Cited 35 times since 2017 (4.5 per year) source: EuropePMC Pharmacogenetics and genomics, Volume 27, Issue 9, 1 1 2017, Pages 313-322 The combination of CYP3A4*22 and CYP3A5*3 single-nucleotide polymorphisms determines tacrolimus dose requirement after kidney transplantation. Lloberas N, Elens L, Llaudó I, Padullés A, van Gelder T, Hesselink DA, Colom H, Andreu F, Torras J, Bestard O, Cruzado JM, Gil-Vernet S, van Schaik R, Grinyó JM
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 (C0) 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 C0 compared with IM. PM had a 26% higher dose-adjusted C0 compared with IM. The percentage of patients with supratherapeutic Tac exposure (C0>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 (C0<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.
