Population Pharmacokinetic Analysis of Tacrolimus in Time-Dependent Increase of Clearance for Patients with Living-Donor Liver Transplantation: A Prospective Observational Study.

Tacrolimus is a first-line immunosuppressant used to prevent rejection in living donor liver transplantation (LDLT) and is subject to therapeutic drug monitoring due to its concentration-dependent effects and side effects. Metabolism of tacrolimus is reduced by the CYP3A5*3 allele. In addition, liver regeneration over time leads to increased tacrolimus clearance. The purpose of this study was to develop a tacrolimus population pharmacokinetic (popPK) model that takes into consideration the CYP3A5*3 allele and the time-dependent increase in clearance. To develop the popPK model, we used data from 25 recipients and 25 donors who received LDLT and tacrolimus at Kumamoto University Hospital. The measured data consisted of four blood concentration points including peak values at 12 h after the first dose of tacrolimus, and trough blood concentrations obtained by TDM on consecutive days. Nonlinear mixed-effects modeling method was used to develop the popPK model, and i-Densy by ARKRAY Co., Ltd. was used for CYP3A5 gene polymorphism analysis. The popPK model was developed as a one-compartment model incorporating a time-dependent sigmoidal model for clearance. Total bilirubin value was found to be a predictor of volume of distribution and rate constant of absorption, while aspartate transaminase was found to be a predictor of volume of distribution. The CYP3A5*3 allele was not found to be a predictor of tacrolimus pharmacokinetics. We developed a popPK model that includes a time-dependent increase in CL of tacrolimus for patients with LDLT.