Multicenter Prospective Trial Evaluating the Utility of CYP3A5 Genotype in Determining Optimal Initial Dosage of Tacrolimus in Chinese Renal Transplant Recipients

Abstract

Abstract Purpose Tacrolimus is a potent immunosuppressant extensively, due to different gene expressions of CYP3A5 in different populations, tacrolimus has a narrow therapeutic index and there is significant heterogeneity in the dose required to achieve target blood concentrations, leading to difficulty in determining the optimal initial dosage. Methods 145 Chinese renal transplant recipients were divided into two groups according to different CYP3A5 genotypes. The initial oral dose of tacrolimus for patients with CYP3A5*1/*3 and *1/*1 genotypes (expressers) was 0.14 to 0.18 mg/kg/day, and 0.08 to 0.1 mg/kg/day for that with CYP3A5*3/*3 genotypes (non-expressing type). The primary endpoints were the time to achieve the first target tacrolimus blood concentration (TBC) (7 ~ 13 ng/ml) and the proportion of patients reaching this target range on Day 3 ~ 7. Secondary endpoints were the mean doses of tacrolimus, acute rejection, and delayed renal allograft function of tacrolimus. Results The time needed to achieve the first target TBC after transplantation is as follows: expressers patients (N = 59) at 7 days (3 to 28) and non-expressers patients (N = 86) at 3 days (3 to 14) (P < 0.01). The proportion of patients was 91.8% for non-expressers, which was significantly higher than 64.4% for expressers (p = 0.02). Within one month after transplantation, the mean daily dose of tacrolimus was 0.151 ± 0.036 mg/kg for expressers and 0.089 ± 0.032 mg/kg for non-expressers. Conclusions We recommend determining CYP3A5*3 genotype prior to transplantation in order to help facilitate determining the optimal tacrolimus dose. For non-expressers, the initial dose of 0.08 ~ 0.1 mg/kg daily of tacrolimus is appropriate. For expressers, a higher initial dose or combination therapy with drugs are potential strategies that require further evaluation.