Impact of CYP3A4*22 Allele on Tacrolimus Pharmacokinetics in Early Period After Renal Transplantation

Abstract

Tacrolimus (Tac) metabolism is mainly mediated by the cytochrome P450 3A (CYP3A) subfamily. Recently, it has been reported that kidney transplant recipients carrying the CYP3A4*22 decrease-of-function allele require lower Tac doses and are more at risk of Tac overexposure than CYP3A4*1/*1 patients. This effect was shown to be independent of the CYP3A5*3 allelic status. However, the pharmacokinetic (PK) parameters assessed in previous studies were limited on single time point whole blood trough concentrations (C0) during routine follow-up of the patient after transplantation. Our study investigates the impact of the CYP3A4*22 allele on Tac PK [C0, area under the time vs concentration curve (AUC0-12h), apparent clearance (Cl/F), Cmax, and dose requirement], time to achieve target C0, and creatinine clearance (CrCl) in 96 kidney transplant recipients considering the 2 first weeks after the graft. All patients were genotyped for both the CYP3A4*22 and the CYP3A5*3 polymorphisms. CYP3A4*22 carriers had higher Tac C0 during the first week with significant longer exposures to C0 > 15 ng/mL. These patients showed reduced Tac Cl/F but higher dose-adjusted AUC0-12h and Cmax and were at increased risk of C0 > 20 ng/mL. These effects were independent from CYP3A5*3 genotype: clustering patients according to both CYP3A4*22 and CYP3A5*3 allelic status did increase the predictive value of the genotype to explain interindividual differences in Tac PK. During the second week after transplantation, CrCl was on average 9.5 mL/min higher for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients (P = 0.007), suggesting that Tac overexposure in CYP3A4*22 carriers might provide a renal function benefit. Our study confirms the decreased CYP3A4 activity toward Tac for CYP3A4*22 carriers early after transplantation and provides evidence for refining genotype-based dosage by adding the CYP3A4*22 genotype information to the CYP3A5*3 allelic status.