Impact of CYP3A4*22 Allele on Tacrolimus Pharmacokinetics in Early Period After Renal Transplantation: Toward Updated Genotype-Based Dosage Guidelines

Background: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 (C-0) during routine follow-up of the patient after transplantation.Methods:Our study investigates the impact of the CYP3A4*22 allele on Tac PK [C-0, area under the time vs concentration curve (AUC(0-12h)), apparent clearance (Cl/F), C-max, and dose requirement], time to achieve target C-0, 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.Results:CYP3A4*22 carriers had higher Tac C-0 during the first week with significant longer exposures to C-0 > 15 ng/mL. These patients showed reduced Tac Cl/F but higher dose-adjusted AUC(0-12h) and C-max and were at increased risk of C-0 > 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.Conclusions: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.