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Effects of CYP3A5, ABCB1 and POR*28 polymorphisms on pharmacokinetics of tacrolimus in the early period after renal transplantation

Abstract 1. We aimed to establish a population pharmacokinetic (PK) model of tacrolimus and identify clinical covariates, especially the genetic polymorphisms of CYP3A5, ABCB1 and POR*28 that affected the PK to prevent fluctuation in the trough concentration of tacrolimus during the early period after renal transplantation. 2. Tacrolimus trough concentration, clinical data and CYP3A5/ABCB1/POR28 genotypes were retrospectively collected from 234 kidney transplant recipients during the first month post-transplantation. The population PK model was built using the non-linear mixed effects modeling software NONMEM. Dosing simulation was performed based on the final model. 3. A one-compartment model with first-order absorption and elimination was used to characterize the PK of tacrolimus. Among the genotypes, only CYP3A5 genotype was confirmed to have clinical significance. The final model describing CL/F (l/h) was as follows: The inter-individual variability in CL/F was 21.9%. Monte Carlo simulation based on the final model was carried out to determine the optimal dosage regimen. 4. CYP3A5 genotype, post-operative day and hematocrit were confirmed as critical PK factors of tacrolimus. The model could be used to accurately predict individual PK parameters of tacrolimus and provide valuable insights into the dosage optimization.