Population pharmacokinetic characteristics of tacrolimus in Chinese lung transplant recipients and optimisation of dosing regimen

Abstract Purpose: To establish a population pharmacokinetic model and optimise tacrolimus dosing regimens in Chinese Han lung transplant recipients. Methods: A total of 780 tacrolimus trough concentrations and clinical data of 127 adult lung transplant recipients were collected. Population pharmacokinetic analysis was performed using a nonlinear mixed effects model. A Monte Carlo simulation was conducted to determine the optimal dosing regimen. 41 patients with 97 tacrolimus trough concentrations were used for external validation.Results: The pharmacokinetics of tacrolimus could be best described by a one-compartment model with first-order absorption and elimination. The estimated apparent clearance and volume of distribution were 3.43 L·h-1 and 60.72 L, respectively. The clearance of tacrolimus in the CYP3A5 rapid and intermediate metabolisers were 2.68 and 2.07 times higher than those of CYP3A5 poor metaboliser, respectively. When HCT decreased from 0.30 to 0.20, the clearance of tacrolimus elevated by 32.28% and the apparent distribution volume increased by 33.90%. The clearance of tacrolimus was decreased of 25.99%, 11.49%, 38.12% by concomitant use of voriconazole, posaconazole, itraconazole respectively. The model was successfully internally and externally validated. Recommended dose regimens were obtained by Monte Carlo simulation based on the established model.Conclusion: A population pharmacokinetic model of tacrolimus in Chinese Han lung transplant recipients was successfully constructed. Recipients with the CYP3A5*1/*1 genotype, low HCT value, and concomitant with AFDs after surgery needed a higher maintenance dose to reach the therapeutic window, which provided a reference for the formulation of individualised tacrolimus regimen.