Effect of CYP3A4*22, CYP3A5*3, and CYP3A Combined Genotypes on Cyclosporine, Everolimus, and Tacrolimus Pharmacokinetics in Renal Transplantation

Cyclosporine, everolimus, and tacrolimus are the cornerstone of maintenance immunosuppressive therapy in renal transplantation. These drugs are characterized by a small therapeutic window and highly variable pharmacokinetics (PK), which makes therapeutic drug monitoring (TDM) essential for maintaining adequate exposure and preventing serious drug-related toxicities.1,2,3 Cyclosporine, everolimus, and tacrolimus are primarily metabolized by cytochrome P450 enzymes, CYP3A4 and CYP3A5.4,5,6,7 Differences in activity of these metabolizing enzymes are likely to be responsible for a significant part of the interindividual variability in PK.8,9 Genetic polymorphisms in genes encoding these metabolizing enzymes have previously been found to explain a part of the variability in PK of these immunosuppressive drugs.1,10,11,12,13,14 Recently, the decreased activity allele CYP3A4*22 was identified as a novel predictive marker for tacrolimus PK;15,16 however, these findings have not been successfully reproduced.11 CYP3A4*22 has also been investigated to a less extent in cyclosporine PK, but its effect on everolimus PK is still unknown.15,16,17 CYP3A5*3 was studied before in relation to PK of everolimus, tacrolimus, and cyclosporine,10,18,19,20 but the CYP3A combined genotype (CYP3A4 and CYP3A5), which most likely better reflect CYP3A activity, has only been evaluated for tacrolimus.15 The studies investigating the effect of CYP3A4*22 on tacrolimus PK were limited by the use of trough concentrations and lack of data on comedications, and did not use population PK analysis. Such an approach enables to differentiate between interpatient and intrapatient variability, which results in enhanced statistical power to identify factors influencing PK. Therefore, we investigated the effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotype on cyclosporine, everolimus, and tacrolimus PK using a population PK analysis.