencing an overdose, the blinatumomab product label recommends to interrupt the infusion, monitor the patient for signs of adverse reactions, and provide supportive care. Re-initiating blinatumomab at the recommended dose should be considered after all adverse reactions have been resolved and no earlier than 12 hours after the infusion is interrupted. The carcinogenic, genotoxic, and fertility effects of blinatumomab have not been evaluated. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Blincyto •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): Blinatumomab is an antineoplastic antibody used to treat CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in relapsed and refractory patients, as well as those in first or second complete remission with minimal residual disease (MRD).

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 Blinatumomab interact? Information: •Drug A: Abatacept •Drug B: Blinatumomab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Blinatumomab. •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): Blinatumomab is indicated for the treatment of adults and children with relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL). It is also indicated in adults and children for the treatment of CD19-positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. •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): Blinatumomab promoted peripheral T-cell redistribution at the start of infusion or dose escalation. In most patients, T-cell counts were lower in the first 1-2 days of treatment and returned to baseline levels within 7-14 days. An increase in T-cell levels, also known as T-cell expansion, was observed in a few patients. In the first treatment cycle, blinatumomab doses higher than ≥ 5 mcg/m2/day or ≥ 9 mcg/day decreased peripheral B-cell counts to 10 cells/microliter or less. During the blinatumomab-free period between treatment cycles (2 weeks), peripheral B-cell counts did not recover. The use of blinatumomab may lead to an elevation of IL-6, IL-10, and IFN-γ; however, cytokine levels return to baseline within 24 to 48 hours. Blinatumomab may lead to the development of cytokine release syndrome, neurological toxicities, infections, tumor lysis syndrome, neutropenia and febrile neutropenia, pancreatitis, leukoencephalopathy and transient elevations in liver enzymes. The use of blinatumomab can also affect a patient’s ability to drive and use machines. •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): Blinatumomab is a bispecific T-cell engager (BiTE) that targets CD19, an antigen expressed on the surface of B-cells, and CD3, an antigen expressed on the surface of T-cells. B-cell malignancies, such as acute lymphoblastic leukemia (ALL), express high levels of CD19, making it a therapeutic target for the treatment of these conditions. Blinatumomab recruits and activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on both benign and malignant B cells. By bringing T-cells and tumor cells together, blinatumomab induces an immune response that leads to T-cell activation and proliferation. It promotes the release of cytokines such as TNF-α, IFN-γ, IL-6, and IL-10 by T-cells, the induction of activation markers, such as CD69 and CD25, and the expression of adhesion molecules on the T-cell surface. Altogether, blinatumomab promotes the lysis of CD19+ 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): In adult patients, the pharmacokinetic profile of blinatumomab appears to be linear between 5 to 90 mcg/m /day (equivalent to 9 to 162 mcg/day). The steady-state serum concentration (C ss ) of blinatumomab was achieved within a day of continuous intravenous infusion, and in the range tested, the mean C ss was approximately dose-proportional. At the clinical doses for the treatment of relapsed or refractory acute lymphoblastic leukemia (9 mcg/day and 28 mcg/day), the C ss was 228 (356) pg/mL and 616 (537) pg/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): Blinatumomab has a volume of distribution based on terminal phase of 4.35 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): The metabolic pathway of blinatumomab has not been characterized. As a monoclonal antibody, blinatumomab is expected to be metabolized into small peptides and amino acids via catabolic pathways. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): At clinical doses, negligible amounts of blinatumomab were 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): Blinatumomab has a half-life of 2.10 hours. In pediatric patients, the half-life was 2.19 hours in the first cycle of blinatumomab at the recommended 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): Blinatumomab has an estimated systemic clearance of 3.11 L/hour in patients receiving blinatumomab with continuous intravenous infusion. There is a 2-fold difference in clearance values between patients with normal renal function and those with moderate renal impairment. Pediatric patients had an estimated clearance of 1.88 L/hour/m in the first cycle of blinatumomab at the recommended 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): Blinatumomab overdose cases have been reported, including a patient that received 133-fold the recommended therapeutic dose over a short period of time. In a study that included pediatric and adolescent patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), a patient receiving 30 mcg/m2/day of blinatumomab (higher than the maximum tolerated dose) experienced a fatal cardiac failure event in the setting of life-threatening cytokine release syndrome (CRS). The adverse reactions observed during blinatumomab overdoses included fever, tremors, and headache, consistent with those observed at the recommended dose. If a patient is experiencing an overdose, the blinatumomab product label recommends to interrupt the infusion, monitor the patient for signs of adverse reactions, and provide supportive care. Re-initiating blinatumomab at the recommended dose should be considered after all adverse reactions have been resolved and no earlier than 12 hours after the infusion is interrupted. The carcinogenic, genotoxic, and fertility effects of blinatumomab have not been evaluated. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Blincyto •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): Blinatumomab is an antineoplastic antibody used to treat CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in relapsed and refractory patients, as well as those in first or second complete remission with minimal residual disease (MRD). 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 Bortezomib interact?

•Drug A: Abatacept •Drug B: Bortezomib •Severity: MAJOR •Description: The metabolism of Bortezomib 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): Bortezomib is indicated for the treatment of adults with multiple myeloma or mantle cell 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): Bortezomib works to target the ubiquitin-proteasome pathway, an essential molecular pathway that regulates intracellular concentrations of proteins and promotes protein degradation. The ubiquitin-proteasome pathway is often dysregulated in pathological conditions, leading to aberrant pathway signalling and the formation of malignant cells. In one study, patient-derived chronic lymphocytic leukemia (CLL) cells contained 3-fold higher levels of chymotrypsin-like proteasome activity than normal lymphocytes. By reversibly inhibiting proteasome, bortezomib prevents proteasome-mediated proteolysis. Bortezomib exerts a cytotoxic effect on various cancer cell types in vitro and delays tumour growth in vivo in nonclinical tumour models. Bortezomib inhibits the proteasome activity in a dose-dependent manner. In one pharmacodynamic study, more than 75% of proteasome inhibition was observed in whole blood samples within one hour after dosing of bortezomib. •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 ubiquitin-proteasome pathway is a homeostatic proteolytic pathway for intracellular protein degradation: proteins marked with a poly-ubiquitin chain are degraded to small peptides and free ubiquitin by the proteasome, which is a large multimeric protease. Aberrant proteasome-dependent proteolysis, as seen in some malignancies, can lead to uncontrolled cell division, leading to tumorigenesis, cancer growth, and spread. Bortezomib is a reversible inhibitor of the 26S proteasome, which is made up of a 20S core complexed with a 19S regulatory complex. Individual β-subunits allow specific catalytic action of the 20S core. In mammalian cells, bortezomib is a potent inhibitor of the proteasome’s chymotryptic-like activity, which is attributed to the β5-subunit of the 20S core particle. Bortezomib binds to the active site of the threonine hydroxyl group in the β5-subunit. A probing study showed bortezomib also binding to and inhibiting the β1-subunit, which mediates the caspase-like activity of the proteasome, and β1i-subunit, which is an altered subunit that is expressed to form immunoproteasomes in response to cell stress or inflammation. By inhibiting the proteasome-mediated degradation of key proteins that promote cell apoptosis, bortezomib induces a cell cycle arrest during the G2-M phase. It is believed that multiple mechanisms, other than proteasome inhibition, may be involved in the anticancer activity of bortezomib. The anticancer activity of bortezomib was largely associated with suppression of the NF-κB signalling pathway, resulting in the downregulation of anti-apoptotic target genes and expression of anti-apoptic proteins. This may be explained by bortezomib preventing uncontrolled degradation of IκB, which is an inhibitory protein of NF-κB. NOXA, which is a pro-apoptotic factor, induced by bortezomib selectively in cancer cells; thus, it is suggested to be another key mechanism of bortezomib. •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 intravenous administration of 1 mg/m and 1.3 mg/m doses, the mean C max of bortezomib were 57 and 112 ng/mL, respectively. In a twice-weekly dosing regimen, the C max ranged from 67 to 106 ng/mL at the dose of 1 mg/m and 89 to 120 ng/mL for the 1.3 mg/m dose. In patients with multiple myeloma, the C max of bortezomib followig subcutaneous administration was lower than that of intravenously-administered dose; however, the total systemic exposure of the drug was equivalent for both routes of administration. There is a wide interpatient variability in drug plasma concentrations. •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 distribution volume of bortezomib ranged from approximately 498 to 1884 L/m in patients with multiple myeloma receiving a single- or repeat-dose of 1 mg/m or 1.3 mg/m. Bortezomib distributes into nearly all tissues, except for the adipose and brain tissue. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Over the concentration range of 100 to 1000 ng/mL, bortezomib is about 83% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Bortezomib is primarily metabolized by CYP3A4, CYP2C19, and CYP1A2. CYP2D6 and CYP2C9 are also involved in drug metabolism, but to a smaller extent. Oxidative deboronation, which involves the removal of boronic acid from the parent compound, is the main metabolic pathway. Metabolites of bortezomib are pharmacologically inactive and more than 30 metabolites have been identified in human and animal studies. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Bortezomib is eliminated by both renal and hepatic routes. •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 elimination half-life of bortezomib ranged from 40 to 193 hours following a multiple dosing regimen at a 1 mg/m dose. The half-life ranged from 76 to 108 hours after multiple dosing of 1.3 mg/m bortezomib. •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 the administration of a first dose of 1 mg/m and 1.3 mg/m, the mean mean total body clearances were 102 and 112 L/h, respectively. The clearances were 15 and 32 L/h after the subsequent dose of 1 and 1.3 mg/m, respectively. •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 published toxic dose (TD Lo ) in mouse was 5 mg/kg/14D following intraperitoneal administration of an intermittent dose and 1.6 mg/kg/12D following subcutaneous administration of a continuous dose. The therapeutic dose of bortezomib is individualized in each patient to prevent overdose. Fatal outcomes occurred in humans following the administration of more than twice the recommended therapeutic dose of bortezomib. The symptoms from overdose included the acute onset of symptomatic hypotension and thrombocytopenia. As there is no known antidote for bortezomib overdosage, monitoring of vital signs and appropriate supportive care should be initiated when drug overdosage is suspected. In monkeys and dogs, increased heart rate, decreased contractility, hypotension, and death were observed with the intravenous dose as low as two times the recommended clinical dose on a mg/m2 basis. A case of a slight increase in the corrected QT interval leading to death occurred in dog studies. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Velcade •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bortezomib •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): Bortezomib is a proteasome inhibitor used to treat multiple myeloma in patients who have not been successfully treated with at least two previous therapies.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Bortezomib interact? Information: •Drug A: Abatacept •Drug B: Bortezomib •Severity: MAJOR •Description: The metabolism of Bortezomib 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): Bortezomib is indicated for the treatment of adults with multiple myeloma or mantle cell 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): Bortezomib works to target the ubiquitin-proteasome pathway, an essential molecular pathway that regulates intracellular concentrations of proteins and promotes protein degradation. The ubiquitin-proteasome pathway is often dysregulated in pathological conditions, leading to aberrant pathway signalling and the formation of malignant cells. In one study, patient-derived chronic lymphocytic leukemia (CLL) cells contained 3-fold higher levels of chymotrypsin-like proteasome activity than normal lymphocytes. By reversibly inhibiting proteasome, bortezomib prevents proteasome-mediated proteolysis. Bortezomib exerts a cytotoxic effect on various cancer cell types in vitro and delays tumour growth in vivo in nonclinical tumour models. Bortezomib inhibits the proteasome activity in a dose-dependent manner. In one pharmacodynamic study, more than 75% of proteasome inhibition was observed in whole blood samples within one hour after dosing of bortezomib. •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 ubiquitin-proteasome pathway is a homeostatic proteolytic pathway for intracellular protein degradation: proteins marked with a poly-ubiquitin chain are degraded to small peptides and free ubiquitin by the proteasome, which is a large multimeric protease. Aberrant proteasome-dependent proteolysis, as seen in some malignancies, can lead to uncontrolled cell division, leading to tumorigenesis, cancer growth, and spread. Bortezomib is a reversible inhibitor of the 26S proteasome, which is made up of a 20S core complexed with a 19S regulatory complex. Individual β-subunits allow specific catalytic action of the 20S core. In mammalian cells, bortezomib is a potent inhibitor of the proteasome’s chymotryptic-like activity, which is attributed to the β5-subunit of the 20S core particle. Bortezomib binds to the active site of the threonine hydroxyl group in the β5-subunit. A probing study showed bortezomib also binding to and inhibiting the β1-subunit, which mediates the caspase-like activity of the proteasome, and β1i-subunit, which is an altered subunit that is expressed to form immunoproteasomes in response to cell stress or inflammation. By inhibiting the proteasome-mediated degradation of key proteins that promote cell apoptosis, bortezomib induces a cell cycle arrest during the G2-M phase. It is believed that multiple mechanisms, other than proteasome inhibition, may be involved in the anticancer activity of bortezomib. The anticancer activity of bortezomib was largely associated with suppression of the NF-κB signalling pathway, resulting in the downregulation of anti-apoptotic target genes and expression of anti-apoptic proteins. This may be explained by bortezomib preventing uncontrolled degradation of IκB, which is an inhibitory protein of NF-κB. NOXA, which is a pro-apoptotic factor, induced by bortezomib selectively in cancer cells; thus, it is suggested to be another key mechanism of bortezomib. •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 intravenous administration of 1 mg/m and 1.3 mg/m doses, the mean C max of bortezomib were 57 and 112 ng/mL, respectively. In a twice-weekly dosing regimen, the C max ranged from 67 to 106 ng/mL at the dose of 1 mg/m and 89 to 120 ng/mL for the 1.3 mg/m dose. In patients with multiple myeloma, the C max of bortezomib followig subcutaneous administration was lower than that of intravenously-administered dose; however, the total systemic exposure of the drug was equivalent for both routes of administration. There is a wide interpatient variability in drug plasma concentrations. •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 distribution volume of bortezomib ranged from approximately 498 to 1884 L/m in patients with multiple myeloma receiving a single- or repeat-dose of 1 mg/m or 1.3 mg/m. Bortezomib distributes into nearly all tissues, except for the adipose and brain tissue. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Over the concentration range of 100 to 1000 ng/mL, bortezomib is about 83% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Bortezomib is primarily metabolized by CYP3A4, CYP2C19, and CYP1A2. CYP2D6 and CYP2C9 are also involved in drug metabolism, but to a smaller extent. Oxidative deboronation, which involves the removal of boronic acid from the parent compound, is the main metabolic pathway. Metabolites of bortezomib are pharmacologically inactive and more than 30 metabolites have been identified in human and animal studies. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Bortezomib is eliminated by both renal and hepatic routes. •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 elimination half-life of bortezomib ranged from 40 to 193 hours following a multiple dosing regimen at a 1 mg/m dose. The half-life ranged from 76 to 108 hours after multiple dosing of 1.3 mg/m bortezomib. •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 the administration of a first dose of 1 mg/m and 1.3 mg/m, the mean mean total body clearances were 102 and 112 L/h, respectively. The clearances were 15 and 32 L/h after the subsequent dose of 1 and 1.3 mg/m, respectively. •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 published toxic dose (TD Lo ) in mouse was 5 mg/kg/14D following intraperitoneal administration of an intermittent dose and 1.6 mg/kg/12D following subcutaneous administration of a continuous dose. The therapeutic dose of bortezomib is individualized in each patient to prevent overdose. Fatal outcomes occurred in humans following the administration of more than twice the recommended therapeutic dose of bortezomib. The symptoms from overdose included the acute onset of symptomatic hypotension and thrombocytopenia. As there is no known antidote for bortezomib overdosage, monitoring of vital signs and appropriate supportive care should be initiated when drug overdosage is suspected. In monkeys and dogs, increased heart rate, decreased contractility, hypotension, and death were observed with the intravenous dose as low as two times the recommended clinical dose on a mg/m2 basis. A case of a slight increase in the corrected QT interval leading to death occurred in dog studies. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Velcade •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bortezomib •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): Bortezomib is a proteasome inhibitor used to treat multiple myeloma in patients who have not been successfully treated with at least two previous therapies. 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 Bosentan interact?

•Drug A: Abatacept •Drug B: Bosentan •Severity: MODERATE •Description: The metabolism of Bosentan 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 pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms). •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): Bosentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects. •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): Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET A and ET B receptors in the endothelium and vascular smooth muscle. It displays a slightly higher affinity towards ET A receptors than ET B receptors. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ET A and ET B. •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): Absolute bioavailability is approximately 50% and food does not affect 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): 18 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Greater than 98% to plasma proteins, mainly albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Bosentan is eliminated by biliary excretion following metabolism in the 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. •Half-life (Drug B): Terminal elimination half-life is about 5 hours in healthy adult subjects. •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): 4 L/h [patients with pulmonary arterial hypertension] •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): Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Stayveer, Tracleer •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): bosentán Bosentan bosentanum •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): Bosentan is a dual endothelin receptor antagonist used to treat pulmonary arterial 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 CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Bosentan interact? Information: •Drug A: Abatacept •Drug B: Bosentan •Severity: MODERATE •Description: The metabolism of Bosentan 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 pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms). •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): Bosentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects. •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): Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET A and ET B receptors in the endothelium and vascular smooth muscle. It displays a slightly higher affinity towards ET A receptors than ET B receptors. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ET A and ET B. •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): Absolute bioavailability is approximately 50% and food does not affect 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): 18 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Greater than 98% to plasma proteins, mainly albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Bosentan is eliminated by biliary excretion following metabolism in the 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. •Half-life (Drug B): Terminal elimination half-life is about 5 hours in healthy adult subjects. •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): 4 L/h [patients with pulmonary arterial hypertension] •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): Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Stayveer, Tracleer •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): bosentán Bosentan bosentanum •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): Bosentan is a dual endothelin receptor antagonist used to treat pulmonary arterial 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 CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Bosutinib interact?

•Drug A: Abatacept •Drug B: Bosutinib •Severity: MAJOR •Description: The metabolism of Bosutinib 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): Bosutinib is indicated for the treatment of adult and pediatric patients 1 year of age and older with chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia that is newly diagnosed or resistant or intolerant to prior therapy. It is also indicated for the treatment of adult patients with accelerated or blast phase Philadelphia chromosome-positive chronic myelogenous leukemia that is newly diagnosed or resistant or intolerant to 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): A greater likelihood of response and a greater likelihood of safety events were observed with higher bosutinib exposure in clinical studies. The time course of bosutinib pharmacodynamic response has not been fully characterized. At a single oral dose of 500 mg bosutinib with ketoconazole (a strong CYP3A inhibitor), bosutinib does not prolong the QT interval to any clinically relevant extent. •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): Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits the BCR-ABL kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of BCR-ABL kinase expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant 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): Bosutinib exhibits dose-proportional increases in C max and AUC over the oral dose range of 200 to 800 mg (0.33 to 1.3 times the maximum approved recommended dosage of 600 mg). Bosutinib steady-state C max was 127 ng/mL (31%), C trough was 68 ng/mL (39%) and AUC was 2370 ng•h/mL (34%) following multiple oral doses of bosutinib 400 mg. Bosutinib steady-state C max was 171 ng/mL (38%), C trough was 91 ng/mL (42%) and AUC was 3150 ng•h/mL (38%) following multiple oral doses of bosutinib 500 mg. No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of either the tablet or capsule dosage forms of bosutinib at the same dose, under fed conditions. The median bosutinib (minimum, maximum) t max was 6.0 (6.0, 6.0) hours following oral administration of a single oral dose of bosutinib 500 mg with food. The absolute bioavailability was 34% in healthy subjects. Bosutinib C max increased 1.8-fold and AUC increased 1.7-fold when bosutinib tablets were given with a high-fat meal to healthy subjects compared to administration under fasted conditions. Bosutinib C max increased 1.6-fold and AUC increased 1.5-fold when bosutinib capsules were given with a high-fat meal to healthy subjects compared to administration under fasted conditions. The high-fat meal (800-1000 total calories) consisted of approximately 150 protein calories, 250 carbohydrate calories, and 500-600 fat calories. •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 bosutinib volume of distribution is 6080 ± 1230 L after an oral dose of 500 mg of bosutinib. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Bosutinib protein binding is 94% in vitro and 96% ex vivo and is independent of concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Bosutinib is primarily metabolized by CYP3A4. The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as a minor circulating metabolite. All the metabolites were deemed inactive. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single oral dose of [ C] radiolabeled bosutinib without food, 91.3% of the dose was recovered in feces and 3.3% of the dose was recovered 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): The mean (SD) bosutinib terminal phase elimination half-life (t ) was 22.5 ± 1.7 hours following a single oral dose of bosutinib. •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 (SD) apparent clearance was 189 ± 48 L/h following a single oral dose of bosutinib. •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 a rat fertility and early embryonic development study, bosutinib was administered orally to female rats for approximately 3 to 6 weeks, depending on the day of mating (2 weeks prior to cohabitation with untreated breeder males until gestation day [GD] 7). Increased embryonic resorptions occurred at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). In an embryo-fetal development study conducted in rabbits, bosutinib was administered orally to pregnant animals during organogenesis at doses of 3, 10, and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae and 2 fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 5.1 and 3.8 times the human exposures at the recommended doses of 400 and 500 mg/day, respectively. Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. In a rat pre-and postnatal development study, bosutinib was administered orally to pregnant animals during the period of organogenesis through lactation day 20 at doses of 10, 30, and 70 mg/kg/day. Reduced number of pups born occurred at greater than or equal to 30 mg/kg/day bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and increased incidence of total litter loss and decreased growth of offspring after birth occurred at 70 mg/kg/day bosutinib (6.9 and 5.1 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). Experience with bosutinib overdose in clinical studies was limited to isolated cases. There were no reports of any serious adverse events associated with the overdoses. Patients who take an overdose of BOSULIF should be observed and given appropriate supportive treatment. Bosutinib was not carcinogenic in rats or transgenic mice. The rat 2-year carcinogenicity study was conducted at bosutinib oral doses up to 25 mg/kg in males and 15 mg/kg in females. Exposures at these doses were approximately 1.5 times (males) and 3.1 times (females) the human exposure at the 400 mg dose and 1.2 times (males) and 2.4 times (females) exposure in humans at the 500 mg dose. The 6-month RasH2 transgenic mouse carcinogenicity study was conducted at bosutinib oral doses up to 60 mg/kg. Bosutinib was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames Test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated male mice. In a rat fertility study, drug-treated males were mated with untreated females or untreated males were mated with drug-treated females. Females were administered the drug from pre-mating through early embryonic development. The dose of 70 mg/kg/day of bosutinib resulted in reduced fertility in males as demonstrated by 16% reduction in the number of pregnancies. There were no lesions in the male reproductive organs at this dose. This dose of 70 mg/kg/day resulted in exposure (AUC) in male rats approximately 1.5 times and equal to human exposure at the recommended doses of 400 and 500 mg/day, respectively. Fertility (number of pregnancies) was not affected when female rats were treated with bosutinib. However, there were increased embryonic resorptions at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 and 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). •Brand Names (Drug A): Orencia •Brand Names (Drug B): Bosulif •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bosutinib •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): Bosutinib is an antineoplastic agent used for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adults with inadequate clinical response to other 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 CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Bosutinib interact? Information: •Drug A: Abatacept •Drug B: Bosutinib •Severity: MAJOR •Description: The metabolism of Bosutinib 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): Bosutinib is indicated for the treatment of adult and pediatric patients 1 year of age and older with chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia that is newly diagnosed or resistant or intolerant to prior therapy. It is also indicated for the treatment of adult patients with accelerated or blast phase Philadelphia chromosome-positive chronic myelogenous leukemia that is newly diagnosed or resistant or intolerant to 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): A greater likelihood of response and a greater likelihood of safety events were observed with higher bosutinib exposure in clinical studies. The time course of bosutinib pharmacodynamic response has not been fully characterized. At a single oral dose of 500 mg bosutinib with ketoconazole (a strong CYP3A inhibitor), bosutinib does not prolong the QT interval to any clinically relevant extent. •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): Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits the BCR-ABL kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of BCR-ABL kinase expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant 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): Bosutinib exhibits dose-proportional increases in C max and AUC over the oral dose range of 200 to 800 mg (0.33 to 1.3 times the maximum approved recommended dosage of 600 mg). Bosutinib steady-state C max was 127 ng/mL (31%), C trough was 68 ng/mL (39%) and AUC was 2370 ng•h/mL (34%) following multiple oral doses of bosutinib 400 mg. Bosutinib steady-state C max was 171 ng/mL (38%), C trough was 91 ng/mL (42%) and AUC was 3150 ng•h/mL (38%) following multiple oral doses of bosutinib 500 mg. No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of either the tablet or capsule dosage forms of bosutinib at the same dose, under fed conditions. The median bosutinib (minimum, maximum) t max was 6.0 (6.0, 6.0) hours following oral administration of a single oral dose of bosutinib 500 mg with food. The absolute bioavailability was 34% in healthy subjects. Bosutinib C max increased 1.8-fold and AUC increased 1.7-fold when bosutinib tablets were given with a high-fat meal to healthy subjects compared to administration under fasted conditions. Bosutinib C max increased 1.6-fold and AUC increased 1.5-fold when bosutinib capsules were given with a high-fat meal to healthy subjects compared to administration under fasted conditions. The high-fat meal (800-1000 total calories) consisted of approximately 150 protein calories, 250 carbohydrate calories, and 500-600 fat calories. •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 bosutinib volume of distribution is 6080 ± 1230 L after an oral dose of 500 mg of bosutinib. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Bosutinib protein binding is 94% in vitro and 96% ex vivo and is independent of concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Bosutinib is primarily metabolized by CYP3A4. The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as a minor circulating metabolite. All the metabolites were deemed inactive. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single oral dose of [ C] radiolabeled bosutinib without food, 91.3% of the dose was recovered in feces and 3.3% of the dose was recovered 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): The mean (SD) bosutinib terminal phase elimination half-life (t ) was 22.5 ± 1.7 hours following a single oral dose of bosutinib. •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 (SD) apparent clearance was 189 ± 48 L/h following a single oral dose of bosutinib. •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 a rat fertility and early embryonic development study, bosutinib was administered orally to female rats for approximately 3 to 6 weeks, depending on the day of mating (2 weeks prior to cohabitation with untreated breeder males until gestation day [GD] 7). Increased embryonic resorptions occurred at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). In an embryo-fetal development study conducted in rabbits, bosutinib was administered orally to pregnant animals during organogenesis at doses of 3, 10, and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae and 2 fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 5.1 and 3.8 times the human exposures at the recommended doses of 400 and 500 mg/day, respectively. Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. In a rat pre-and postnatal development study, bosutinib was administered orally to pregnant animals during the period of organogenesis through lactation day 20 at doses of 10, 30, and 70 mg/kg/day. Reduced number of pups born occurred at greater than or equal to 30 mg/kg/day bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and increased incidence of total litter loss and decreased growth of offspring after birth occurred at 70 mg/kg/day bosutinib (6.9 and 5.1 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). Experience with bosutinib overdose in clinical studies was limited to isolated cases. There were no reports of any serious adverse events associated with the overdoses. Patients who take an overdose of BOSULIF should be observed and given appropriate supportive treatment. Bosutinib was not carcinogenic in rats or transgenic mice. The rat 2-year carcinogenicity study was conducted at bosutinib oral doses up to 25 mg/kg in males and 15 mg/kg in females. Exposures at these doses were approximately 1.5 times (males) and 3.1 times (females) the human exposure at the 400 mg dose and 1.2 times (males) and 2.4 times (females) exposure in humans at the 500 mg dose. The 6-month RasH2 transgenic mouse carcinogenicity study was conducted at bosutinib oral doses up to 60 mg/kg. Bosutinib was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames Test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated male mice. In a rat fertility study, drug-treated males were mated with untreated females or untreated males were mated with drug-treated females. Females were administered the drug from pre-mating through early embryonic development. The dose of 70 mg/kg/day of bosutinib resulted in reduced fertility in males as demonstrated by 16% reduction in the number of pregnancies. There were no lesions in the male reproductive organs at this dose. This dose of 70 mg/kg/day resulted in exposure (AUC) in male rats approximately 1.5 times and equal to human exposure at the recommended doses of 400 and 500 mg/day, respectively. Fertility (number of pregnancies) was not affected when female rats were treated with bosutinib. However, there were increased embryonic resorptions at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 and 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). •Brand Names (Drug A): Orencia •Brand Names (Drug B): Bosulif •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bosutinib •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): Bosutinib is an antineoplastic agent used for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adults with inadequate clinical response to other 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 CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Brentuximab vedotin interact?

•Drug A: Abatacept •Drug B: Brentuximab vedotin •Severity: MAJOR •Description: The metabolism of Brentuximab vedotin 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): Brentuximab vedotin is indicated in adult patients for the treatment of previously untreated stage III or IV classical Hodgkin's lymphoma (cHL) in combination with doxorubicin, vinblastine, and dacarbazine. It is also indicated for the treatment of cHL post-autologous hematopoietic stem cell transplantation (auto-HSCT) in patients at high risk of relapse or progression. Finally, it may be used in the treatment of adult patients with cHL who have previously failed either auto-HSCT or at least two prior multi-agent chemotherapy regimens if they are not candidates for auto-HSCT. Brentuximab vedotin is additionally indicated in the treatment of previously untreated systemic anaplastic large cell lymphoma (sALCL), or other CD30-expressing peripheral T-cell lymphomas (PTCL), in combination with cyclophosphamide, doxorubicin, and prednisone. It may also be used as monotherapy in sALCL after therapeutic failure of a least one prior multi-agent chemotherapy regimen. Brentuximab vedotin is also indicated in the treatment of primary cutaneous large anaplastic large cell lymphoma, or CD30-expressing mycosis fungoides, who have received prior systemic 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): Brentuximab vedotin causes apoptosis of tumor cells by preventing cell cycle progression of the G2 to M phase through disruption of the cytosolic microtuble network, thus preventing tumor growth and proliferation. Hodgkin lymphoma (HL) is characterized by malignant Reed-Sternberg cells which express CD30, a marker of large cell lymphoma. Until March 2018, USA National Comprehensive Cancer Network guidelines for patients with advanced HL (stage III/IV disease) recommend treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), or escalated bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) as first-line regimens. ABVD appears to be as effective, with fewer side effects, as escalated BEACOPP. Escalated BEACOPP leads to a greater progression-free survival but no difference in overall survival. Recent progress in technology has enabled a new shift to cancer therapy targeting specific molecules. Brentuximab vedotin, a CD30-directed antibody conjugate, selectively targets malignant HL cells. The effect of Brentuximab vedotin (1.8 mg/kg) on the QTc interval was studied in an open-label, single-group study in 46 patients diagnosed with CD30-expressing hematologic malignancies. Ingestion of brentuximab vedotin did not prolong the mean cardiac QTc interval >10 ms from baseline levels. Smaller increases in the mean QTc interval (<10 ms) cannot be ruled out because this study did not include a placebo arm and a positive control arm. •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): Brentuximab vedotin is composed of 3 parts: a chimeric human-murine IgG1 that selectively targets CD30, monomethyl auristatin E (MMAE), which is a microtubule-disrupting agent, and a protease-susceptible linker that links the antibody and MMAE. The IgG1 antibody enables Brentuximab vedotin to target tumor cells expressing CD30 on their surface. Following this Brentuximab vedotin enters the cell. Once inside, the linker is cleaved releasing MMAE which binds disrupts the microtubule network. The antibody component of this drug is a chimeric IgG1 directed against CD30. The small molecule, MMAE, is a microtubule-disrupting particle. MMAE is covalently attached to the antibody by a linker. Data suggest that the anticancer activity of Adcertris is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC-CD30 complex, and the subsequent release of MMAE by proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, inducing cell cycle arrest and apoptotis of the 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): Steady-state of the ADC is achieved within 21 days with every 3-week dosing of Adcetris. Minimal to no accumulation of ADC is observed with multiple doses at the every 3-week schedule. The time to maximum concentration for MMAE ranges from approximately 1 to 3 days. Similar to the ADC, steady-state of MMAE is achieved within 21 days with every 3-week dosing of Adcetris. MMAE exposures decrease with continued administration of Adcetris with about 50% to 80% of the exposure of the first dose being observed at future doses. The AUC of MMAE was measured to be approximately 2.2-fold higher in patients with hepatic impairment in comparison with patients with normal hepatic function. •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): MMAE is unlikely to displace or to be displaced by highly protein-bound drugs. In vitro studies show that MMAE is a substrate of P-gp and was not a potent inhibitor of P-gp. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, the binding of MMAE to human plasma proteins is in the range of 68–82%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Data in both animals and humans suggest that only a small fraction of MMAE released from brentuximab vedotin is metabolized. In vitro data indicate that the MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP isoforms. MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): This drug appears follow metabolite kinetics, with the elimination of appearing to be limited by its rate of release from the antibody-drug conjugate (ADC). An excretion study was done in patients receiving a dose of 1.8 mg/kg of Adcetris. About 24% of the total MMAE ingested as part of the ADC during an ADCETRIS infusion was recovered in both urine and feces over a 7-day time frame. Of the recovered MMAE, approximately 72% was found in the feces and the majority of the excreted MMAE was excreted 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): The terminal half-life is approximately 4-6 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): The liver is the primary route of clearance for MMAE. The pharmacokinetics and safety of Brentuximab vedotin and MMAE were examined after the administration of 1.2 mg/kg of Adcetris to patients with mild, moderate, and severe hepatic impairment. In patients with moderate and severe hepatic impairment, the rate of ≥Grade 3 adverse reactions was 6/6 (100%) compared to 3/8 (38%) in patients with normal hepatic function. It is recommended to avoid use in patients with severe renal impairment (CrCl <30mL/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 severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy (PML) follows infection by the JC virus (which is not related to Creutzfeldt-Jakob disease). Symptoms of this condition begin insidiously and usually worsen progressively. The symptoms vary depending on which region of the brain is infected. In about two out of three patients, mental function deteriorates rapidly, leading to dementia. Speaking and walking may become increasingly difficult. Vision may be impaired, and total blindness may occur. Rarely, headaches and seizures can occur, mainly in immunocompromised patients. The most serious sequela of this condition is death. Common adverse effects of Adcetris may include: neutropenia, anemia, peripheral neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and fever. In one trial, neutropenia occurred in 91 percent of patients treated with Adcetris plus chemotherapy, which was associated with a 19 percent rate of febrile neutropenia (neutropenia and fever). Preventive treatment with G-CSF, a growth factor for the bone marrow to produce white blood cells, is recommended with Adcetris plus chemotherapy for the first-line treatment of Stage III or IV cHL. Adcetris has a boxed warning that emphasizes the risk of John Cunningham virus infection leading to progressive multifocal leukoencephalopathy, or PML, a rare but serious brain infection that may be lethal. Serious risks of Adcetris include peripheral neuropathy; severe allergic (anaphylaxis) or infusion-site reactions; damage to the blood, lungs and liver (hematologic, pulmonary and hepato-toxicities); severe/opportunistic infections; metabolic abnormalities (tumor lysis syndrome); dermatologic reactions and gastrointestinal complications. Adcetris may cause harm to the fetus and newborn baby; women should be warned of the potential risk to the fetus and to use effective contraception, and to avoid breastfeeding while taking Adcetris. MMAE was found to be genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting drug. Fertility studies with Brentuximab vedotin or MMAE have not been conducted. Despite this, results of repeat-dose toxicity studies in rats suggest the potential for Brentuximab vedotin to have a negative effect on male reproductive function and fertility. In a 4-week repeated-dose toxicity study in rats with weekly dosing at 0.5, 5 or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell vacuolation, reduced spermatogenesis, and aspermia were observed. Effects in animals were seen mostly at 5 and 10 mg/kg doses of brentuximab vedotin. These dosages are approximately 3 and 6-fold the human recommended dose of 1.8 mg/kg, respectively, based on individual body weight. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Adcetris •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): Brentuximab vedotin is a CD30-directed antibody-drug conjugate used to treat various types of 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 CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Brentuximab vedotin interact? Information: •Drug A: Abatacept •Drug B: Brentuximab vedotin •Severity: MAJOR •Description: The metabolism of Brentuximab vedotin 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): Brentuximab vedotin is indicated in adult patients for the treatment of previously untreated stage III or IV classical Hodgkin's lymphoma (cHL) in combination with doxorubicin, vinblastine, and dacarbazine. It is also indicated for the treatment of cHL post-autologous hematopoietic stem cell transplantation (auto-HSCT) in patients at high risk of relapse or progression. Finally, it may be used in the treatment of adult patients with cHL who have previously failed either auto-HSCT or at least two prior multi-agent chemotherapy regimens if they are not candidates for auto-HSCT. Brentuximab vedotin is additionally indicated in the treatment of previously untreated systemic anaplastic large cell lymphoma (sALCL), or other CD30-expressing peripheral T-cell lymphomas (PTCL), in combination with cyclophosphamide, doxorubicin, and prednisone. It may also be used as monotherapy in sALCL after therapeutic failure of a least one prior multi-agent chemotherapy regimen. Brentuximab vedotin is also indicated in the treatment of primary cutaneous large anaplastic large cell lymphoma, or CD30-expressing mycosis fungoides, who have received prior systemic 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): Brentuximab vedotin causes apoptosis of tumor cells by preventing cell cycle progression of the G2 to M phase through disruption of the cytosolic microtuble network, thus preventing tumor growth and proliferation. Hodgkin lymphoma (HL) is characterized by malignant Reed-Sternberg cells which express CD30, a marker of large cell lymphoma. Until March 2018, USA National Comprehensive Cancer Network guidelines for patients with advanced HL (stage III/IV disease) recommend treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), or escalated bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) as first-line regimens. ABVD appears to be as effective, with fewer side effects, as escalated BEACOPP. Escalated BEACOPP leads to a greater progression-free survival but no difference in overall survival. Recent progress in technology has enabled a new shift to cancer therapy targeting specific molecules. Brentuximab vedotin, a CD30-directed antibody conjugate, selectively targets malignant HL cells. The effect of Brentuximab vedotin (1.8 mg/kg) on the QTc interval was studied in an open-label, single-group study in 46 patients diagnosed with CD30-expressing hematologic malignancies. Ingestion of brentuximab vedotin did not prolong the mean cardiac QTc interval >10 ms from baseline levels. Smaller increases in the mean QTc interval (<10 ms) cannot be ruled out because this study did not include a placebo arm and a positive control arm. •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): Brentuximab vedotin is composed of 3 parts: a chimeric human-murine IgG1 that selectively targets CD30, monomethyl auristatin E (MMAE), which is a microtubule-disrupting agent, and a protease-susceptible linker that links the antibody and MMAE. The IgG1 antibody enables Brentuximab vedotin to target tumor cells expressing CD30 on their surface. Following this Brentuximab vedotin enters the cell. Once inside, the linker is cleaved releasing MMAE which binds disrupts the microtubule network. The antibody component of this drug is a chimeric IgG1 directed against CD30. The small molecule, MMAE, is a microtubule-disrupting particle. MMAE is covalently attached to the antibody by a linker. Data suggest that the anticancer activity of Adcertris is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC-CD30 complex, and the subsequent release of MMAE by proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, inducing cell cycle arrest and apoptotis of the 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): Steady-state of the ADC is achieved within 21 days with every 3-week dosing of Adcetris. Minimal to no accumulation of ADC is observed with multiple doses at the every 3-week schedule. The time to maximum concentration for MMAE ranges from approximately 1 to 3 days. Similar to the ADC, steady-state of MMAE is achieved within 21 days with every 3-week dosing of Adcetris. MMAE exposures decrease with continued administration of Adcetris with about 50% to 80% of the exposure of the first dose being observed at future doses. The AUC of MMAE was measured to be approximately 2.2-fold higher in patients with hepatic impairment in comparison with patients with normal hepatic function. •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): MMAE is unlikely to displace or to be displaced by highly protein-bound drugs. In vitro studies show that MMAE is a substrate of P-gp and was not a potent inhibitor of P-gp. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, the binding of MMAE to human plasma proteins is in the range of 68–82%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Data in both animals and humans suggest that only a small fraction of MMAE released from brentuximab vedotin is metabolized. In vitro data indicate that the MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP isoforms. MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): This drug appears follow metabolite kinetics, with the elimination of appearing to be limited by its rate of release from the antibody-drug conjugate (ADC). An excretion study was done in patients receiving a dose of 1.8 mg/kg of Adcetris. About 24% of the total MMAE ingested as part of the ADC during an ADCETRIS infusion was recovered in both urine and feces over a 7-day time frame. Of the recovered MMAE, approximately 72% was found in the feces and the majority of the excreted MMAE was excreted 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): The terminal half-life is approximately 4-6 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): The liver is the primary route of clearance for MMAE. The pharmacokinetics and safety of Brentuximab vedotin and MMAE were examined after the administration of 1.2 mg/kg of Adcetris to patients with mild, moderate, and severe hepatic impairment. In patients with moderate and severe hepatic impairment, the rate of ≥Grade 3 adverse reactions was 6/6 (100%) compared to 3/8 (38%) in patients with normal hepatic function. It is recommended to avoid use in patients with severe renal impairment (CrCl <30mL/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 severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy (PML) follows infection by the JC virus (which is not related to Creutzfeldt-Jakob disease). Symptoms of this condition begin insidiously and usually worsen progressively. The symptoms vary depending on which region of the brain is infected. In about two out of three patients, mental function deteriorates rapidly, leading to dementia. Speaking and walking may become increasingly difficult. Vision may be impaired, and total blindness may occur. Rarely, headaches and seizures can occur, mainly in immunocompromised patients. The most serious sequela of this condition is death. Common adverse effects of Adcetris may include: neutropenia, anemia, peripheral neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and fever. In one trial, neutropenia occurred in 91 percent of patients treated with Adcetris plus chemotherapy, which was associated with a 19 percent rate of febrile neutropenia (neutropenia and fever). Preventive treatment with G-CSF, a growth factor for the bone marrow to produce white blood cells, is recommended with Adcetris plus chemotherapy for the first-line treatment of Stage III or IV cHL. Adcetris has a boxed warning that emphasizes the risk of John Cunningham virus infection leading to progressive multifocal leukoencephalopathy, or PML, a rare but serious brain infection that may be lethal. Serious risks of Adcetris include peripheral neuropathy; severe allergic (anaphylaxis) or infusion-site reactions; damage to the blood, lungs and liver (hematologic, pulmonary and hepato-toxicities); severe/opportunistic infections; metabolic abnormalities (tumor lysis syndrome); dermatologic reactions and gastrointestinal complications. Adcetris may cause harm to the fetus and newborn baby; women should be warned of the potential risk to the fetus and to use effective contraception, and to avoid breastfeeding while taking Adcetris. MMAE was found to be genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting drug. Fertility studies with Brentuximab vedotin or MMAE have not been conducted. Despite this, results of repeat-dose toxicity studies in rats suggest the potential for Brentuximab vedotin to have a negative effect on male reproductive function and fertility. In a 4-week repeated-dose toxicity study in rats with weekly dosing at 0.5, 5 or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell vacuolation, reduced spermatogenesis, and aspermia were observed. Effects in animals were seen mostly at 5 and 10 mg/kg doses of brentuximab vedotin. These dosages are approximately 3 and 6-fold the human recommended dose of 1.8 mg/kg, respectively, based on individual body weight. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Adcetris •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): Brentuximab vedotin is a CD30-directed antibody-drug conjugate used to treat various types of 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 CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Brexpiprazole interact?

•Drug A: Abatacept •Drug B: Brexpiprazole •Severity: MODERATE •Description: The metabolism of Brexpiprazole 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): Brexpiprazole is indicated as adjunctive therapy to antidepressants for the treatment of major depressive disorder in adults. It is also indicated for the treatment of schizophrenia in patients 13 years of age and older. Brexpiprazole is also indicated for the treatment of agitation associated with dementia due to Alzheimer’s disease; however, it is not indicated as an as-needed (“prn”) treatment for this condition. •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): Brexpiprazole is an atypical antipsychotic agent used to ameliorate the symptoms of psychiatric conditions, such as cognitive deficits and affective symptoms. Brexpiprazole has affinity (expressed as Ki) for multiple monoaminergic receptors including serotonin 5-HT 1A (0.12 nM), 5-HT 2A (0.47 nM), 5-HT 2B (1.9 nM), 5-HT 7 (3.7 nM), dopamine D2 (0.30 nM), D3 (1.1 nM), and noradrenergic α 1A (3.8 nM), α 1B (0.17 nM), α 1D (2.6 nM), and α 2C (0.59 nM) receptors. Brexpiprazole acts as a partial agonist at the 5-HT 1A, D2, and D3 receptors and as an antagonist at 5-HT 2A, 5-HT 2B, 5-HT 7, α 1A, α 1B, α 1D, and α 2C receptors. Brexpiprazole also exhibits affinity for histamine H1 receptor (19 nM) and for muscarinic M1 receptor (67% inhibition at 10 µM). •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): Although the exact mechanism of action of brexpiprazole in psychiatric disorders has not been fully elucidated, the efficacy of brexpiprazole may be attributed to combined partial agonist activity at 5-HT 1A and dopamine D2 receptors, and antagonist activity at 5-HT 2A receptors. Brexpiprazole binds to these receptors with subnanomolar affinities. These therapeutic targets have been implicated in psychiatric conditions such as schizophrenia and depression. Partial D2 receptor agonism allows the drug to stimulate D2 receptors under low dopamine conditions, while attenuating their activation when dopamine levels are high. Partial agonism at 5-HT 1A receptors may be tied to improved memory function and cognitive performance. Antagonism at α-adrenergic receptors has also been implicated in schizophrenia and 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): After a single-dose administration, the T max was four hours and the absolute oral bioavailability was 95%. Brexpiprazole steady-state concentrations were attained within 10 to 12 days of dosing. After single and multiple once-daily dose administration, the C max and AUC increased dose-proportionally. A high-fat meal did not significantly affect the C max or AUC of brexpiprazole. •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 brexpiprazole following intravenous administration is 1.56 ± 0.42 L/kg, indicating extravascular distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, brexpiprazole was 99% bound to plasma proteins, mainly serum albumin and α1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): According to in vitro studies, brexpiprazole is mainly metabolized by CYP3A4 and CYP2D6. Brexpiprazole and its major metabolite, DM-3411, were the predominant drug moieties in the systemic circulation following single and multiple dose administration. At steady-state, DM-3411 represented 23% to 48% of brexpiprazole exposure (AUC) in plasma. DM-3411 is considered not to be pharmacologically active. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single oral dose of radiolabeled brexpiprazole, approximately 25% and 46% of radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine, and approximately 14% of the oral dose was recovered unchanged 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): After multiple once-daily administrations, the terminal elimination half-lives of brexpiprazole and its major metabolite, DM-3411, were 91 hours and 86 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 oral clearance of brexpiprazole after once-daily administration is 19.8 (±11.4) mL/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): There is limited information regarding acute toxicity and human overdosage with brexpiprazole. Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Oral activated charcoal and sorbitol (50 g/240 mL), administered one hour after ingesting oral brexpiprazole, decreased brexpiprazole C max and area under the curve (AUC) by approximately 5% to 23% and 31% to 39% respectively; however, there is insufficient information available on the therapeutic potential of activated charcoal in treating an overdose with brexpiprazole. There is no information on the effect of hemodialysis in treating an overdose with brexpiprazole; hemodialysis is unlikely to be useful because brexpiprazole is highly bound to plasma proteins. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Rexulti •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): Brexpiprazole is a serotonin–dopamine activity modulator used in the treatment of major depressive disorder as an adjunct, schizophrenia, and agitation associated with dementia due to 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 Brexpiprazole interact? Information: •Drug A: Abatacept •Drug B: Brexpiprazole •Severity: MODERATE •Description: The metabolism of Brexpiprazole 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): Brexpiprazole is indicated as adjunctive therapy to antidepressants for the treatment of major depressive disorder in adults. It is also indicated for the treatment of schizophrenia in patients 13 years of age and older. Brexpiprazole is also indicated for the treatment of agitation associated with dementia due to Alzheimer’s disease; however, it is not indicated as an as-needed (“prn”) treatment for this condition. •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): Brexpiprazole is an atypical antipsychotic agent used to ameliorate the symptoms of psychiatric conditions, such as cognitive deficits and affective symptoms. Brexpiprazole has affinity (expressed as Ki) for multiple monoaminergic receptors including serotonin 5-HT 1A (0.12 nM), 5-HT 2A (0.47 nM), 5-HT 2B (1.9 nM), 5-HT 7 (3.7 nM), dopamine D2 (0.30 nM), D3 (1.1 nM), and noradrenergic α 1A (3.8 nM), α 1B (0.17 nM), α 1D (2.6 nM), and α 2C (0.59 nM) receptors. Brexpiprazole acts as a partial agonist at the 5-HT 1A, D2, and D3 receptors and as an antagonist at 5-HT 2A, 5-HT 2B, 5-HT 7, α 1A, α 1B, α 1D, and α 2C receptors. Brexpiprazole also exhibits affinity for histamine H1 receptor (19 nM) and for muscarinic M1 receptor (67% inhibition at 10 µM). •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): Although the exact mechanism of action of brexpiprazole in psychiatric disorders has not been fully elucidated, the efficacy of brexpiprazole may be attributed to combined partial agonist activity at 5-HT 1A and dopamine D2 receptors, and antagonist activity at 5-HT 2A receptors. Brexpiprazole binds to these receptors with subnanomolar affinities. These therapeutic targets have been implicated in psychiatric conditions such as schizophrenia and depression. Partial D2 receptor agonism allows the drug to stimulate D2 receptors under low dopamine conditions, while attenuating their activation when dopamine levels are high. Partial agonism at 5-HT 1A receptors may be tied to improved memory function and cognitive performance. Antagonism at α-adrenergic receptors has also been implicated in schizophrenia and 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): After a single-dose administration, the T max was four hours and the absolute oral bioavailability was 95%. Brexpiprazole steady-state concentrations were attained within 10 to 12 days of dosing. After single and multiple once-daily dose administration, the C max and AUC increased dose-proportionally. A high-fat meal did not significantly affect the C max or AUC of brexpiprazole. •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 brexpiprazole following intravenous administration is 1.56 ± 0.42 L/kg, indicating extravascular distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, brexpiprazole was 99% bound to plasma proteins, mainly serum albumin and α1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): According to in vitro studies, brexpiprazole is mainly metabolized by CYP3A4 and CYP2D6. Brexpiprazole and its major metabolite, DM-3411, were the predominant drug moieties in the systemic circulation following single and multiple dose administration. At steady-state, DM-3411 represented 23% to 48% of brexpiprazole exposure (AUC) in plasma. DM-3411 is considered not to be pharmacologically active. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following a single oral dose of radiolabeled brexpiprazole, approximately 25% and 46% of radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine, and approximately 14% of the oral dose was recovered unchanged 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): After multiple once-daily administrations, the terminal elimination half-lives of brexpiprazole and its major metabolite, DM-3411, were 91 hours and 86 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 oral clearance of brexpiprazole after once-daily administration is 19.8 (±11.4) mL/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): There is limited information regarding acute toxicity and human overdosage with brexpiprazole. Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Oral activated charcoal and sorbitol (50 g/240 mL), administered one hour after ingesting oral brexpiprazole, decreased brexpiprazole C max and area under the curve (AUC) by approximately 5% to 23% and 31% to 39% respectively; however, there is insufficient information available on the therapeutic potential of activated charcoal in treating an overdose with brexpiprazole. There is no information on the effect of hemodialysis in treating an overdose with brexpiprazole; hemodialysis is unlikely to be useful because brexpiprazole is highly bound to plasma proteins. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Rexulti •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): Brexpiprazole is a serotonin–dopamine activity modulator used in the treatment of major depressive disorder as an adjunct, schizophrenia, and agitation associated with dementia due to 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 Brigatinib interact?

•Drug A: Abatacept •Drug B: Brigatinib •Severity: MAJOR •Description: The metabolism of Brigatinib 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 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): The anaplastic lymphoma kinase positive, metastatic non-small cell lung cancer (ALK+ NSCLC), represents only 3-5% of the NSCLC cancer cases, but the ALK mutation, overexpression and presence in several oncogenic fusion proteins in solid and hematologic tumors have pointed out the importance as well as its potential as a cancer therapy target. The ALK-related cases of NSCLC are associated with the presence of the fusion gene EML4-ALK which fused the ALK protein with the echinoderm microtubule-associated protein like-4 whose original function is the correct formation of microtubules. The presence of the aberrant fusion protein results in abnormal signaling that provokes increased cell growth, proliferation and survival. Crizotinib is indicated for the treatment of such cases but the presence of ALK kinase domain mutations confer resistance to the treatment. Thus, brigatinib is indicated for the treatment of patients with ALK+ NSCLC with intolerance to Crizotinib. •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): Brigitanib inhibits proliferation and in vitro viability of cells expressing the fusion protein EML4-ALK as well as 17 crizotinib-resistant ALK mutants. Its action is expanded to cells expressing EGFR deletions, ROS1-L2026M, FLT3-F691L and FLT3-D835Y. Brigitanib presents a dose-dependent inhibition of tumor growth, tumor burden and prolonged survival in mice EML4-ALK xenograft models. Time course of Brigatinib and exposure-response studies are still 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): Brigitanib acts as a tyrosine kinase inhibitor with activity against multiple kinases including ALK, ROS1, insulin-like growth factor 1 receptor and against EGFR deletions and point mutations. It acts by inhibiting ALK phosphorylation and the activation of downstream signaling 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): Administration of brigatinib at a concentration of 90 mg generates a Cmax of 552 ng/ml and AUC of 8165 ng h/ml while the administration of 180 mg presents a Cmax of 1452 ng/ml and AUC of 20276 ng h/ml. It has a dose proportional exposure with an accumulation ratio on the range of 1.9 to 2.4. Following oral administration of brigatinib, the Tmax is presented in a range from 1 to 4 hours. Consumption of a high-fat meal compared to overnight fasting reduces Cmax by 13% without presenting an effect on AUC. •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 153 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 66% of brigatinib dose is bound to plasma proteins, which gives a blood-to-plasma concentration ratio of 0.69. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Brigatinib is metabolized by CYP2C8 (72.4%) and CYP3A4 (27.6%) in human liver microsomes and hepatocytes. The two major metabolites generated are the N-demethylated form and the cysteine conjugated form. Oral administration of radiolabelled brigatinib showed the systemic presence of 91.5% in the unchanged form and 3.5% of the primary metabolite AP26123. The AUC of AP26123 is less than 10% of the AUC of brigatinib and presented an inhibitory effect 3 fold lower. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The elimination of brigatinib is divided in 65% in feces and 25% in urine. From the elimination in both compartments, the unchanged for of brigatinib represented 41% of the total in feces and 86% 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): The half-life of brigatinib at steady-state was 25 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): After oral administration of180 mg of brigatinib, the apparent oral clearance at steady-state is 12.7 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): Treatment with brigatinib generated not mutagenic chromosomal damage. Testicular toxicity, reported as lower weight of seminal vesicles and prostate gland, testicular tubular degeneration and lower weight as well as reduced size of testes with evidence of hypoespermatogenesis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alunbrig •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): Brigatinib is an anaplastic lymphoma kinase inhibitor used to treat anaplastic lymphoma kinase positive metastatic non small cell lung 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 CYP2C8 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Brigatinib interact? Information: •Drug A: Abatacept •Drug B: Brigatinib •Severity: MAJOR •Description: The metabolism of Brigatinib 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 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): The anaplastic lymphoma kinase positive, metastatic non-small cell lung cancer (ALK+ NSCLC), represents only 3-5% of the NSCLC cancer cases, but the ALK mutation, overexpression and presence in several oncogenic fusion proteins in solid and hematologic tumors have pointed out the importance as well as its potential as a cancer therapy target. The ALK-related cases of NSCLC are associated with the presence of the fusion gene EML4-ALK which fused the ALK protein with the echinoderm microtubule-associated protein like-4 whose original function is the correct formation of microtubules. The presence of the aberrant fusion protein results in abnormal signaling that provokes increased cell growth, proliferation and survival. Crizotinib is indicated for the treatment of such cases but the presence of ALK kinase domain mutations confer resistance to the treatment. Thus, brigatinib is indicated for the treatment of patients with ALK+ NSCLC with intolerance to Crizotinib. •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): Brigitanib inhibits proliferation and in vitro viability of cells expressing the fusion protein EML4-ALK as well as 17 crizotinib-resistant ALK mutants. Its action is expanded to cells expressing EGFR deletions, ROS1-L2026M, FLT3-F691L and FLT3-D835Y. Brigitanib presents a dose-dependent inhibition of tumor growth, tumor burden and prolonged survival in mice EML4-ALK xenograft models. Time course of Brigatinib and exposure-response studies are still 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): Brigitanib acts as a tyrosine kinase inhibitor with activity against multiple kinases including ALK, ROS1, insulin-like growth factor 1 receptor and against EGFR deletions and point mutations. It acts by inhibiting ALK phosphorylation and the activation of downstream signaling 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): Administration of brigatinib at a concentration of 90 mg generates a Cmax of 552 ng/ml and AUC of 8165 ng h/ml while the administration of 180 mg presents a Cmax of 1452 ng/ml and AUC of 20276 ng h/ml. It has a dose proportional exposure with an accumulation ratio on the range of 1.9 to 2.4. Following oral administration of brigatinib, the Tmax is presented in a range from 1 to 4 hours. Consumption of a high-fat meal compared to overnight fasting reduces Cmax by 13% without presenting an effect on AUC. •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 153 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 66% of brigatinib dose is bound to plasma proteins, which gives a blood-to-plasma concentration ratio of 0.69. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Brigatinib is metabolized by CYP2C8 (72.4%) and CYP3A4 (27.6%) in human liver microsomes and hepatocytes. The two major metabolites generated are the N-demethylated form and the cysteine conjugated form. Oral administration of radiolabelled brigatinib showed the systemic presence of 91.5% in the unchanged form and 3.5% of the primary metabolite AP26123. The AUC of AP26123 is less than 10% of the AUC of brigatinib and presented an inhibitory effect 3 fold lower. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The elimination of brigatinib is divided in 65% in feces and 25% in urine. From the elimination in both compartments, the unchanged for of brigatinib represented 41% of the total in feces and 86% 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): The half-life of brigatinib at steady-state was 25 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): After oral administration of180 mg of brigatinib, the apparent oral clearance at steady-state is 12.7 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): Treatment with brigatinib generated not mutagenic chromosomal damage. Testicular toxicity, reported as lower weight of seminal vesicles and prostate gland, testicular tubular degeneration and lower weight as well as reduced size of testes with evidence of hypoespermatogenesis. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Alunbrig •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): Brigatinib is an anaplastic lymphoma kinase inhibitor used to treat anaplastic lymphoma kinase positive metastatic non small cell lung 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 CYP2C8 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Brivaracetam interact?

•Drug A: Abatacept •Drug B: Brivaracetam •Severity: MODERATE •Description: The metabolism of Brivaracetam 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 as adjunctive therapy for partial-onset seizures in patients 16 years of age or 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): Brivaracetam binds SV2A with high affinity. SV2A is known to play a role in epileptogenesis through modulation of synaptic GABA release. It is thought that brivaracetam exerts its anti-epileptogenic effects through its binding to SV2A. Brivaracetam is also known to inhibit Na+ channels which may also contribute to its anti-epileptogenic action. •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 of brivaracetam's anti-epileptogenic activity 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): Nearly 100% oral bioavailability. •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): 0.5L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): <20% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily metabolized by hydrolysis of the acetamide moeity to form a carboxylic acid metabolite. Another metabolite is created via oxidation of the propyl side chain by CYP2C8 as well as CYP3A4, CYP2C19, and CYP2B6. Some conjugation with glucuronic acid and taurine account for a small amount of metabolism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): >95% excreted in urine with <10% of the parent compound unchanged. <1% excreted 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): 7-8h. •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): CL/F of 0.7-1.07 mL/min kg. Clearance is primarily metabolic with less than 10% of the parent drug excreted unchanged. •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 carcinogenesis or fertility impairment found. Overdose is associated with somnolence and dizziness. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Briviact •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): Brivaracetam is an anticonvulsant used for the treatment of partial-onset seizures that functions by binding to synaptic vesicle glycoprotein 2A (SV2A) in the brain.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Brivaracetam interact? Information: •Drug A: Abatacept •Drug B: Brivaracetam •Severity: MODERATE •Description: The metabolism of Brivaracetam 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 as adjunctive therapy for partial-onset seizures in patients 16 years of age or 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): Brivaracetam binds SV2A with high affinity. SV2A is known to play a role in epileptogenesis through modulation of synaptic GABA release. It is thought that brivaracetam exerts its anti-epileptogenic effects through its binding to SV2A. Brivaracetam is also known to inhibit Na+ channels which may also contribute to its anti-epileptogenic action. •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 of brivaracetam's anti-epileptogenic activity 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): Nearly 100% oral bioavailability. •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): 0.5L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): <20% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily metabolized by hydrolysis of the acetamide moeity to form a carboxylic acid metabolite. Another metabolite is created via oxidation of the propyl side chain by CYP2C8 as well as CYP3A4, CYP2C19, and CYP2B6. Some conjugation with glucuronic acid and taurine account for a small amount of metabolism. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): >95% excreted in urine with <10% of the parent compound unchanged. <1% excreted 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): 7-8h. •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): CL/F of 0.7-1.07 mL/min kg. Clearance is primarily metabolic with less than 10% of the parent drug excreted unchanged. •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 carcinogenesis or fertility impairment found. Overdose is associated with somnolence and dizziness. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Briviact •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): Brivaracetam is an anticonvulsant used for the treatment of partial-onset seizures that functions by binding to synaptic vesicle glycoprotein 2A (SV2A) in the brain. 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 Brodalumab interact?

•Drug A: Abatacept •Drug B: Brodalumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Brodalumab. •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): Brodalumab has been approved for the treatment of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. •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): Increase in the level of IL-17 due to blocking of its 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): Brodalumab binds with high affinity to interleukin (IL)-17 receptor A, thereby inhibiting several pro-inflammatory cytokines from the IL-17 family. •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): 4.62 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): 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): 0.223 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): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Siliq •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): Brodalumab 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 Brodalumab interact? Information: •Drug A: Abatacept •Drug B: Brodalumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Brodalumab. •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): Brodalumab has been approved for the treatment of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. •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): Increase in the level of IL-17 due to blocking of its 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): Brodalumab binds with high affinity to interleukin (IL)-17 receptor A, thereby inhibiting several pro-inflammatory cytokines from the IL-17 family. •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): 4.62 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): 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): 0.223 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): No toxicity available •Brand Names (Drug A): Orencia •Brand Names (Drug B): Siliq •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): Brodalumab 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 Bromazepam interact?

•Drug A: Abatacept •Drug B: Bromazepam •Severity: MODERATE •Description: The metabolism of Bromazepam 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 short-term treatment of insomnia, short-term treatment of anxiety or panic attacks, if a benzodiazepine is required, and the alleviation of the symptoms of alcohol- and opiate-withdrawal. •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): Bromazepam is a lipophilic, long-acting benzodiazepine and with sedative, hypnotic, anxiolytic and skeletal muscle relaxant properties. It does not possess any antidepressant qualities. Bromazepam, like other benzodiazepines, presents a risk of abuse, misuse, and dependence. According to many psychiatric experts, Bromazepam has a greater abuse potential than other benzodiazepines because of fast resorption and rapid onset of action. •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): Bromazepam binds to the GABA-A receptor producing a conformational change and potentiating its inhibitory effects. Other neurotransmitters are not influenced. •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): Bioavailability is 84% following oral administration. The time to peak plasma level is 1 - 4 hours. Bromazepam is generally well 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): 1.56 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 70% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatically, via oxidative pathways (via an enzyme belonging to the Cytochrome P450 family of enzymes). One of the main metabolites is 3-hydroxybromazepam. It is pharmacologically active and the half life is similar to that of the parent compound. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Urine (69%), as 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): 10-20 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): 0.82 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): 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): Bromazepam is a short-acting benzodiazepine with intermediate onset commonly used to treat panic disorders and severe anxiety.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Bromazepam interact? Information: •Drug A: Abatacept •Drug B: Bromazepam •Severity: MODERATE •Description: The metabolism of Bromazepam 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 short-term treatment of insomnia, short-term treatment of anxiety or panic attacks, if a benzodiazepine is required, and the alleviation of the symptoms of alcohol- and opiate-withdrawal. •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): Bromazepam is a lipophilic, long-acting benzodiazepine and with sedative, hypnotic, anxiolytic and skeletal muscle relaxant properties. It does not possess any antidepressant qualities. Bromazepam, like other benzodiazepines, presents a risk of abuse, misuse, and dependence. According to many psychiatric experts, Bromazepam has a greater abuse potential than other benzodiazepines because of fast resorption and rapid onset of action. •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): Bromazepam binds to the GABA-A receptor producing a conformational change and potentiating its inhibitory effects. Other neurotransmitters are not influenced. •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): Bioavailability is 84% following oral administration. The time to peak plasma level is 1 - 4 hours. Bromazepam is generally well 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): 1.56 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 70% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatically, via oxidative pathways (via an enzyme belonging to the Cytochrome P450 family of enzymes). One of the main metabolites is 3-hydroxybromazepam. It is pharmacologically active and the half life is similar to that of the parent compound. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Urine (69%), as 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): 10-20 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): 0.82 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): 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): Bromazepam is a short-acting benzodiazepine with intermediate onset commonly used to treat panic disorders and severe anxiety. 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 Bromotheophylline interact?

•Drug A: Abatacept •Drug B: Bromotheophylline •Severity: MODERATE •Description: The metabolism of Bromotheophylline 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): Bromotheophylline is used as a diuretic and also, in combination with Acetaminophen, it is used for the relief of temporary water weight gain, bloating, swelling and full feeling associated with the premenstrual and menstrual periods. •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): Bromotheophylline diuretic action will produce an immediate increase in urination frequency. This effect aids in the relief of bloating and menstrual pain. This diuretic function is performed by the an increase in glomerular filtration and a potential effect in the tubular reabsorption as it is established that the administration of these agents produce a rise in the urinary concentration of sodium a chloride and thus, an increase in their rates of excretion. •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): Bromotheophylline is part of the group of the xanthines. As part of this group, it is thought that bromotheophylline increases the permeability of the renal tubule, increases glomerular filtration rate and inhibits the sodium reabsorption in the proximal tubule. It is thought but not confirmed that pamabrom as a mixture seems to have an additional mechanism of action in which the presence of 2-amino-2-methyl-1-propanol produces the suppression of the antidiuretic hormone in the posterior pituitary gland. •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): When administered after one single oral dosage, bromotheophylline is rapidly absorbed and it reaches a maximal plasma concentration of 2.5 mg/L in 0.78 hours. The mean residence time is registered to be of 12 hours with an AUC in the first 8 hours of 27 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): This pharmacokinetic property has not been determined. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): This pharmacokinetic property has not been determined. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): This pharmacokinetic property has not been determined. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): This pharmacokinetic property 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 apparent elimination half-life is registered to be 21.35 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): This pharmacokinetic property has not been determined. •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 overdose, bromotheophylline does not produce hepatic toxicity. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Pamprin Multi-symptom, Premsyn Pms •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 CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Bromotheophylline interact? Information: •Drug A: Abatacept •Drug B: Bromotheophylline •Severity: MODERATE •Description: The metabolism of Bromotheophylline 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): Bromotheophylline is used as a diuretic and also, in combination with Acetaminophen, it is used for the relief of temporary water weight gain, bloating, swelling and full feeling associated with the premenstrual and menstrual periods. •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): Bromotheophylline diuretic action will produce an immediate increase in urination frequency. This effect aids in the relief of bloating and menstrual pain. This diuretic function is performed by the an increase in glomerular filtration and a potential effect in the tubular reabsorption as it is established that the administration of these agents produce a rise in the urinary concentration of sodium a chloride and thus, an increase in their rates of excretion. •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): Bromotheophylline is part of the group of the xanthines. As part of this group, it is thought that bromotheophylline increases the permeability of the renal tubule, increases glomerular filtration rate and inhibits the sodium reabsorption in the proximal tubule. It is thought but not confirmed that pamabrom as a mixture seems to have an additional mechanism of action in which the presence of 2-amino-2-methyl-1-propanol produces the suppression of the antidiuretic hormone in the posterior pituitary gland. •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): When administered after one single oral dosage, bromotheophylline is rapidly absorbed and it reaches a maximal plasma concentration of 2.5 mg/L in 0.78 hours. The mean residence time is registered to be of 12 hours with an AUC in the first 8 hours of 27 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): This pharmacokinetic property has not been determined. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): This pharmacokinetic property has not been determined. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): This pharmacokinetic property has not been determined. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): This pharmacokinetic property 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 apparent elimination half-life is registered to be 21.35 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): This pharmacokinetic property has not been determined. •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 overdose, bromotheophylline does not produce hepatic toxicity. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Pamprin Multi-symptom, Premsyn Pms •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 CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Brompheniramine interact?

•Drug A: Abatacept •Drug B: Brompheniramine •Severity: MODERATE •Description: The metabolism of Brompheniramine 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 the treatment of the symptoms of the common cold and allergic rhinitis, such as runny nose, itchy eyes, watery eyes, and sneezing. •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): Brompheniramine is an antihistaminergic medication of the propylamine class. It is a first-generation antihistamine. In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H 1 -receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Brompheniramine is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •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): Brompheniramine is an antagonist of the H1 histamine receptors with moderate antimuscarinic actions, as with other common antihistamines such as diphenhydramine. Due to its anticholindergic effects, brompheniramine may cause drowsiness, sedation, dry mouth, dry throat, blurred vision, and increased 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): Antihistamines are well absorbed from the gastrointestinal tract 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): 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 (cytochrome P-450 system), some renal. •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): Oral, rat: LD 50 = 318 mg/kg. Signs of overdose include fast or irregular heartbeat, mental or mood changes, tightness in the chest, and unusual tiredness or weakness. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Bromfed DM, Lodrane D, M-end PE, Mar-cof BP •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bromfeniramina Brompheniramin Bromphéniramine Brompheniramine Brompheniraminum •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): Brompheniramine is a histamine H1 antagonist used to treat coughs, upper respiratory symptoms, and nasal congestion associated with allergies and the common cold.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Brompheniramine interact? Information: •Drug A: Abatacept •Drug B: Brompheniramine •Severity: MODERATE •Description: The metabolism of Brompheniramine 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 the treatment of the symptoms of the common cold and allergic rhinitis, such as runny nose, itchy eyes, watery eyes, and sneezing. •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): Brompheniramine is an antihistaminergic medication of the propylamine class. It is a first-generation antihistamine. In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H 1 -receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Brompheniramine is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •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): Brompheniramine is an antagonist of the H1 histamine receptors with moderate antimuscarinic actions, as with other common antihistamines such as diphenhydramine. Due to its anticholindergic effects, brompheniramine may cause drowsiness, sedation, dry mouth, dry throat, blurred vision, and increased 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): Antihistamines are well absorbed from the gastrointestinal tract 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): 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 (cytochrome P-450 system), some renal. •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): Oral, rat: LD 50 = 318 mg/kg. Signs of overdose include fast or irregular heartbeat, mental or mood changes, tightness in the chest, and unusual tiredness or weakness. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Bromfed DM, Lodrane D, M-end PE, Mar-cof BP •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bromfeniramina Brompheniramin Bromphéniramine Brompheniramine Brompheniraminum •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): Brompheniramine is a histamine H1 antagonist used to treat coughs, upper respiratory symptoms, and nasal congestion associated with allergies and the common cold. 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 Budesonide interact?

•Drug A: Abatacept •Drug B: Budesonide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Budesonide 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): Budesonide extended-release capsules are indicated for the treatment and maintenance of mild to moderate Crohn’s disease. Various inhaled budesonide products are indicated for prophylactic therapy in asthma and to reduce exacerbations of COPD. A budesonide nasal spray is available over the counter for symptoms of hay fever and upper respiratory allergies. Extended-release capsules are indicated to induce remission of mild to moderate ulcerative colitis and a rectal foam is used for mild to moderate distal ulcerative colitis. In addition, a delayed-release capsule formulation of budesonide is indicated to reduce proteinuria in adults with IgA nephropathy at risk of rapid disease progression. Budesonide is indicated to treat eosinophilic esophagitis (EoE): For this indication, it is only approved for use in adults in Europe while it is approved for short-term use (12 weeks) in patients 11 years of age and older in the US. •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): Budesonide is a glucocorticoid used to treat respiratory and digestive conditions by reducing inflammation. It has a wide therapeutic index, as dosing varies highly from patient to patient. Patients should be counselled regarding the risk of hypercorticism and adrenal axis suppression. •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): Extended release oral capsules are 9-21% bioavailable. A 9mg dose reaches a C max of 1.50±0.79ng/mL with a T max of 2-8h and an AUC of 7.33ng*hr/mL. A high fat meal increases the T max by 2.3h but otherwise does not affect the pharmacokinetics of budesonide. 180-360µg metered inhaled doses of budesonide are 34% deposited in the lungs, 39% bioavailable, and reach a C max of 0.6-1.6nmol/L with a T max of 10 minutes. A 1mg nebulized dose is 6% bioavailable, reaching a C max of 2.6nmol/L with a T max of 20 minutes. A 9mg oral extended release tablet reaches a C max of 1.35±0.96ng/mL with a T max of 13.3±5.9h and an AUC of 16.43±10.52ng*hr/mL. Budesonide rectal foam 2mg twice daily has an AUC of 4.31ng*hr/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 budesonide is 2.2-3.9L/kg. •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. Budesonide is 85-90% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Budesonide is 80-90% metabolized at first pass. Budesonide is metabolized by CYP3A to its 2 major metabolites, 6beta-hydroxybudesonide and 16alpha-hydroxyprednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. CYP3A4 is the strongest metabolizer of budesonide, followed by CYP3A5, and CYP3A7. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 60% of a budesonide dose is recovered in the urine as the major metabolites 6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone, and their conjugates. No unchanged budesonide is recovered 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): Budesonide has a plasma elimination half life of 2-3.6h. The terminal elimination half life in asthmatic children 4-6 years old is 2.3h. •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): Budesonide has a plasma clearance of 0.9-1.8L/min. The 22R form has a clearance of 1.4L/min while the 22S form has a clearance of 1.0L/min. The clearance in asthmatic children 4-6 years old is 0.5L/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): Acute overdose of corticosteroids is rare, however prolonged high dosing of corticosteroids can lead to hypercorticism and adrenal axis suppression. In the case of overdose, reduce the dosage of corticosteroids temporarily. A 200mg oral dose is lethal to female mice while a 400mg oral dose is lethal to male mice. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Airsupra, Breyna, Breztri, Cortiment, Entocort, Eohilia, Pulmicort, Pulmicort Turbuhaler, Rhinocort, Symbicort, Tarpeyo, Uceris •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Budesónida Budesonide •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): Budesonide is a corticosteroid used to treat Crohn's disease, asthma, COPD, hay fever and allergies, and ulcerative colitis.

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 Budesonide interact? Information: •Drug A: Abatacept •Drug B: Budesonide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Budesonide 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): Budesonide extended-release capsules are indicated for the treatment and maintenance of mild to moderate Crohn’s disease. Various inhaled budesonide products are indicated for prophylactic therapy in asthma and to reduce exacerbations of COPD. A budesonide nasal spray is available over the counter for symptoms of hay fever and upper respiratory allergies. Extended-release capsules are indicated to induce remission of mild to moderate ulcerative colitis and a rectal foam is used for mild to moderate distal ulcerative colitis. In addition, a delayed-release capsule formulation of budesonide is indicated to reduce proteinuria in adults with IgA nephropathy at risk of rapid disease progression. Budesonide is indicated to treat eosinophilic esophagitis (EoE): For this indication, it is only approved for use in adults in Europe while it is approved for short-term use (12 weeks) in patients 11 years of age and older in the US. •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): Budesonide is a glucocorticoid used to treat respiratory and digestive conditions by reducing inflammation. It has a wide therapeutic index, as dosing varies highly from patient to patient. Patients should be counselled regarding the risk of hypercorticism and adrenal axis suppression. •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): Extended release oral capsules are 9-21% bioavailable. A 9mg dose reaches a C max of 1.50±0.79ng/mL with a T max of 2-8h and an AUC of 7.33ng*hr/mL. A high fat meal increases the T max by 2.3h but otherwise does not affect the pharmacokinetics of budesonide. 180-360µg metered inhaled doses of budesonide are 34% deposited in the lungs, 39% bioavailable, and reach a C max of 0.6-1.6nmol/L with a T max of 10 minutes. A 1mg nebulized dose is 6% bioavailable, reaching a C max of 2.6nmol/L with a T max of 20 minutes. A 9mg oral extended release tablet reaches a C max of 1.35±0.96ng/mL with a T max of 13.3±5.9h and an AUC of 16.43±10.52ng*hr/mL. Budesonide rectal foam 2mg twice daily has an AUC of 4.31ng*hr/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 budesonide is 2.2-3.9L/kg. •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. Budesonide is 85-90% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Budesonide is 80-90% metabolized at first pass. Budesonide is metabolized by CYP3A to its 2 major metabolites, 6beta-hydroxybudesonide and 16alpha-hydroxyprednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. CYP3A4 is the strongest metabolizer of budesonide, followed by CYP3A5, and CYP3A7. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Approximately 60% of a budesonide dose is recovered in the urine as the major metabolites 6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone, and their conjugates. No unchanged budesonide is recovered 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): Budesonide has a plasma elimination half life of 2-3.6h. The terminal elimination half life in asthmatic children 4-6 years old is 2.3h. •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): Budesonide has a plasma clearance of 0.9-1.8L/min. The 22R form has a clearance of 1.4L/min while the 22S form has a clearance of 1.0L/min. The clearance in asthmatic children 4-6 years old is 0.5L/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): Acute overdose of corticosteroids is rare, however prolonged high dosing of corticosteroids can lead to hypercorticism and adrenal axis suppression. In the case of overdose, reduce the dosage of corticosteroids temporarily. A 200mg oral dose is lethal to female mice while a 400mg oral dose is lethal to male mice. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Airsupra, Breyna, Breztri, Cortiment, Entocort, Eohilia, Pulmicort, Pulmicort Turbuhaler, Rhinocort, Symbicort, Tarpeyo, Uceris •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Budesónida Budesonide •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): Budesonide is a corticosteroid used to treat Crohn's disease, asthma, COPD, hay fever and allergies, and ulcerative colitis. 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 Bupivacaine interact?

•Drug A: Abatacept •Drug B: Bupivacaine •Severity: MODERATE •Description: The metabolism of Bupivacaine 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): As an implant, bupivacaine is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair. Bupivacaine, in liposome suspension, is indicated in patients aged 6 years and older for single-dose infiltration to produce postsurgical local analgesia. In adults, it is also indicated to produce regional analgesia via an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block. Bupivicaine, in combination with meloxicam, 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. Bupivacaine, alone or in combination with epinephrine, is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations are recommended for each type of block indicated to produce local or regional anesthesia or analgesia. Finally, its use is not indicated in all blocks given clinically significant risks associated with 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): Bupivacaine is a widely used local anesthetic agent. Bupivacaine is often administered by spinal injection prior to total hip arthroplasty. It is also commonly injected into surgical wound sites to reduce pain for up to 20 hours after surgery. In comparison to other local anesthetics it has a long duration of action. It is also the most toxic to the heart when administered in large doses. This problem has led to the use of other long-acting local anaesthetics:ropivacaine and levobupivacaine. Levobupivacaine is a derivative, specifically an enantiomer, of bupivacaine. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. •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): Like lidocaine, bupivacaine is an amide local anesthetic that provides local anesthesia through blockade of nerve impulse generation and conduction. These impulses, also known as action potentials, critically depend on membrane depolarization produced by the influx of sodium ions into the neuron through voltage-gated sodium channels. Bupivacaine crosses the neuronal membrane and exerts its anesthetic action through blockade of these channels at the intracellular portion of their pore-forming transmembrane segments. The block is use-dependent, where repetitive or prolonged depolarization increases sodium channel blockade. Without sodium ions passing through the channel’s pore, bupivacaine stabilizes the membrane at rest and therefore prevents neurotransmission. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. While it is well-established that the main action of bupivacaine is through sodium channel block, additional analgesic effects of bupivacaine are thought to potentially be due to its binding to the prostaglandin E2 receptors, subtype EP1 (PGE2EP1), which inhibits the production of prostaglandins, thereby reducing fever, inflammation, and hyperalgesia. •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): Systemic absorption of local anesthetics is dose- and concentration-dependendent on the total drug administered. Other factors that affect the rate of systemic absorption include the route of administration, blood flow at the administration site, and the presence or absence of epinephrine in the anesthetic solution. Bupivacaine formulated for instillation with meloxicam produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 60 mg of bupivacaine produced a C max of 54 ± 33 ng/mL, a median T max of 3 h, and an AUC ∞ of 1718 ± 1211 ng*h/mL. For a 300 mg dose used in herniorrhaphy, the corresponding values were 271 ± 147 ng/mL, 18 h, and 15,524 ± 8921 ng*h/mL. Lastly, a 400 mg dose used in total knee arthroplasty produced values of 695 ± 411 ng/mL, 21 h, and 38,173 ± 29,400 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): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Bupivacaine is ~95% protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. The major metabolite of bupivacaine is 2,6-pipecoloxylidine, which is mainly catalyzed via cytochrome P450 3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Only 6% of bupivacaine 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): 2.7 hours in adults and 8.1 hours in neonates. Bupivacaine applied together with meloxicam for postsurgical analgesia had a median half-life of 15-17 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): 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 mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD 50 in mice is 6 to 8 mg/kg and 38 to 54 mg/kg respectively. Recent clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Exparel, Kenalog, Marbeta, Marcaine, Marcaine With Epinephrine, Marvona Suik, P-Care M, P-Care MG, P-care, Posimir, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Sensorcaine, Sensorcaine With Epinephrine, Vivacaine, Xaracoll, Zynrelef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bupivacaina Bupivacaine Bupivacainum DL-Bupivacaine Racemic bupivacaine •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): Bupivacaine 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 CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Bupivacaine interact? Information: •Drug A: Abatacept •Drug B: Bupivacaine •Severity: MODERATE •Description: The metabolism of Bupivacaine 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): As an implant, bupivacaine is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair. Bupivacaine, in liposome suspension, is indicated in patients aged 6 years and older for single-dose infiltration to produce postsurgical local analgesia. In adults, it is also indicated to produce regional analgesia via an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block. Bupivicaine, in combination with meloxicam, 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. Bupivacaine, alone or in combination with epinephrine, is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations are recommended for each type of block indicated to produce local or regional anesthesia or analgesia. Finally, its use is not indicated in all blocks given clinically significant risks associated with 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): Bupivacaine is a widely used local anesthetic agent. Bupivacaine is often administered by spinal injection prior to total hip arthroplasty. It is also commonly injected into surgical wound sites to reduce pain for up to 20 hours after surgery. In comparison to other local anesthetics it has a long duration of action. It is also the most toxic to the heart when administered in large doses. This problem has led to the use of other long-acting local anaesthetics:ropivacaine and levobupivacaine. Levobupivacaine is a derivative, specifically an enantiomer, of bupivacaine. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. •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): Like lidocaine, bupivacaine is an amide local anesthetic that provides local anesthesia through blockade of nerve impulse generation and conduction. These impulses, also known as action potentials, critically depend on membrane depolarization produced by the influx of sodium ions into the neuron through voltage-gated sodium channels. Bupivacaine crosses the neuronal membrane and exerts its anesthetic action through blockade of these channels at the intracellular portion of their pore-forming transmembrane segments. The block is use-dependent, where repetitive or prolonged depolarization increases sodium channel blockade. Without sodium ions passing through the channel’s pore, bupivacaine stabilizes the membrane at rest and therefore prevents neurotransmission. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. While it is well-established that the main action of bupivacaine is through sodium channel block, additional analgesic effects of bupivacaine are thought to potentially be due to its binding to the prostaglandin E2 receptors, subtype EP1 (PGE2EP1), which inhibits the production of prostaglandins, thereby reducing fever, inflammation, and hyperalgesia. •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): Systemic absorption of local anesthetics is dose- and concentration-dependendent on the total drug administered. Other factors that affect the rate of systemic absorption include the route of administration, blood flow at the administration site, and the presence or absence of epinephrine in the anesthetic solution. Bupivacaine formulated for instillation with meloxicam produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 60 mg of bupivacaine produced a C max of 54 ± 33 ng/mL, a median T max of 3 h, and an AUC ∞ of 1718 ± 1211 ng*h/mL. For a 300 mg dose used in herniorrhaphy, the corresponding values were 271 ± 147 ng/mL, 18 h, and 15,524 ± 8921 ng*h/mL. Lastly, a 400 mg dose used in total knee arthroplasty produced values of 695 ± 411 ng/mL, 21 h, and 38,173 ± 29,400 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): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Bupivacaine is ~95% protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. The major metabolite of bupivacaine is 2,6-pipecoloxylidine, which is mainly catalyzed via cytochrome P450 3A4. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Only 6% of bupivacaine 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): 2.7 hours in adults and 8.1 hours in neonates. Bupivacaine applied together with meloxicam for postsurgical analgesia had a median half-life of 15-17 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): 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 mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD 50 in mice is 6 to 8 mg/kg and 38 to 54 mg/kg respectively. Recent clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Exparel, Kenalog, Marbeta, Marcaine, Marcaine With Epinephrine, Marvona Suik, P-Care M, P-Care MG, P-care, Posimir, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Sensorcaine, Sensorcaine With Epinephrine, Vivacaine, Xaracoll, Zynrelef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bupivacaina Bupivacaine Bupivacainum DL-Bupivacaine Racemic bupivacaine •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): Bupivacaine 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 CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Buprenorphine interact?

•Drug A: Abatacept •Drug B: Buprenorphine •Severity: MODERATE •Description: The metabolism of Buprenorphine 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): Buprenorphine is available in different formulations, such as sublingual tablets, buccal films, transdermal films, and injections, alone or in combination with naloxone. The buccal film, intramuscular or intravenous injection, and transdermal formulation are indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. The extended-release subcutaneous injections of buprenorphine are indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine. Injections are part of a complete treatment plan that includes counselling and psychosocial support. Sublingual tablets and buccal films, in combination with naloxone, are indicated for the maintenance treatment of opioid dependence as part of a complete treatment plan that includes counselling and psychosocial support. •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): Buprenorphine interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, buprenorphine exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Buprenorphine depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Dependence Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.[F4718] Withdrawal Abrupt discontinuation of treatment is not recommended as it may result in an opioid withdrawal syndrome that may be delayed in onset. Signs and symptoms may 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.[F4718] Risk of Respiratory and Central Nervous System (CNS) Depression and Overdose Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressant, including alcohol. Use buprenorphine and naloxone sublingual tablets with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression). Risk of Overdose in Opioid Naïve Patients There have been reported deaths of opioid-naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. Buprenorphine and naloxone sublingual tablets are not appropriate as an analgesic in opioid-naïve patients. Precipitation of Opioid Withdrawal Signs and Symptoms If buprenorphine is started in opioid-dependent individuals, it will displace the other opioids and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms. Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine. Because it contains naloxone, buprenorphine and naloxone sublingual tablets are also highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Gastrointestinal Effects Buprenorphine and other morphine-like opioids have been shown to decrease bowel motility and cause constipation. Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions and should be administered with caution to patients with dysfunction of the biliary tract. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Use in Patients With Impaired Hepatic Function Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. The doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually titrated, and hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine. Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine’s efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. However, buprenorphine/naloxone products are not recommended for initiation of (treatment induction) in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal. Buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone. However, patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphine’s efficacy. Risk of Hepatitis, Hepatic Events Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, buprenorphine and naloxone sublingual tablets may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated. Orthostatic Hypotension Like other opioids, buprenorphine and naloxone sublingual tablets may produce orthostatic hypotension in ambulatory patients. Elevation of Cerebrospinal Fluid Pressure Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation. Elevation of Intracholedochal Pressure Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract. •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): Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. It demonstrates a high affinity for the mu-opioid receptor but has lower intrinsic activity compared to other full mu-opioid agonists such as heroin, oxycodone, or methadone. This means that buprenorphine preferentially binds the opioid receptor and displaces lower affinity opioids without activating the receptor to a comparable degree. Clinically, this results in a slow onset of action and a clinical phenomenon known as the "ceiling effect" where once a certain dose is reached buprenorphine's effects plateau. This effect can be beneficial, however, as dose-related side effects such as respiratory depression, sedation, and intoxication also plateau at around 32mg, resulting in a lower risk of overdose compared to methadone and other full agonist opioids. It also means that opioid-dependent patients do not experience sedation or euphoria at the same rate that they might experience with more potent opioids, improving quality of life for patients with severe pain and reducing the reinforcing effects of opioids which can lead to drug-seeking behaviours. Buprenorphine's high affinity, but low intrinsic activity for the mu-opioid receptor also means that if it is started in opioid-dependent individuals, it will displace the other opioids without creating an equal opioid effect and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms (i.e. anxiety, restlessness, gastrointestinal distress, diaphoresis, intense drug cravings, and tachycardia). Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine. Buprenorphine is commercially available as the brand name product Suboxone which is formulated in a 4:1 fixed-dose combination product along with naloxone, a non-selective competitive opioid receptor antagonist. Combination of an opioid agonist with an opioid antagonist may seem counterintuitive, however this combination with naloxone is intended to reduce the abuse potential of Suboxone, as naloxone is poorly absorbed by the oral route (and has no effect when taken orally), but would reverse the opioid agonist effects of buprenorphine if injected intravenously. •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): Bioavailablity of buprenorphine/naloxone is very high following intravenous or subcutaneous administration, lower by the sublingual or buccal route, and very low when administered by the oral route. It is therefore provided as a sublingual tablet that is absorbed from the oral mucosa directly into systemic circulation. Clinical pharmacokinetic studies found that there was wide inter-patient variability in the sublingual absorption of buprenorphine and naloxone, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased in a linear fashion with the increase in dose (in the range of 4 to 16 mg), although the increase was not directly dose-proportional. Buprenorphine combination with naloxone (2mg/0.5mg) provided in sublingual tablets demonstrated a Cmax of 0.780 ng/mL with a Tmax of 1.50 hr and AUC of 7.651 ng.hr/mL. Coadministration with naloxone does not effect the pharmacokinetics of buprenorphine. •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): Buprenorphine is highly lipophilic, and therefore extensively distributed, with rapid penetration through the blood-brain barrier. The estimated volume of distribution is 188 - 335 L when given intravenously. It is able to cross into the placenta and breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Buprenorphine is approximately 96% protein-bound, primarily to alpha- and beta-globulin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Buprenorphine is metabolized to norbuprenorphine via Cytochrome P450 3A4/3A5-mediated N-dealkylation. Buprenorphine and norbuprenorphine both also undergo glucuronidation to the inactive metabolites buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, respectively. While norbuprenorphine has been found to bind to opioid receptors in-vitro, brain concentrations are very low which suggests that it does not contribute to the clinical effects of buprenorphine. Naloxone undergoes direct glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Buprenorphine, like morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow. It is primarily eliminated via feces (as free forms of buprenorphine and norbuprenorphine) while 10 - 30% of the dose is excreted in urine (as conjugated forms of buprenorphine and norbuprenorphine). The overall mean elimination half-life of buprenorphine in plasma ranges from 31 to 42 hours, although the levels are very low 10 hours after dosing (majority of AUC of buprenorphine is captured within 10 hours), indicating that the effective half-life may be shorter. •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): Buprenorphine demonstrates slow dissociation kinetics (~166 min), which contributes to its long duration of action and allows for once-daily or even every-second-day dosing. In clinical trial studies, the half-life of sublingually administered buprenorphine/naloxone 2mg/0.5mg was found to be 30.75 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): Clearance may be higher in children than in adults. Plasma clearance rate, IV administration, anaesthetized patients = 901.2 ± 39.7 mL/min; Plasma clearance rate, IV administration, healthy subjects = 1042 - 1280 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): Manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression and death. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Belbuca, Brixadi, Buprenex, Buprenorphine, Butrans, Sublocade, Suboxone, Subutex, Zubsolv •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Buprenophine Buprenorfina Buprenorphine Buprenorphinum •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): Buprenorphine is a partial opioid agonist used for management of severe pain that is not responsive to alternative treatments. Also used for 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 CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Buprenorphine interact? Information: •Drug A: Abatacept •Drug B: Buprenorphine •Severity: MODERATE •Description: The metabolism of Buprenorphine 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): Buprenorphine is available in different formulations, such as sublingual tablets, buccal films, transdermal films, and injections, alone or in combination with naloxone. The buccal film, intramuscular or intravenous injection, and transdermal formulation are indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. The extended-release subcutaneous injections of buprenorphine are indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine. Injections are part of a complete treatment plan that includes counselling and psychosocial support. Sublingual tablets and buccal films, in combination with naloxone, are indicated for the maintenance treatment of opioid dependence as part of a complete treatment plan that includes counselling and psychosocial support. •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): Buprenorphine interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, buprenorphine exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Buprenorphine depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Dependence Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.[F4718] Withdrawal Abrupt discontinuation of treatment is not recommended as it may result in an opioid withdrawal syndrome that may be delayed in onset. Signs and symptoms may 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.[F4718] Risk of Respiratory and Central Nervous System (CNS) Depression and Overdose Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressant, including alcohol. Use buprenorphine and naloxone sublingual tablets with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression). Risk of Overdose in Opioid Naïve Patients There have been reported deaths of opioid-naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. Buprenorphine and naloxone sublingual tablets are not appropriate as an analgesic in opioid-naïve patients. Precipitation of Opioid Withdrawal Signs and Symptoms If buprenorphine is started in opioid-dependent individuals, it will displace the other opioids and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms. Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine. Because it contains naloxone, buprenorphine and naloxone sublingual tablets are also highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Gastrointestinal Effects Buprenorphine and other morphine-like opioids have been shown to decrease bowel motility and cause constipation. Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions and should be administered with caution to patients with dysfunction of the biliary tract. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Use in Patients With Impaired Hepatic Function Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. The doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually titrated, and hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine. Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine’s efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. However, buprenorphine/naloxone products are not recommended for initiation of (treatment induction) in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal. Buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone. However, patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphine’s efficacy. Risk of Hepatitis, Hepatic Events Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, buprenorphine and naloxone sublingual tablets may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated. Orthostatic Hypotension Like other opioids, buprenorphine and naloxone sublingual tablets may produce orthostatic hypotension in ambulatory patients. Elevation of Cerebrospinal Fluid Pressure Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation. Elevation of Intracholedochal Pressure Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract. •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): Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. It demonstrates a high affinity for the mu-opioid receptor but has lower intrinsic activity compared to other full mu-opioid agonists such as heroin, oxycodone, or methadone. This means that buprenorphine preferentially binds the opioid receptor and displaces lower affinity opioids without activating the receptor to a comparable degree. Clinically, this results in a slow onset of action and a clinical phenomenon known as the "ceiling effect" where once a certain dose is reached buprenorphine's effects plateau. This effect can be beneficial, however, as dose-related side effects such as respiratory depression, sedation, and intoxication also plateau at around 32mg, resulting in a lower risk of overdose compared to methadone and other full agonist opioids. It also means that opioid-dependent patients do not experience sedation or euphoria at the same rate that they might experience with more potent opioids, improving quality of life for patients with severe pain and reducing the reinforcing effects of opioids which can lead to drug-seeking behaviours. Buprenorphine's high affinity, but low intrinsic activity for the mu-opioid receptor also means that if it is started in opioid-dependent individuals, it will displace the other opioids without creating an equal opioid effect and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms (i.e. anxiety, restlessness, gastrointestinal distress, diaphoresis, intense drug cravings, and tachycardia). Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine. Buprenorphine is commercially available as the brand name product Suboxone which is formulated in a 4:1 fixed-dose combination product along with naloxone, a non-selective competitive opioid receptor antagonist. Combination of an opioid agonist with an opioid antagonist may seem counterintuitive, however this combination with naloxone is intended to reduce the abuse potential of Suboxone, as naloxone is poorly absorbed by the oral route (and has no effect when taken orally), but would reverse the opioid agonist effects of buprenorphine if injected intravenously. •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): Bioavailablity of buprenorphine/naloxone is very high following intravenous or subcutaneous administration, lower by the sublingual or buccal route, and very low when administered by the oral route. It is therefore provided as a sublingual tablet that is absorbed from the oral mucosa directly into systemic circulation. Clinical pharmacokinetic studies found that there was wide inter-patient variability in the sublingual absorption of buprenorphine and naloxone, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased in a linear fashion with the increase in dose (in the range of 4 to 16 mg), although the increase was not directly dose-proportional. Buprenorphine combination with naloxone (2mg/0.5mg) provided in sublingual tablets demonstrated a Cmax of 0.780 ng/mL with a Tmax of 1.50 hr and AUC of 7.651 ng.hr/mL. Coadministration with naloxone does not effect the pharmacokinetics of buprenorphine. •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): Buprenorphine is highly lipophilic, and therefore extensively distributed, with rapid penetration through the blood-brain barrier. The estimated volume of distribution is 188 - 335 L when given intravenously. It is able to cross into the placenta and breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Buprenorphine is approximately 96% protein-bound, primarily to alpha- and beta-globulin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Buprenorphine is metabolized to norbuprenorphine via Cytochrome P450 3A4/3A5-mediated N-dealkylation. Buprenorphine and norbuprenorphine both also undergo glucuronidation to the inactive metabolites buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, respectively. While norbuprenorphine has been found to bind to opioid receptors in-vitro, brain concentrations are very low which suggests that it does not contribute to the clinical effects of buprenorphine. Naloxone undergoes direct glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Buprenorphine, like morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow. It is primarily eliminated via feces (as free forms of buprenorphine and norbuprenorphine) while 10 - 30% of the dose is excreted in urine (as conjugated forms of buprenorphine and norbuprenorphine). The overall mean elimination half-life of buprenorphine in plasma ranges from 31 to 42 hours, although the levels are very low 10 hours after dosing (majority of AUC of buprenorphine is captured within 10 hours), indicating that the effective half-life may be shorter. •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): Buprenorphine demonstrates slow dissociation kinetics (~166 min), which contributes to its long duration of action and allows for once-daily or even every-second-day dosing. In clinical trial studies, the half-life of sublingually administered buprenorphine/naloxone 2mg/0.5mg was found to be 30.75 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): Clearance may be higher in children than in adults. Plasma clearance rate, IV administration, anaesthetized patients = 901.2 ± 39.7 mL/min; Plasma clearance rate, IV administration, healthy subjects = 1042 - 1280 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): Manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression and death. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Belbuca, Brixadi, Buprenex, Buprenorphine, Butrans, Sublocade, Suboxone, Subutex, Zubsolv •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Buprenophine Buprenorfina Buprenorphine Buprenorphinum •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): Buprenorphine is a partial opioid agonist used for management of severe pain that is not responsive to alternative treatments. Also used for 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 CYP2C9 substrates. The severity of the interaction is moderate.

Does Abatacept and Bupropion interact?

•Drug A: Abatacept •Drug B: Bupropion •Severity: MODERATE •Description: The metabolism of Bupropion 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): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •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): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •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): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •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): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, 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): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •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): 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): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •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): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Bupropion interact? Information: •Drug A: Abatacept •Drug B: Bupropion •Severity: MODERATE •Description: The metabolism of Bupropion 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): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •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): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •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): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •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): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, 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): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •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): 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): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •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): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. 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 Buspirone interact?

•Drug A: Abatacept •Drug B: Buspirone •Severity: MODERATE •Description: The metabolism of Buspirone 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 management of anxiety disorders or the short-term relief of the symptoms of anxiety. •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 clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •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 therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •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): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •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 a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •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 single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 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): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 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 oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Buspar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Buspiron Buspirona Buspirone Buspironum •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): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of 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 CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Buspirone interact? Information: •Drug A: Abatacept •Drug B: Buspirone •Severity: MODERATE •Description: The metabolism of Buspirone 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 management of anxiety disorders or the short-term relief of the symptoms of anxiety. •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 clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •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 therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •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): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •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 a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •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 single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 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): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 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 oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Buspar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Buspiron Buspirona Buspirone Buspironum •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): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of 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 CYP2D6 substrates. The severity of the interaction is moderate.

Does Abatacept and Busulfan interact?

•Drug A: Abatacept •Drug B: Busulfan •Severity: MAJOR •Description: The metabolism of Busulfan 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): For use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia (FDA has designated busulfan as an orphan drug for this use). It is also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases. •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): Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn leads to a miscoding of DNA. Alkylating agents are cell cycle-nonspecific and work by three different mechanisms, all of which achieve the same end result - disruption of DNA function and cell death. Overexpression of MGST2, a glutathione s-transferase, is thought to confer resistance to busulfan. The role of MGST2 in the metabolism of busulfan is unknown however. •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): Busulfan is an alkylating agent that contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain. Once busulfan is hydrolyzed, the methanesulfonate groups are released and carbonium ions are produced. These carbonium ions alkylate DNA, which results in the interference of DNA replication and RNA transcription, ultimately leading to the disruption of nucleic acid function. Specifically, its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks. These crosslinks occur through a SN2 reaction guanine N7 nucleophilically attacks the carbon adjacent to the mesylate leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis. •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): Completely absorbed from the gastrointestinal tract. Busulfan is a small, highly lipophilic molecule that crosses the blood-brain-barrier. The absolute bioavailability, if a single 2 mg IV bolus injection is given to adult patients, is 80% ± 20%. In children (1.5 - 6 years old), the absolute bioavailability was 68% ± 31%. When a single oral dose is given to patients, the area under the curve (AUC) was 130 ng•hr/mL. The peak plasma concentration when given orally is 30 ng/mL (after dose normalization to 2 mg). It takes 0.9 hours to reach peak plasma concentration after dose normalization to 4 mg. •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): 32% bound to plasma proteins and 47% bound to red blood cells. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Busulfan is extensively metabolizes in the hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. GSTA1 is the primary GST isoform that facilitates the the metabolism of busulfan. Other GST isoforms that are also involved are GSTM1 and GSTP1. At least 12 metabolites have been identified among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following administration of 14C- labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces. Less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. Elimination of busulfan is independent of renal function. •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): 2.6 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): 2.52 ml/min/kg [Following an infusion of dose of 0.8 mg/kg every six hours, for a total of 16 doses over four 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): Signs of overdose include allergic reaction, unusual bleeding or bruising, sudden weakness or unusual fatigue, persistent cough, congestion, or shortness of breath; flank, stomach or joint pain; pronounced nausea, vomiting, diarrhea, dizziness, confusion, or darkening of the skin, chills, fever, collapse, and loss of consciousness. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Busulfex, Myleran •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1,4-Dimesyloxybutane Busulfan Busulfano Busulfanum Busulphan •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): Busulfan is an alkylating agent used to treat chronic myelogenous 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 with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Busulfan interact? Information: •Drug A: Abatacept •Drug B: Busulfan •Severity: MAJOR •Description: The metabolism of Busulfan 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): For use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia (FDA has designated busulfan as an orphan drug for this use). It is also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases. •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): Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn leads to a miscoding of DNA. Alkylating agents are cell cycle-nonspecific and work by three different mechanisms, all of which achieve the same end result - disruption of DNA function and cell death. Overexpression of MGST2, a glutathione s-transferase, is thought to confer resistance to busulfan. The role of MGST2 in the metabolism of busulfan is unknown however. •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): Busulfan is an alkylating agent that contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain. Once busulfan is hydrolyzed, the methanesulfonate groups are released and carbonium ions are produced. These carbonium ions alkylate DNA, which results in the interference of DNA replication and RNA transcription, ultimately leading to the disruption of nucleic acid function. Specifically, its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks. These crosslinks occur through a SN2 reaction guanine N7 nucleophilically attacks the carbon adjacent to the mesylate leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis. •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): Completely absorbed from the gastrointestinal tract. Busulfan is a small, highly lipophilic molecule that crosses the blood-brain-barrier. The absolute bioavailability, if a single 2 mg IV bolus injection is given to adult patients, is 80% ± 20%. In children (1.5 - 6 years old), the absolute bioavailability was 68% ± 31%. When a single oral dose is given to patients, the area under the curve (AUC) was 130 ng•hr/mL. The peak plasma concentration when given orally is 30 ng/mL (after dose normalization to 2 mg). It takes 0.9 hours to reach peak plasma concentration after dose normalization to 4 mg. •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): 32% bound to plasma proteins and 47% bound to red blood cells. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Busulfan is extensively metabolizes in the hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. GSTA1 is the primary GST isoform that facilitates the the metabolism of busulfan. Other GST isoforms that are also involved are GSTM1 and GSTP1. At least 12 metabolites have been identified among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Following administration of 14C- labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces. Less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. Elimination of busulfan is independent of renal function. •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): 2.6 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): 2.52 ml/min/kg [Following an infusion of dose of 0.8 mg/kg every six hours, for a total of 16 doses over four 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): Signs of overdose include allergic reaction, unusual bleeding or bruising, sudden weakness or unusual fatigue, persistent cough, congestion, or shortness of breath; flank, stomach or joint pain; pronounced nausea, vomiting, diarrhea, dizziness, confusion, or darkening of the skin, chills, fever, collapse, and loss of consciousness. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Busulfex, Myleran •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1,4-Dimesyloxybutane Busulfan Busulfano Busulfanum Busulphan •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): Busulfan is an alkylating agent used to treat chronic myelogenous 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 with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Cabazitaxel interact?

•Drug A: Abatacept •Drug B: Cabazitaxel •Severity: MAJOR •Description: The metabolism of Cabazitaxel 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): Cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel -containing treatment regimen. In Europe and Canada, it can also be used in combination with prednisolone. •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): Cabazitaxel demonstrates a broad spectrum of antitumour activity against advanced human tumours xenografted in mice, including intracranial human glioblastomas. Cabazitaxel has a low affinity to P-glycoprotein, allowing it to penetrate the blood-brain barrier without being subject to extensive P-gp-mediated active efflux. Cabazitaxel works against docetaxel-sensitive tumours and tumour models resistant to docetaxel and other chemotherapy 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): Microtubules are cytoskeletal polymers that regulate cell shape, vesicle transport, cell signalling, and cell division. They are made up of alpha-tubulin and beta-tubulin heterodimers. Microtubules extend toward the mitotic spindle during mitosis to allow the separation and distribution of chromosomes during cell division. Cabazitaxel binds to the N-terminal amino acids of the beta-tubulin subunit and promotes microtubule polymerization while simultaneously inhibiting disassembly: this results in the stabilization of microtubules, preventing microtubule cell division. Cabazitaxel ultimately blocks mitotic and interphase cellular functions and tumour 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): Based on the population pharmacokinetic analysis, after an intravenous dose of cabazitaxel 25 mg/m every three weeks, the mean C max in patients with metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end of the one-hour infusion (T max ). The mean AUC in patients with metastatic prostate cancer was 991 ng x h/mL (CV 34%). No major deviation from the dose proportionality was observed from 10 to 30 mg/m in patients with advanced solid tumours. •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): Steady-state volume of distribution (V ss ) was 4,864 L (2,643 L/m for a patient with a median BSA of 1.84 m ). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, the binding of cabazitaxel to human serum proteins was 89% to 92% and was not saturable up to 50,000 ng/mL. Cabazitaxel is mainly bound to human serum albumin (82%) and lipoproteins (88% for HDL, 70% for LDL, and 56% for VLDL). The in vitro blood-to-plasma concentration ratio in human blood ranged from 0.90 to 0.99, indicating that cabazitaxel was equally distributed between blood and plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): More than 95% of cabazitaxel is extensively metabolized in the liver. CYP3A4 and CYP3A5 are responsible for 80% to 90% of drug metabolism, while CYP2C8 is involved to a lesser extent. While cabazitaxel is the main circulating moiety in human plasma, seven metabolites have been detected in plasma, including three active metabolites arising from O-demethylation - docetaxel, RPR112698, and RPR123142. The main metabolite accounts for 5% of total cabazitaxel exposure. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After a one-hour intravenous infusion [ C]-cabazitaxel 25 mg/m, approximately 80% of the administered dose was eliminated within two weeks. Cabazitaxel is mainly excreted in the feces as numerous metabolites (76% of the dose), while renal excretion of cabazitaxel and metabolites account for 3.7% of the dose (2.3% as unchanged drug in urine). Around 20 metabolites of cabazitaxel are excreted into human urine and 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 a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic model with α-, β-, and γ- half-lives of four minutes, two hours, and 95 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): Based on the population pharmacokinetic analysis, cabazitaxel has a plasma clearance of 48.5 L/h (CV 39%; 26.4 L/h/m for a patient with a median BSA of 1.84 m ) in patients with metastatic prostate cancer. •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 500 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Jevtana •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): Cabazitaxel is an antineoplastic agent used in combination with corticosteroids to treat metastatic castration-resistant prostate cancer in patients previously treated with a docetaxel-containing treatment regimen.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Cabazitaxel interact? Information: •Drug A: Abatacept •Drug B: Cabazitaxel •Severity: MAJOR •Description: The metabolism of Cabazitaxel 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): Cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel -containing treatment regimen. In Europe and Canada, it can also be used in combination with prednisolone. •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): Cabazitaxel demonstrates a broad spectrum of antitumour activity against advanced human tumours xenografted in mice, including intracranial human glioblastomas. Cabazitaxel has a low affinity to P-glycoprotein, allowing it to penetrate the blood-brain barrier without being subject to extensive P-gp-mediated active efflux. Cabazitaxel works against docetaxel-sensitive tumours and tumour models resistant to docetaxel and other chemotherapy 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): Microtubules are cytoskeletal polymers that regulate cell shape, vesicle transport, cell signalling, and cell division. They are made up of alpha-tubulin and beta-tubulin heterodimers. Microtubules extend toward the mitotic spindle during mitosis to allow the separation and distribution of chromosomes during cell division. Cabazitaxel binds to the N-terminal amino acids of the beta-tubulin subunit and promotes microtubule polymerization while simultaneously inhibiting disassembly: this results in the stabilization of microtubules, preventing microtubule cell division. Cabazitaxel ultimately blocks mitotic and interphase cellular functions and tumour 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): Based on the population pharmacokinetic analysis, after an intravenous dose of cabazitaxel 25 mg/m every three weeks, the mean C max in patients with metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end of the one-hour infusion (T max ). The mean AUC in patients with metastatic prostate cancer was 991 ng x h/mL (CV 34%). No major deviation from the dose proportionality was observed from 10 to 30 mg/m in patients with advanced solid tumours. •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): Steady-state volume of distribution (V ss ) was 4,864 L (2,643 L/m for a patient with a median BSA of 1.84 m ). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, the binding of cabazitaxel to human serum proteins was 89% to 92% and was not saturable up to 50,000 ng/mL. Cabazitaxel is mainly bound to human serum albumin (82%) and lipoproteins (88% for HDL, 70% for LDL, and 56% for VLDL). The in vitro blood-to-plasma concentration ratio in human blood ranged from 0.90 to 0.99, indicating that cabazitaxel was equally distributed between blood and plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): More than 95% of cabazitaxel is extensively metabolized in the liver. CYP3A4 and CYP3A5 are responsible for 80% to 90% of drug metabolism, while CYP2C8 is involved to a lesser extent. While cabazitaxel is the main circulating moiety in human plasma, seven metabolites have been detected in plasma, including three active metabolites arising from O-demethylation - docetaxel, RPR112698, and RPR123142. The main metabolite accounts for 5% of total cabazitaxel exposure. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After a one-hour intravenous infusion [ C]-cabazitaxel 25 mg/m, approximately 80% of the administered dose was eliminated within two weeks. Cabazitaxel is mainly excreted in the feces as numerous metabolites (76% of the dose), while renal excretion of cabazitaxel and metabolites account for 3.7% of the dose (2.3% as unchanged drug in urine). Around 20 metabolites of cabazitaxel are excreted into human urine and 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 a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic model with α-, β-, and γ- half-lives of four minutes, two hours, and 95 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): Based on the population pharmacokinetic analysis, cabazitaxel has a plasma clearance of 48.5 L/h (CV 39%; 26.4 L/h/m for a patient with a median BSA of 1.84 m ) in patients with metastatic prostate cancer. •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 500 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Jevtana •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): Cabazitaxel is an antineoplastic agent used in combination with corticosteroids to treat metastatic castration-resistant prostate cancer in patients previously treated with a docetaxel-containing treatment regimen. 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 Cabergoline interact?

•Drug A: Abatacept •Drug B: Cabergoline •Severity: MAJOR •Description: The metabolism of Cabergoline 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): For the treatment of hyperprolactinemic disorders, either idiopathic or due to prolactinoma (prolactin-secreting adenomas). May also be used to manage symptoms of Parkinsonian Syndrome as monotherapy during initial symptomatic management or as an adjunct to levodopa therapy during advanced stages of 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): Cabergoline stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D 1 and D 5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D 2, D 3 and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D 2 and D 3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D 2 - and D 3 -receptors. It also exhibits: agonist activity (in order of decreasing binding affinities) on 5-hydroxytryptamine (5-HT) 2B, 5-HT 2A, 5-HT 1D, dopamine D 4, 5-HT 1A, dopamine D 1, 5-HT 1B and 5-HT 2C receptors and antagonist activity on α 2B, α 2A, and α 2C receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT 2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion. •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 dopamine D 2 receptor is a 7-transmembrane G-protein coupled receptor associated with G i proteins. In lactotrophs, stimulation of dopamine D 2 causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D 2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders. Cabergoline is a long-acting dopamine receptor agonist with a high affinity for D2 receptors. Receptor-binding studies indicate that cabergoline has low affinity for dopamine D1, α 1,- and α 2 - adrenergic, and 5-HT 1 - and 5-HT 2 -serotonin 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): First-pass effect is seen, however the absolute bioavailability 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): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Moderately bound (40% to 42%) to human plasma proteins in a concentration-independent manner. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Cabergoline is extensively metabolized, predominately via hydrolysis of the acylurea bond of the urea moiety. Cytochrome P-450 mediated metabolism appears to be minimal. The main metabolite identified in urine is 6-allyl-8b-carboxy-ergoline (4-6% of dose). Three other metabolites were identified urine (less than 3% of dose). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After oral dosing of radioactive cabergoline to five healthy volunteers, approximately 22% and 60% of the dose was excreted within 20 days in the urine and feces, respectively. Less than 4% of the dose was 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): The elimination half-life is estimated from urinary data of 12 healthy subjects to range between 63 to 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): renal cl=0,008 L/min nonrenal cl=3.2 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): Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Dostinex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cabergolina Cabergoline Cabergolinum •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): Cabergoline is a dopamine receptor agonist used for the treatment of hyperprolactinemic conditions due to various causes.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Cabergoline interact? Information: •Drug A: Abatacept •Drug B: Cabergoline •Severity: MAJOR •Description: The metabolism of Cabergoline 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): For the treatment of hyperprolactinemic disorders, either idiopathic or due to prolactinoma (prolactin-secreting adenomas). May also be used to manage symptoms of Parkinsonian Syndrome as monotherapy during initial symptomatic management or as an adjunct to levodopa therapy during advanced stages of 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): Cabergoline stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D 1 and D 5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D 2, D 3 and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D 2 and D 3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D 2 - and D 3 -receptors. It also exhibits: agonist activity (in order of decreasing binding affinities) on 5-hydroxytryptamine (5-HT) 2B, 5-HT 2A, 5-HT 1D, dopamine D 4, 5-HT 1A, dopamine D 1, 5-HT 1B and 5-HT 2C receptors and antagonist activity on α 2B, α 2A, and α 2C receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT 2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion. •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 dopamine D 2 receptor is a 7-transmembrane G-protein coupled receptor associated with G i proteins. In lactotrophs, stimulation of dopamine D 2 causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D 2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders. Cabergoline is a long-acting dopamine receptor agonist with a high affinity for D2 receptors. Receptor-binding studies indicate that cabergoline has low affinity for dopamine D1, α 1,- and α 2 - adrenergic, and 5-HT 1 - and 5-HT 2 -serotonin 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): First-pass effect is seen, however the absolute bioavailability 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): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Moderately bound (40% to 42%) to human plasma proteins in a concentration-independent manner. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Cabergoline is extensively metabolized, predominately via hydrolysis of the acylurea bond of the urea moiety. Cytochrome P-450 mediated metabolism appears to be minimal. The main metabolite identified in urine is 6-allyl-8b-carboxy-ergoline (4-6% of dose). Three other metabolites were identified urine (less than 3% of dose). •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): After oral dosing of radioactive cabergoline to five healthy volunteers, approximately 22% and 60% of the dose was excreted within 20 days in the urine and feces, respectively. Less than 4% of the dose was 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): The elimination half-life is estimated from urinary data of 12 healthy subjects to range between 63 to 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): renal cl=0,008 L/min nonrenal cl=3.2 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): Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Dostinex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cabergolina Cabergoline Cabergolinum •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): Cabergoline is a dopamine receptor agonist used for the treatment of hyperprolactinemic conditions due to various causes. 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 Cabozantinib interact?

•Drug A: Abatacept •Drug B: Cabozantinib •Severity: MAJOR •Description: The metabolism of Cabozantinib 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 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): Cabozantinib is indicated for the treatment of progressive, metastatic medullary thyroid cancer. It is also indicated for the treatment of advanced renal cell carcinoma and for hepatocellular carcinoma in patients previously treated with sorafenib. •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): Cabozantinib suppresses metastasis, angiogenesis, and oncognesis by inhibiting receptor tyrosine kinases. •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): Cabozantinib inhibits specific receptor tyrosine kinases such as VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, RET, MET, and TIE-2. •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, peak plasma concentration was achieved in 2-5 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): The volume of distribution is 349L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cabozantinib has extensive plasma protein binding (≥ 99.7%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cabozantinib is metabolized mostly by CYP3A4 and, to a minor extent, by CYP2C9. Both enzyme produce an N-oxide metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Cabozantinib is eliminated mostly by the feces (54%) and also by the urine (27%). •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): Cabozantinib has a long half-life of 55 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): At steady state, the clearance is 4.4 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): Cabozantinib carries a warning of serious gastrointestinal fistulas and perforations, and potentially fatal hemoptysis and gastrointestinal hemorrhage. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cabometyx, Cometriq •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): Cabozantinib is a tyrosine kinase inhibitor used to treat advanced renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid 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 CYP2C9 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Abatacept and Cabozantinib interact? Information: •Drug A: Abatacept •Drug B: Cabozantinib •Severity: MAJOR •Description: The metabolism of Cabozantinib 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 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): Cabozantinib is indicated for the treatment of progressive, metastatic medullary thyroid cancer. It is also indicated for the treatment of advanced renal cell carcinoma and for hepatocellular carcinoma in patients previously treated with sorafenib. •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): Cabozantinib suppresses metastasis, angiogenesis, and oncognesis by inhibiting receptor tyrosine kinases. •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): Cabozantinib inhibits specific receptor tyrosine kinases such as VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, RET, MET, and TIE-2. •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, peak plasma concentration was achieved in 2-5 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): The volume of distribution is 349L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cabozantinib has extensive plasma protein binding (≥ 99.7%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cabozantinib is metabolized mostly by CYP3A4 and, to a minor extent, by CYP2C9. Both enzyme produce an N-oxide metabolite. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): Cabozantinib is eliminated mostly by the feces (54%) and also by the urine (27%). •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): Cabozantinib has a long half-life of 55 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): At steady state, the clearance is 4.4 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): Cabozantinib carries a warning of serious gastrointestinal fistulas and perforations, and potentially fatal hemoptysis and gastrointestinal hemorrhage. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Cabometyx, Cometriq •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): Cabozantinib is a tyrosine kinase inhibitor used to treat advanced renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid 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 CYP2C9 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Abatacept and Caffeine interact?

•Drug A: Abatacept •Drug B: Caffeine •Severity: MODERATE •Description: The metabolism of Caffeine 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): Caffeine is indicated for the short term treatment of apnea of prematurity in infants and off label for the prevention and treatment of bronchopulmonary dysplasia caused by premature birth. In addition, it is indicated in combination with sodium benzoate to treat respiratory depression resulting from an overdose with CNS depressant drugs. Caffeine has a broad range of over the counter uses, and is found in energy supplements, athletic enhancement products, pain relief products, as well as cosmetic products. •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): Caffeine stimulates the central nervous system (CNS), heightening alertness, and sometimes causing restlessness and agitation. It relaxes smooth muscle, stimulates the contraction of cardiac muscle, and enhances athletic performance. Caffeine promotes gastric acid secretion and increases gastrointestinal motility. It is often combined in products with analgesics and ergot alkaloids, relieving the symptoms of migraine and other types of headaches. Finally, caffeine acts as a mild diuretic. •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 caffeine is complex, as it impacts several body systems, which are listed below. The effects as they relate to various body systems are described as follows: General and cellular actions Caffeine exerts several actions on cells, but the clinical relevance is poorly understood. One probable mechanism is the inhibition of nucleotide phosphodiesterase enzymes, adenosine receptors, regulation of calcium handling in cells, and participates in adenosine receptor antagonism. Phosphodiesterase enzymes regulate cell function via actions on second messengers cAMP and cGMP. This causes lipolysis through activation of hormone-sensitive lipases, releasing fatty acids and glycerol. Respiratory The exact mechanism of action of caffeine in treating apnea related to prematurity is unknown, however, there are several proposed mechanisms, including respiratory center stimulation in the central nervous system, a reduced threshold to hypercapnia with increased response, and increased consumption of oxygen, among others. The blocking of the adenosine receptors enhances respiratory drive via an increase in brain medullary response to carbon dioxide, stimulating ventilation and respiratory drive, while increasing contractility of the diaphragm. Central nervous system Caffeine demonstrates antagonism of all 4 adenosine receptor subtypes (A1, A2a, A2b, A3) in the central nervous system. Caffeine's effects on alertness and combatting drowsiness are specifically related to the antagonism of the A2a receptor. Renal system Caffeine has diuretic effects due to is stimulatory effects on renal blood flow, increase in glomerular filtration, and increase in sodium excretion. Cardiovascular system Adenosine receptor antagonism at the A1 receptor by caffeine stimulates inotropic effects in the heart. Blocking of adenosine receptors promotes catecholamine release, leading to stimulatory effects occurring in the heart and the rest of the body. In the blood vessels, caffeine exerts direct antagonism of adenosine receptors, causing vasodilation. It stimulates the endothelial cells in the blood vessel wall to release nitric oxide, potentiating blood vessel relaxation. Catecholamine release, however, antagonizes this and exerts inotropic and chronotropic effects on the heart, ultimately leading to vasoconstriction. Finally, caffeine is shown to raise systolic blood pressure measurements by 5 to 10 mmHg when it is not taken regularly, versus no effect in those who consume it regularly. The vasoconstricting effects of caffeine are beneficial in migraines and other types of headache, which are normally caused by vasodilation in the brain. •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): Caffeine is rapidly absorbed after oral or parenteral administration, reaching peak plasma concentration within 30 minutes to 2 hours after administration. After oral administration, onset of action takes place within 45 to 1 hour. Food may delay caffeine absorption. The peak plasma level for caffeine ranges from 6-10mg/L. The absolute bioavailability is unavailable in neonates, but reaches about 100% in adults. •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): Caffeine has the ability to rapidly cross the blood-brain barrier. It is water and fat soluble and distributes throughout the body. Caffeine concentrations in the cerebrospinal fluid of preterm newborns are similar to the concentrations found in the plasma. The mean volume of distribution of caffeine in infants is 0.8-0.9 L/kg and 0.6 L/kg in the adult population. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of caffeine has not been determined for neonates or infants. In vitro studies indicate a protein binding of about 10%-36%. Caffeine is reversibly bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Caffeine metabolism occurs mainly in the liver via the cytochrome CYP1A2 enzyme. The products of caffeine metabolism include paraxanthine, theobromine, and theophylline. The first step of caffeine metabolism is demethylation, yielding paraxanthine (a major metabolite), followed by theobromine, and theophylline, which are both minor metabolites. They are then excreted in urine as urates after additional metabolism. The enzymes xanthine oxidase and N-acetyltransferase 2 (NAT2) also participate in the metabolism of caffeine. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The major metabolites of caffeine can be found excreted in the urine. About 0.5% to 2% of a caffeine dose is found excreted in urine, as it because it is heavily absorbed in the renal tubules. •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 an average-sized adult or child above the age of 9, the half-life of caffeine is approximately 5 hours. Various characteristics and conditions can alter caffeine half-life. It can be reduced by up to 50% in smokers. Pregnant women show an increased half-life of 15 hours or higher, especially in the third trimester. The half-life in newborns is prolonged to about 8 hours at full-term and 100 hours in premature infants, likely due to reduced ability to metabolize it. Liver disease or drugs that inhibit CYP1A2 can increase caffeine half-life. •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 caffeine varies, but on average, is about 0.078 L/kg/h (1.3 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): The oral LD50 of caffeine in rats is 192 mg/kg. An acute fatal overdose of caffeine in humans is about 10–14 grams (equivalent to 150–200 mg/kg of body weight). Caffeine overdose In the case of caffeine overdose, seizures may occur, as caffeine is a central nervous system stimulant. It should be used with extreme caution in those with epilepsy or other seizure disorders. Symptoms of overdose may include nausea, vomiting, diarrhea, and gastrointestinal upset. Intoxication with caffeine is included in the World Health Organization’s International Classification of Diseases (ICD-10). Agitation, anxiety, restlessness, insomnia, tachycardia, tremors, tachycardia, psychomotor agitation, and, in some cases, death can occur, depending on the amount of caffeine consumed. Overdose is more likely to occur in individuals who do not consume caffeine regularly but consume energy drinks. Overdose management For a mild caffeine overdose, offer symptomatic treatment. In the case of a severe overdose, intubation for airway protection from changes in mental status or vomiting may be needed. Activated charcoal and hemodialysis can prevent further complications of an overdose and prevent absorption and metabolism. Benzodiazepine drugs can be administered to prevent or treat seizures. IV fluids and vasopressors may be necessary to combat hypotension associated with caffeine overdose. In addition, magnesium and beta blocking drugs can be used to treat arrhythmias that may occur, with defibrillation and resuscitation if the arrhythmias are lethal. Follow local ACLS protocols. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Anacin, Arthriten Inflammatory Pain, Ascomp, Bc Arthritis, Bc Original Formula, Diurex, Dvorah, Esgic, Exaprin, Excedrin, Excedrin Tension Headache, Fioricet, Fioricet With Codeine, Fiorinal, Goody's Extra Strength, Goody's Headache Relief Shot, Goody's PM, Midol Complete, Midol Cramps & Bodyaches, Migergot, Norgesic, Norgesic Forte, Orbivan, Orphengesic, Pamprin Max Formula, Peyona, Stanback Headache Powder Reformulated Jan 2011, Trezix, Trianal, Trianal C, Triatec, Triatec-8, Vanatol, Vanatol S, Vanquish, Vivarin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-methyltheobromine 7-methyltheophylline Cafeína Caféine Caffeine Caffeinum Coffein Coffeinum Guaranine Koffein Mateína Methyltheobromine Teína Thein Theine •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): Caffeine is a stimulant present in tea, coffee, cola beverages, analgesic drugs, and agents used to increase alertness. It is also used in to prevent and treat pulmonary complications of premature 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 CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Abatacept and Caffeine interact? Information: •Drug A: Abatacept •Drug B: Caffeine •Severity: MODERATE •Description: The metabolism of Caffeine 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): Caffeine is indicated for the short term treatment of apnea of prematurity in infants and off label for the prevention and treatment of bronchopulmonary dysplasia caused by premature birth. In addition, it is indicated in combination with sodium benzoate to treat respiratory depression resulting from an overdose with CNS depressant drugs. Caffeine has a broad range of over the counter uses, and is found in energy supplements, athletic enhancement products, pain relief products, as well as cosmetic products. •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): Caffeine stimulates the central nervous system (CNS), heightening alertness, and sometimes causing restlessness and agitation. It relaxes smooth muscle, stimulates the contraction of cardiac muscle, and enhances athletic performance. Caffeine promotes gastric acid secretion and increases gastrointestinal motility. It is often combined in products with analgesics and ergot alkaloids, relieving the symptoms of migraine and other types of headaches. Finally, caffeine acts as a mild diuretic. •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 caffeine is complex, as it impacts several body systems, which are listed below. The effects as they relate to various body systems are described as follows: General and cellular actions Caffeine exerts several actions on cells, but the clinical relevance is poorly understood. One probable mechanism is the inhibition of nucleotide phosphodiesterase enzymes, adenosine receptors, regulation of calcium handling in cells, and participates in adenosine receptor antagonism. Phosphodiesterase enzymes regulate cell function via actions on second messengers cAMP and cGMP. This causes lipolysis through activation of hormone-sensitive lipases, releasing fatty acids and glycerol. Respiratory The exact mechanism of action of caffeine in treating apnea related to prematurity is unknown, however, there are several proposed mechanisms, including respiratory center stimulation in the central nervous system, a reduced threshold to hypercapnia with increased response, and increased consumption of oxygen, among others. The blocking of the adenosine receptors enhances respiratory drive via an increase in brain medullary response to carbon dioxide, stimulating ventilation and respiratory drive, while increasing contractility of the diaphragm. Central nervous system Caffeine demonstrates antagonism of all 4 adenosine receptor subtypes (A1, A2a, A2b, A3) in the central nervous system. Caffeine's effects on alertness and combatting drowsiness are specifically related to the antagonism of the A2a receptor. Renal system Caffeine has diuretic effects due to is stimulatory effects on renal blood flow, increase in glomerular filtration, and increase in sodium excretion. Cardiovascular system Adenosine receptor antagonism at the A1 receptor by caffeine stimulates inotropic effects in the heart. Blocking of adenosine receptors promotes catecholamine release, leading to stimulatory effects occurring in the heart and the rest of the body. In the blood vessels, caffeine exerts direct antagonism of adenosine receptors, causing vasodilation. It stimulates the endothelial cells in the blood vessel wall to release nitric oxide, potentiating blood vessel relaxation. Catecholamine release, however, antagonizes this and exerts inotropic and chronotropic effects on the heart, ultimately leading to vasoconstriction. Finally, caffeine is shown to raise systolic blood pressure measurements by 5 to 10 mmHg when it is not taken regularly, versus no effect in those who consume it regularly. The vasoconstricting effects of caffeine are beneficial in migraines and other types of headache, which are normally caused by vasodilation in the brain. •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): Caffeine is rapidly absorbed after oral or parenteral administration, reaching peak plasma concentration within 30 minutes to 2 hours after administration. After oral administration, onset of action takes place within 45 to 1 hour. Food may delay caffeine absorption. The peak plasma level for caffeine ranges from 6-10mg/L. The absolute bioavailability is unavailable in neonates, but reaches about 100% in adults. •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): Caffeine has the ability to rapidly cross the blood-brain barrier. It is water and fat soluble and distributes throughout the body. Caffeine concentrations in the cerebrospinal fluid of preterm newborns are similar to the concentrations found in the plasma. The mean volume of distribution of caffeine in infants is 0.8-0.9 L/kg and 0.6 L/kg in the adult population. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of caffeine has not been determined for neonates or infants. In vitro studies indicate a protein binding of about 10%-36%. Caffeine is reversibly bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Caffeine metabolism occurs mainly in the liver via the cytochrome CYP1A2 enzyme. The products of caffeine metabolism include paraxanthine, theobromine, and theophylline. The first step of caffeine metabolism is demethylation, yielding paraxanthine (a major metabolite), followed by theobromine, and theophylline, which are both minor metabolites. They are then excreted in urine as urates after additional metabolism. The enzymes xanthine oxidase and N-acetyltransferase 2 (NAT2) also participate in the metabolism of caffeine. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The major metabolites of caffeine can be found excreted in the urine. About 0.5% to 2% of a caffeine dose is found excreted in urine, as it because it is heavily absorbed in the renal tubules. •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 an average-sized adult or child above the age of 9, the half-life of caffeine is approximately 5 hours. Various characteristics and conditions can alter caffeine half-life. It can be reduced by up to 50% in smokers. Pregnant women show an increased half-life of 15 hours or higher, especially in the third trimester. The half-life in newborns is prolonged to about 8 hours at full-term and 100 hours in premature infants, likely due to reduced ability to metabolize it. Liver disease or drugs that inhibit CYP1A2 can increase caffeine half-life. •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 caffeine varies, but on average, is about 0.078 L/kg/h (1.3 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): The oral LD50 of caffeine in rats is 192 mg/kg. An acute fatal overdose of caffeine in humans is about 10–14 grams (equivalent to 150–200 mg/kg of body weight). Caffeine overdose In the case of caffeine overdose, seizures may occur, as caffeine is a central nervous system stimulant. It should be used with extreme caution in those with epilepsy or other seizure disorders. Symptoms of overdose may include nausea, vomiting, diarrhea, and gastrointestinal upset. Intoxication with caffeine is included in the World Health Organization’s International Classification of Diseases (ICD-10). Agitation, anxiety, restlessness, insomnia, tachycardia, tremors, tachycardia, psychomotor agitation, and, in some cases, death can occur, depending on the amount of caffeine consumed. Overdose is more likely to occur in individuals who do not consume caffeine regularly but consume energy drinks. Overdose management For a mild caffeine overdose, offer symptomatic treatment. In the case of a severe overdose, intubation for airway protection from changes in mental status or vomiting may be needed. Activated charcoal and hemodialysis can prevent further complications of an overdose and prevent absorption and metabolism. Benzodiazepine drugs can be administered to prevent or treat seizures. IV fluids and vasopressors may be necessary to combat hypotension associated with caffeine overdose. In addition, magnesium and beta blocking drugs can be used to treat arrhythmias that may occur, with defibrillation and resuscitation if the arrhythmias are lethal. Follow local ACLS protocols. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Anacin, Arthriten Inflammatory Pain, Ascomp, Bc Arthritis, Bc Original Formula, Diurex, Dvorah, Esgic, Exaprin, Excedrin, Excedrin Tension Headache, Fioricet, Fioricet With Codeine, Fiorinal, Goody's Extra Strength, Goody's Headache Relief Shot, Goody's PM, Midol Complete, Midol Cramps & Bodyaches, Migergot, Norgesic, Norgesic Forte, Orbivan, Orphengesic, Pamprin Max Formula, Peyona, Stanback Headache Powder Reformulated Jan 2011, Trezix, Trianal, Trianal C, Triatec, Triatec-8, Vanatol, Vanatol S, Vanquish, Vivarin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-methyltheobromine 7-methyltheophylline Cafeína Caféine Caffeine Caffeinum Coffein Coffeinum Guaranine Koffein Mateína Methyltheobromine Teína Thein Theine •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): Caffeine is a stimulant present in tea, coffee, cola beverages, analgesic drugs, and agents used to increase alertness. It is also used in to prevent and treat pulmonary complications of premature 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 CYP1A2 substrates. The severity of the interaction is moderate.

Does Abatacept and Canakinumab interact?

•Drug A: Abatacept •Drug B: Canakinumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Canakinumab. •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): Canakinumab is indicated for the treatment of periodic fever syndromes in specific patient populations. In patients ≥4 years of age, canakinumab is indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS). In adult and pediatric patients, canakinumab is also indicated for the treatment of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD), and Familial Mediterranean Fever (FMF). Canakinumab is additionally indicated in patients ≥2 years of age for the treatment of active Still's disease, including Adult-Onset Still's Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA). Canakinumab is also indicated for the treatment of gout flares in adult patients in whom standard therapies (e.g. NSAIDs, colchicine) are contraindicated, not tolerated, or ineffective, and in whom repeated courses of corticosteroids are not 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): Canakinumab neutralizes the activity of human IL-1β, which is involved in several inflammatory disorders. Canakinumab has promising clinical safety and pharmacokinetic properties, and demonstrated potential for the treatment of cryopyrin-associated periodic syndromes (CAPS), systemic juvenile idiopathic arthritis (SJIA), and possibly for other complex inflammatory diseases, such as rheumatoid arthritis, COPD disease and ocular diseases. •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): In inflammatory diseases involving Cryopyrin-Associated Periodic Syndromes (CAPS), interleukin-1 beta (IL-1β) is excessively activated and drives inflammation. The protein cryopyrin controls the activation of IL-1β, and mutations in cryopyrin's gene, NLRP-3, up-regulate IL-1β activation. Canakinumab binds to human IL-1β and neutralizes its inflammatory activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1α or IL-1 receptor antagonist (IL-1ra). •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 subcutaneously administered canakinumab is estimated to be 66%. Peak serum concentration is 16 ± 3.5 mcg/mL and occurs approximately 7 days following a single subcutaneous dose of 150mg. Exposure to canakinumab increases proportionately to the administered 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 steady-state volume of distribution of canakinumab is variable based on weight - it was estimated to be 6.01 liters in a typical CAPS patient weighing 70 kg, 3.2 liters in a SJIA patient weighing 33 kg, 6.34 liters for a Periodic Fever Syndrome (TRAPS, HIDS/MKD, FMF) patient weighing 70 kg and 7.9 liters in a typical patient with gout flares weighing 93 kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Canakinumab binds to plasma IL-1β, but plasma protein binding has not been quantified. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Canakinumab, like other therapeutic proteins, is likely degraded via non-specific catabolic processes to smaller peptides and amino acids. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The route of elimination for canakinumab has not yet 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): 26 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 canakinumab is variable based on weight - it was estimated to be 0.174 L/day in a typical CAPS patient weighing 70 kg, 0.11 L/day in an SJIA patient weighing 33 kg, 0.17 L/day in a Periodic Fever Syndrome (TRAPS, HIDS/MKD, FMF) patient weighing 70 kg and 0.23 L/day in a typical patient with gout flares of body weight 93 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): There are no confirmed cases of overdosage with canakinumab. In the event of an overdose, the patient should be monitored closely and appropriate symptomatic treatment should be administered immediately as clinically indicated. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ilaris •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): Canakinumab is an interleukin-1β blocker used to treat Periodic Fever Syndromes such as Cryopyrin-Associated Periodic Syndromes (CAPS) and Familial Mediterranean Fever (FMF), and also to treat active Systemic Juvenile Idiopathic Arthritis (SJIA).

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 Canakinumab interact? Information: •Drug A: Abatacept •Drug B: Canakinumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Abatacept is combined with Canakinumab. •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): Canakinumab is indicated for the treatment of periodic fever syndromes in specific patient populations. In patients ≥4 years of age, canakinumab is indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS). In adult and pediatric patients, canakinumab is also indicated for the treatment of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD), and Familial Mediterranean Fever (FMF). Canakinumab is additionally indicated in patients ≥2 years of age for the treatment of active Still's disease, including Adult-Onset Still's Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA). Canakinumab is also indicated for the treatment of gout flares in adult patients in whom standard therapies (e.g. NSAIDs, colchicine) are contraindicated, not tolerated, or ineffective, and in whom repeated courses of corticosteroids are not 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): Canakinumab neutralizes the activity of human IL-1β, which is involved in several inflammatory disorders. Canakinumab has promising clinical safety and pharmacokinetic properties, and demonstrated potential for the treatment of cryopyrin-associated periodic syndromes (CAPS), systemic juvenile idiopathic arthritis (SJIA), and possibly for other complex inflammatory diseases, such as rheumatoid arthritis, COPD disease and ocular diseases. •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): In inflammatory diseases involving Cryopyrin-Associated Periodic Syndromes (CAPS), interleukin-1 beta (IL-1β) is excessively activated and drives inflammation. The protein cryopyrin controls the activation of IL-1β, and mutations in cryopyrin's gene, NLRP-3, up-regulate IL-1β activation. Canakinumab binds to human IL-1β and neutralizes its inflammatory activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1α or IL-1 receptor antagonist (IL-1ra). •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 subcutaneously administered canakinumab is estimated to be 66%. Peak serum concentration is 16 ± 3.5 mcg/mL and occurs approximately 7 days following a single subcutaneous dose of 150mg. Exposure to canakinumab increases proportionately to the administered 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 steady-state volume of distribution of canakinumab is variable based on weight - it was estimated to be 6.01 liters in a typical CAPS patient weighing 70 kg, 3.2 liters in a SJIA patient weighing 33 kg, 6.34 liters for a Periodic Fever Syndrome (TRAPS, HIDS/MKD, FMF) patient weighing 70 kg and 7.9 liters in a typical patient with gout flares weighing 93 kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Canakinumab binds to plasma IL-1β, but plasma protein binding has not been quantified. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Canakinumab, like other therapeutic proteins, is likely degraded via non-specific catabolic processes to smaller peptides and amino acids. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): The route of elimination for canakinumab has not yet 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): 26 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 canakinumab is variable based on weight - it was estimated to be 0.174 L/day in a typical CAPS patient weighing 70 kg, 0.11 L/day in an SJIA patient weighing 33 kg, 0.17 L/day in a Periodic Fever Syndrome (TRAPS, HIDS/MKD, FMF) patient weighing 70 kg and 0.23 L/day in a typical patient with gout flares of body weight 93 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): There are no confirmed cases of overdosage with canakinumab. In the event of an overdose, the patient should be monitored closely and appropriate symptomatic treatment should be administered immediately as clinically indicated. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Ilaris •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): Canakinumab is an interleukin-1β blocker used to treat Periodic Fever Syndromes such as Cryopyrin-Associated Periodic Syndromes (CAPS) and Familial Mediterranean Fever (FMF), and also to treat active Systemic Juvenile Idiopathic Arthritis (SJIA). 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 Candesartan cilexetil interact?

•Drug A: Abatacept •Drug B: Candesartan cilexetil •Severity: MODERATE •Description: The metabolism of Candesartan cilexetil 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): May be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line agent to delay progression of diabetic nephropathy. Candesartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors. •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): Candesartan cilexetil is an ARB prodrug that is rapidly converted to candesartan, its active metabolite, during absorption from the gastrointestinal tract. Candesartan confers blood pressure lowering effects by antagonizing the hypertensive effects of angiotensin II via the RAAS. RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. Renin cleaves circulating angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering cardiovascular structure. Angiotensin II binds to two receptors: type-1 angiotensin II receptor (AT1) and type-2 angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Studies performed in recent years suggest that AT2 antagonizes AT1-mediated effects and directly affects long-term blood pressure control by inducing vasorelaxation and increasing urinary sodium excretion. Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1. ARBs block the ability of angiotensin II to stimulate pressor and cell proliferative effects. Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation. The overall effect of ARBs is a decrease in blood pressure. •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): Candesartan selectively blocks the binding of angiotensin II to AT1 in many tissues including vascular smooth muscle and the adrenal glands. This inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in an overall decrease in blood pressure. Candesartan is greater than 10,000 times more selective for AT1 than AT2. Inhibition of aldosterone secretion may increase sodium and water excretion while decreasing potassium excretion. •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 administration of the candesartan cilexetil prodrug, the absolute bioavailability of candesartan was estimated to be 15%. Food with a high fat content has no effect on the bioavailability of candesartan from candesartan cilexetil. •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): Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The prodrug candesartan cilexetil undergoes rapid and complete ester hydrolysis in the intestinal wall to form the active drug, candesartan. Elimination of candesartan is primarily as unchanged drug in the urine and, by the biliary route, in the feces. Minor hepatic metabolism of candesartan (<20%) occurs by O-deethylation via cytochrome P450 2C9 to form an inactive metabolite. Candesartan undergoes N-glucuronidation in the tetrazole ring by uridine diphosphate glucuronosyltransferase 1A3 (UGT1A3). O-glucuronidation may also occur. 75% of candesartan is excreted as unchanged drug in urine and feces. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Candesartan is mainly excreted unchanged in urine and feces (via 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): Approximately 9 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): 0.37 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): No lethality was observed in acute toxicity studies in mice, rats and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil or in rats given single oral doses of up to 2000 mg/kg of candesartan cilexetil in combination with 1000 mg/kg of hydrochlorothiazide. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Atacand, Atacand Hct •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): Candesartan cilexetil is an angiotensin receptor blocker used to treat hypertension, systolic hypertension, left ventricular hypertrophy, and delay progression of diabetic nephropathy.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Candesartan cilexetil interact? Information: •Drug A: Abatacept •Drug B: Candesartan cilexetil •Severity: MODERATE •Description: The metabolism of Candesartan cilexetil 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): May be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line agent to delay progression of diabetic nephropathy. Candesartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors. •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): Candesartan cilexetil is an ARB prodrug that is rapidly converted to candesartan, its active metabolite, during absorption from the gastrointestinal tract. Candesartan confers blood pressure lowering effects by antagonizing the hypertensive effects of angiotensin II via the RAAS. RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. Renin cleaves circulating angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering cardiovascular structure. Angiotensin II binds to two receptors: type-1 angiotensin II receptor (AT1) and type-2 angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Studies performed in recent years suggest that AT2 antagonizes AT1-mediated effects and directly affects long-term blood pressure control by inducing vasorelaxation and increasing urinary sodium excretion. Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1. ARBs block the ability of angiotensin II to stimulate pressor and cell proliferative effects. Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation. The overall effect of ARBs is a decrease in blood pressure. •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): Candesartan selectively blocks the binding of angiotensin II to AT1 in many tissues including vascular smooth muscle and the adrenal glands. This inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in an overall decrease in blood pressure. Candesartan is greater than 10,000 times more selective for AT1 than AT2. Inhibition of aldosterone secretion may increase sodium and water excretion while decreasing potassium excretion. •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 administration of the candesartan cilexetil prodrug, the absolute bioavailability of candesartan was estimated to be 15%. Food with a high fat content has no effect on the bioavailability of candesartan from candesartan cilexetil. •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): Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The prodrug candesartan cilexetil undergoes rapid and complete ester hydrolysis in the intestinal wall to form the active drug, candesartan. Elimination of candesartan is primarily as unchanged drug in the urine and, by the biliary route, in the feces. Minor hepatic metabolism of candesartan (<20%) occurs by O-deethylation via cytochrome P450 2C9 to form an inactive metabolite. Candesartan undergoes N-glucuronidation in the tetrazole ring by uridine diphosphate glucuronosyltransferase 1A3 (UGT1A3). O-glucuronidation may also occur. 75% of candesartan is excreted as unchanged drug in urine and feces. •Route of elimination (Drug A): Kidney and liver •Route of elimination (Drug B): When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Candesartan is mainly excreted unchanged in urine and feces (via 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): Approximately 9 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): 0.37 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): No lethality was observed in acute toxicity studies in mice, rats and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil or in rats given single oral doses of up to 2000 mg/kg of candesartan cilexetil in combination with 1000 mg/kg of hydrochlorothiazide. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg. •Brand Names (Drug A): Orencia •Brand Names (Drug B): Atacand, Atacand Hct •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): Candesartan cilexetil is an angiotensin receptor blocker used to treat hypertension, systolic hypertension, left ventricular hypertrophy, and delay progression of diabetic nephropathy. 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.