Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, No. 1277, Jie Fang Road, Wuhan, Hubei province, 430022, PR China.
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.
Pharmacogenomics. 2019 Jan;20(1):21-35. doi: 10.2217/pgs-2018-0116. Epub 2018 Dec 6.
The aim of this study was to evaluate tacrolimus population pharmacokinetics and investigate factors that explain tacrolimus variability in adult heart transplant patients.
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.
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.
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.
本研究旨在评估他克莫司在成人心脏移植患者中的群体药代动力学，并探讨解释他克莫司变异性的因素。
共纳入 107 例成年心脏移植患者的 707 个他克莫司浓度用于模型开发。使用非线性混合效应模型评估了人口统计学、临床因素和 CYP3A5 基因型对他克莫司清除率的影响。24 例患者的 106 个他克莫司浓度用于外部验证。
他克莫司的药代动力学数据通过具有一级吸收和消除的单室模型得到了很好的描述。他克莫司的估计表观清除率和分布容积分别为 13.7 l/h 和 791 l。CYP3A5 无表达者（CYP3A5*3/*3）、同时使用唑类抗真菌药物和五酯胶囊（WZ）时，他克莫司的表观清除率显著降低。贝叶斯估计进一步在外部验证中确认了预测性能。根据建立的模型进行模拟获得了推荐的剂量方案。
这是在中国心脏移植受者中进行的首次群体药代动力学研究。这些发现对于心脏移植患者中他克莫司剂量优化具有重要意义。
