European journal of clinical pharmacology · 2025
Population pharmacokinetic characteristics of tacrolimus in Chinese lung transplant recipients and optimisation of dosing regimen during the early post-transplantation phase.
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Zhou Shouning, Lian Qiaoyan, Luo Huilong, Xie Hui, Guan Yanping, He Jianxing, Wei Li, Ju Chunrong
Аннотация
PURPOSE: This study aimed to establish a population pharmacokinetic model and optimise tacrolimus dosing regimens in Chinese lung transplant recipients.
METHODS: A total of 988 tacrolimus trough concentrations and clinical data of 142 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.
RESULTS: The pharmacokinetics of tacrolimus could be best described by a one-compartment model with first-order absorption and elimination. The typical population parameter estimates of apparent clearance and apparent volume of distribution were 7.58 L·h-1 and 701.39 L, respectively. The clearance of tacrolimus in rapid and intermediate metabolisers of CYP3A5 was 2.72-fold and 1.87-fold higher, respectively, than in poor metabolisers of CYP3A5. The concurrent use of voriconazole, posaconazole, and itraconazole led to a reduction in tacrolimus clearance by 38.21%, 26.30%, and 57.98%, respectively. Recommended dose regimens were obtained by Monte Carlo simulation based on the established model.
CONCLUSION: Recipients with the CYP3A5*3/*3 genotype, elevated haematocrit levels, short postoperative days, and concurrent administration of azole antifungal drugs needed a reduced maintenance dose to reach the therapeutic window, which provided a reference for the formulation of individualised tacrolimus regimen during the early post-transplantation phase.
METHODS: A total of 988 tacrolimus trough concentrations and clinical data of 142 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.
RESULTS: The pharmacokinetics of tacrolimus could be best described by a one-compartment model with first-order absorption and elimination. The typical population parameter estimates of apparent clearance and apparent volume of distribution were 7.58 L·h-1 and 701.39 L, respectively. The clearance of tacrolimus in rapid and intermediate metabolisers of CYP3A5 was 2.72-fold and 1.87-fold higher, respectively, than in poor metabolisers of CYP3A5. The concurrent use of voriconazole, posaconazole, and itraconazole led to a reduction in tacrolimus clearance by 38.21%, 26.30%, and 57.98%, respectively. Recommended dose regimens were obtained by Monte Carlo simulation based on the established model.
CONCLUSION: Recipients with the CYP3A5*3/*3 genotype, elevated haematocrit levels, short postoperative days, and concurrent administration of azole antifungal drugs needed a reduced maintenance dose to reach the therapeutic window, which provided a reference for the formulation of individualised tacrolimus regimen during the early post-transplantation phase.