Yong Han1, Hong Zhou1, Jie Cai2, Jun Huang3, Jing Zhang2, Shao-Jun Shi1, Ya-Ni Liu1, Yu Zhang1. 1. Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, No. 1277, Jie Fang Road, Wuhan, Hubei province, 430022, PR China. 2. Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, No. 1277, Jie Fang Road, Wuhan, Hubei province, 430022, PR China. 3. Institutes of Antibiotics, Huashan Hospital, Fudan University.12 Middle Urumqi Road, Shanghai, 200040, PR China.
Abstract
AIM: The aim of this study was to evaluate tacrolimus population pharmacokinetics and investigate factors that explain tacrolimus variability in adult heart transplant patients. METHODS: A total of 707 tacrolimus concentrations from 107 adult heart transplant patients were included in model development. The effects of demographic, clinical factors and CYP3A5 genotype on tacrolimus clearance were evaluated using a nonlinear mixed-effects modeling. 24 patients with 106 tacrolimus concentrations were used for external validation. RESULTS: The pharmacokinetic data were adequately described by a one-compartment model with first-order absorption and elimination. The estimated apparent clearance and volume of distribution of tacrolimus were 13.7 l/h and 791 l, respectively. Tacrolimus apparent clearance was significantly reduced in CYP3A5 nonexpressers (CYP3A5*3/*3), concomitant with azole antifungal drugs and Wuzhi capsule (WZ). A predictive performance was further confirmed in an external validation by Bayesian estimation. Recommended dose regimens were obtained by simulations based on the established model. CONCLUSION: This is the first population pharmacokinetic study conducted in Chinese heart transplant recipients. These findings are of great importance with regards to tacrolimus dose optimization in heart transplantation patients.
AIM: The aim of this study was to evaluate tacrolimus population pharmacokinetics and investigate factors that explain tacrolimus variability in adult heart transplant patients. METHODS: A total of 707 tacrolimus concentrations from 107 adult heart transplant patients were included in model development. The effects of demographic, clinical factors and CYP3A5 genotype on tacrolimus clearance were evaluated using a nonlinear mixed-effects modeling. 24 patients with 106 tacrolimus concentrations were used for external validation. RESULTS: The pharmacokinetic data were adequately described by a one-compartment model with first-order absorption and elimination. The estimated apparent clearance and volume of distribution of tacrolimus were 13.7 l/h and 791 l, respectively. Tacrolimus apparent clearance was significantly reduced in CYP3A5 nonexpressers (CYP3A5*3/*3), concomitant with azole antifungal drugs and Wuzhi capsule (WZ). A predictive performance was further confirmed in an external validation by Bayesian estimation. Recommended dose regimens were obtained by simulations based on the established model. CONCLUSION: This is the first population pharmacokinetic study conducted in Chinese heart transplant recipients. These findings are of great importance with regards to tacrolimus dose optimization in heart transplantation patients.
Entities:
Keywords:
heart transplantation; population pharmacokinetics; tacrolimus
Authors: Jing Zhu; Olivia Campagne; Chad D Torrice; Gabrielle Flynn; Jordan A Miller; Tejendra Patel; Oscar Suzuki; Jonathan R Ptachcinski; Paul M Armistead; Tim Wiltshire; Donald E Mager; Daniel L Weiner; Daniel J Crona Journal: Clin Transl Sci Date: 2021-01-27 Impact factor: 4.689