Impact of the CYP3A5 genotype on the distributions of dose-adjusted trough concentrations and incidence of rejection in Japanese renal transplant recipients receiving different tacrolimus formulations.

BACKGROUND

We investigated the impact of the CYP3A5 genotype on the distributions of dose-adjusted trough concentrations (C /D) and the incidence of rejection in Japanese recipients taking twice-daily (Tac-BID, n = 140) or modified-release once-daily (Tac-QD, n = 80) tacrolimus formulations for 1 year after renal transplantation.

METHODS

Logistic regression analysis was carried out to estimate the distinction rate of CYP3A5 genotypes based on the C /D of Tac-BID or Tac-QD. The coefficients of variation (%CVs) were compared in each recipient to estimate the stability of tacrolimus C /D between formulations or CYP3A5 genotypes.

RESULTS

Recipients with at least one CYP3A51 wild-type allele (EMs) and recipients with homozygous expression of the variant allele CYP3A53 (PMs) were significantly identified using the tacrolimus C /D cut-off values of 2.77 and 0.85 ng/mL/mg, respectively, and discrimination rates of 75.3 and 85.4%, respectively, for Tac-BID and Tac-QD groups. The %CV of the tacrolimus C /D in CYP3A5 EMs taking Tac-QD was significantly lower than that in those taking Tac-BID (20.4 versus 23.3%, P = 0.003). The %CV of the tacrolimus C /D was an independent risk factor for rejection (odds ratio = 1.028, P = 0.033).

CONCLUSIONS

The tacrolimus C /D values with definite cut-offs for CYP3A5 genotypes were specifically identified in Japanese renal transplant recipients taking Tac-QD. In addition, a larger %CV for the tacrolimus C /D correlated with the incidence of rejection. Consequently, the stability of the C /D achieved using Tac-QD, which was clearly influenced by the CYP3A5 polymorphism, may prevent the development of rejection.