Mechanism of action<unk> BP12, the target protein of<unk> <unk>  is a<unk> lide calcineurin inhibitor. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor nuclear factor of activated T-cells (NF-AT), which moves to the nucleus of the T-cell and increases the activity of genes coding for IL-2 and related cytokines.<unk>  prevents the dephosphorylation of NF-AT. In detail,<unk>  reduces peptidylprolyl isomerase activity by binding to the immunophilin<unk> BP12 <unk> 506 binding protein), creating a new complex. This<unk> BP12–FK506 complex interacts with and inhibits calcineurin, thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription. Although this activity is similar to that of cyclosporin, the incidence of acute rejection is reduced by<unk>  use over cyclosporin use. Although short-term immunosuppression concerning patient and graft survival is found to be similar between the two drugs,<unk>  results in a more favorable lipid profile, and this may have important long-term implications given the prognostic influence of rejection on graft survival. Pharmacokinetics Oral<unk>  is slowly absorbed in the gastrointestinal tract, with a total bioavailability of 20 to 25% (but with variations from 5 to 67%) and highest blood plasma concentrations (Cmax) reached after one to three hours. Taking the drug together with a meal, especially one rich in fat, slows down resorption and reduces bioavailability. In the blood,<unk>  is mainly bound to erythrocytes; only 5% are found in the plasma, of which more than 98.8% are bound to plasma proteins. The substance is metabolized in the liver, mainly via CYP3A, and in the intestinal wall. All metabolites found in the circulation are inactive. Biological half-life varies widely and seems to be higher for healthy persons (43 hours on average) than for patients with liver transplants (12 hours) or kidney transplants (16 hours), due to differences in clearance.<unk>  is predominantly eliminated via the faeces in form of its metabolites. When applied locally on eczema,<unk>  has little to no bioavailability. Pharmacogenetics The predominant enzyme responsible for metabolism of<unk>  is CYP3A5. Genetic variations within CYP3A5 that result in changes to the activity of the CYP3A5 protein can affect concentrations of<unk>  within the body. In particular, individuals who are homozygous for the G allele at the single nucleotide polymorphism (SNP) rs776746 (also known as CYP3A5 *3/*3) have a non-functional CYP3A5 protein. The frequency of the G allele varies worldwide, from 4% in some African populations to 80–90% in Caucasian populations.<unk> ss a large number of studies, individuals homozygous for the G allele have been shown to have higher concentrations of<unk>  and require lower doses of the drug, as compared to individuals who are not homozygous for the G allele. Achieving target concentrations of<unk>  is important – if levels are too low, then there is a risk of transplant rejection, if levels are too high, there is a risk of drug toxicities. There is evidence to suggest that dosing patients based on rs776746 genotype can result in faster and more frequent achievement of target<unk>  levels. However, there is a lack of consistent evidence as to whether dosing based on rs776746 genotype results in improved clinical outcomes (such as a decreased risk for transplant rejection or drug toxicities), likely because patients taking<unk>  are subject to therapeutic drug monitoring. Studies have shown that genetic polymorphisms of genes other than CYP3A5, such as NR1I2 (encoding PXR), also significantly influence the pharmacokinetics of<unk> .
Tacrolimus
Sirolimus
Temsirolimus
Pimecrolimus
Ruxolitinib
Rituximab
Tofacitinib
Ropeginterferon alfa-2b