A lack of significant effect of POR*28 allelic variant on tacrolimus exposure in kidney transplant recipients
Résumé
BACKGROUND: POR*28 is a recently newly described allelic variant of the cytochrome P450 oxydoreductase (POR) which might be associated with an increased metabolic activity of P450 cytochromes (CYP) 3A5 and 3A4. Consequently, carriers of at least one allele of this polymorphism could require increased calcineurin inhibitors doses to reach the target residual concentrations (Co). The objective of this study is to test whether the allelic variant of POR, which is associated with an increased metabolic activity of CYP3A, impacts Tacrolimus (Tac) pharmacokinetics. METHODS: We tested this hypothesis in a population of 229 kidney transplant recipients (KTR) from a large, multicenter, prospective and randomized study. We have analyzed the association between POR*28 genotype and the proportion of individuals reaching the target Tac residual concentration (Tac Co) 10 days after transplantation. We have also measured the association between POR*28 and the Tac Co, and adjusted Tac Co (Tac Co/Tac dose) over time using generalized mixed linear models. RESULTS: Ten days after transplantation, there was no difference of frequencies of KTR within the target range of Tac Co (Co 10-15 ng/ml) according to the POR*28 genotype (p=0.8). The mean Tac Co at day 10 in the POR*1/*1 group was 15.3±9.7 ng/ml compared with 15.7±7.8 ng/ml in the POR*1/*28 group and 14.2 ±6.8 ng/ml, in the POR*28/*28 group, p=0.8. The adjusted Tac Co was not associated with POR*28 genotype over time (random effects model, p=0.9). When restricted to KTR expressing CYP3A5, POR*28 gentoype did not impact the proportion of individuals within the Tac Co target range neither the adjusted Tac Co (random effects model, p=0.1). CONCLUSIONS: POR*28 does not significantly influence Tac pharmacokinetic parameters in a large cohort of KTR. This study does not confirm recent findings indicating that POR*28 carriers require more Tac to reach target Co