The combination of CYP3A4*22 and CYP3A5*3 single-nucleotide polymorphisms determines tacrolimus dose requirement after kidney transplantation

Introduction Tacrolimus (Tac) has a narrow therapeutic window and shows large between-patient pharmacokinetic variability. As a result, over-immunosuppression and under-immunosuppression are frequently encountered in daily clinical practice. Unraveling the impact of genetic polymorphisms on Tac pharmacokinetics may help to refine therapy. In this study, the associations of single-nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes (CYP3A) with Tac pharmacokinetics were investigated in renal transplant recipients. Participants and methods In a cohort of 272 kidney transplant recipients, associations between functional genetic variants (CYP3A4*22 and CYP3A5*3) and dose-adjusted predose Tac concentrations (C-0) and daily doses of Tac at days 5-7 and 15 and 1, 3, 6 and 12 months after renal transplantation were evaluated. Patients were genotyped and clustered according to both CYP3A4*22 and CYP3A5*3 allelic status: poor (PM) (CYP3A4*22 carriers with CYP3A5*3/*3), intermediate (IM) (CYP3A4*1/*1 with CYP3A5*3/*3 or CYP3A4*22 carriers with CYP3A5*1 carriers) and extensive CYP3A-metabolizers (EM) (CYP3A4*1/*1 and CYP3A5*1 carriers). Results EM had an 88% lower dose-adjusted C-0 compared with IM. PM had a 26% higher dose-adjusted C-0 compared with IM. The percentage of patients with supratherapeutic Tac exposure (C-0> 15 ng/ml) was significantly higher in PM (43.5%) compared with EM (0%) at days 5-7 after transplantation (P= 0.01). About 30% of EM had subtherapeutic exposure (C-0< 5 ng/ml) at days 5-7 after transplantation (P= 0.001). Conclusion The combined CYP3A4 and CYP3A5 genotype of renal transplant recipients has a major influence on the Tac dose required to reach the target exposure. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.