Population pharmacokinetics of tacrolimus in adult kidney transplant patients: impact of CYP3A5 genotype on starting dose

OBJECTIVES: The aims of this study were to develop a population pharmacokinetic model of tacrolimus in adult kidney transplant recipients, to use this model to compare cytochrome P450 3A5 (CYP3A5) genotype-based initial dosing of tacrolimus with standard per-kilogram-based dosing, and to predict the best starting dose of tacrolimus based on patient genotype to achieve a trough concentration between 6 and 10 µg/L by day 5 posttransplantation.

METHODS: Population analysis was performed using the software program NONMEM. Tacrolimus dosing regimens were compared by predicting tacrolimus trough concentrations in a simulated data set by running NONMEM with population parameters fixed at the final model estimates. Data from 173 patients with 1554 tacrolimus concentration-time measurements were modeled.

RESULTS: Tacrolimus disposition was well described by a 2-compartment model with first-order elimination and first-order absorption after a lag time. Patient CYP3A5 genotype (rs776746), weight, hematocrit, and postoperative day were identified as significant covariates effecting tacrolimus apparent oral clearance (CL/F), with higher CL/F in CYP3A5*1 allele carriers, heavier patients, patients with low hematocrit, and in the immediate posttransplantation period. Typical population estimates for tacrolimus CL/F in CYP3A5*1 allele carriers and noncarriers were 40.8 and 25.5 L/h, respectively.

CONCLUSIONS: In patients carrying the CYP3A5*1 allele, a per-kilogram dose of 0.075 mg/kg twice daily seemed too much low with approximately 65% of simulated subjects predicted to achieve a trough below 6 µg/L at day 5 posttransplantation. To reduce the risk of under immunosuppression in the immediate posttransplantation period, carriers of a CYP3A5*1 allele are likely to benefit from a tacrolimus starting dose of either 10 mg or 0.115 mg/kg twice daily.