Chen Lizhi, Yang Yunyun, Wang Xuebin, Wang Chenyu, Lin Weiwei, Jiao Zheng, Wang Zhuo
Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, People's Republic of China.
Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China.
Pharmgenomics Pers Med. 2021 Sep 3;14:1093-1106. doi: 10.2147/PGPM.S321997. eCollection 2021.
In this study, we aimed to establish a tacrolimus population pharmacokinetic model and better understand the drug-drug interaction between Wuzhi capsule and tacrolimus in Chinese renal transplant recipients.
We performed a population pharmacokinetic analysis using a non-linear mixed-effects model to determine the suitable Wuzhi capsule dose in combination with tacrolimus. Data on 1378 tacrolimus steady-state concentrations were obtained from 142 patients who received kidney transplant in Changhai Hospital and Huashan Hospital. Demographic characteristics, laboratory tests, genetic polymorphisms, and co-medications were evaluated.
The one-compartment model best described data. Our final model identified creatinine clearance rate, hematocrit, Wuzhi capsule dose, genetic polymorphisms, and tacrolimus daily dose as significant covariates for tacrolimus clearance, with the value of 14.4 L h, and the between-subject variability (BSV) was 25.4%. The Wuzhi capsule showed a dose-dependent effect on tacrolimus pharmacokinetics, demonstrating a stronger inhibitory effect than inductive effect.
Our model can accurately describe population pharmacokinetics of tacrolimus when combined with different doses of Wuzhi capsule. Additionally, this model can be used for individualizing tacrolimus dose following kidney transplantation.
在本研究中，我们旨在建立他克莫司群体药代动力学模型，并更好地理解在中国肾移植受者中，五酯胶囊与他克莫司之间的药物相互作用。
我们采用非线性混合效应模型进行群体药代动力学分析，以确定与他克莫司联合使用时合适的五酯胶囊剂量。从长海医院和华山医院接受肾移植的142例患者中获取了1378个他克莫司稳态浓度的数据。对人口统计学特征、实验室检查、基因多态性和合并用药进行了评估。
一室模型能最好地描述数据。我们的最终模型确定肌酐清除率、血细胞比容、五酯胶囊剂量、基因多态性和他克莫司每日剂量是他克莫司清除率的显著协变量，其值为14.4 L/h，个体间变异性（BSV）为25.4%。五酯胶囊对他克莫司的药代动力学表现出剂量依赖性效应，其抑制作用强于诱导作用。
我们的模型能够准确描述与不同剂量五酯胶囊联合使用时他克莫司的群体药代动力学。此外，该模型可用于肾移植后他克莫司剂量的个体化。
