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

• DOI: 10.1097/ftd.0b013e318296045b
• Publication Date: 2013-09-19T14:35:59Z
• Authors: Laure Elens; Arnaud Capron; Ron HN van Schaik; Martine De Meyer; Luc De Pauw; Djamila C. Eddour; Dominique Latinne; Pierre Wallemacq; Michel Mourad; Vincent Haufroid
• Keywords: EMC MM-01-25-01; Graft Rejection; Male; Polymorphism, Genetic; Dose-Response Relationship, Drug; Genotype; Middle Aged; Kidney Transplantation; Tacrolimus; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Cytochrome P-450 CYP3A; Humans; Female; Alleles; Immunosuppressive Agents

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