Introduction: Tacrolimus (TAC) is a cornerstone immunosuppressant in liver transplantation, characterized by a narrow therapeutic index and substantial pharmacokinetic variability, making dose optimization challenging.
Objective: This study aimed to develop a population pharmacokinetic (PopPK) model for TAC in Vietnamese liver transplant patients, integrating CYP3A5 genetic polymorphisms to support individualized dosing.
Methods: Data from 95 Vietnamese liver transplant recipients (1,986 whole-blood tacrolimus concentrations) were analyzed using a nonlinear mixed-effects modeling approach implemented in Monolix (version 2024R1). Stepwise covariate modeling evaluated the effects of CYP3A5 genotypes (donor and recipient), demographic, and clinical variables. Model selection and validation were based on objective function value, parameter precision, and diagnostic plots. The final model was used to perform Monte Carlo simulations for genotype-guided initial dosing recommendations.
Results: A 2‑compartment model with lag time, first‑order absorption and elimination best described the data. High interindividual variability was observed, particularly for V1/F and Q/F (ω = 0.97 and 1.72, respectively). The CYP3A5 genotype of both donor and recipients, together with total bilirubin, were identified as significant covariates of CL/F, while postoperative days influenced Vp/F. Final parameter estimates showed acceptable precision, and model diagnostic plots demonstrated good agreement between observed and predicted data. Monte Carlo simulations indicated that CYP3A5 expressors required higher initial TAC doses, whereas standard dosing was generally adequate for CYP3A5 non-expressors. These findings support genotype-guided tacrolimus dosing in liver transplant recipients.
Conclusion: A robust PopPK model of TAC was developed in Vietnamese liver transplant patients, incorporating CYP3A5 genotype and relevant clinical covariates to optimize TAC dosing in clinical practice.