Population pharmacokinetics of tacrolimus in Chinese adult liver transplant patients
Population pharmacokinetics of tacrolimus in Chinese adult liver transplant patients
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DOI：
10.1002/bdd.2311
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发表时间：
2022-03-23
影响因子：
2.1
通讯作者：
Wei, Hua
中科院分区：
文献类型：
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作者：
Teng, Fei;Zhang, Weiyue;Wei, Hua
他克莫司被广泛用于器官移植以防止排斥反应。然而，他克莫司的治疗窗口狭窄，个体间和个体内药代动力学(PK)变化很大，这使得他克莫司的个体化给药变得困难。本研究旨在建立一个群体药代动力学模型来估计中国肝移植患者他克莫司的口服清除量，并找出影响他克莫司PK变异性的因素。本研究对151例肝移植患者接受他克莫司治疗的资料进行了分析。采用非线性混合效应建模方法，对群体PK模型进行了分析，探讨了群体人口学特征、生化特征、药物组合、遗传多态等协变量。建立单室群体PK模型，最终模型为CL/F=(14.6-2.38x细胞色素P450(CYP)3A5-3.72x WZC+1.04x(POD/9)+2.48x COR)x Exp(ETA(I))，其中，他克莫司联合WZC时，CYP3A5为1，WZC为1，否则为0，COR为1，POD为0。目测检验和Bootstrap检验表明，最终模型是稳定的，具有较强的鲁棒性。在本研究中，我们首次在中国成人肝移植患者中建立了他克莫司群体PK模型。我们首次测定了WZC对这些受试者他克莫司的影响，为他克莫司与WZC的联合用药提供了有用的PK信息。我们还揭示了CYP3A5、POD和COR的组合基因多态性对他克莫司PK的影响。因此，在优化给药方案时应考虑这些重要因素。
Tacrolimus is widely used in organ transplantation to prevent rejection. However, the narrow therapeutic window and the large inter-and intra-individual variability in the pharmacokinetics (PK) of tacrolimus make it difficult for individualization of dosing. This study aimed at developing a population pharmacokinetic model for estimating the oral clearance of tacrolimus in Chinese liver transplant patients, and identifying factors that contribute to the PK variability of tacrolimus. Data of 151 liver transplant patients who received tacrolimus were analyzed in this study. The population PK model was analyzed and the covariates including population demographic and biochemical characteristics, drug combination, and genetic polymorphism were explored using non-linear mixed-effects modeling approach. A single-compartment population PK model was developed, and the final model was CL/F = (14.6-2.38 x cytochrome P450 (CYP) 3A5-3.72 x WZC+1.04 x (POD/9)+2.48 x COR) x Exp(eta(i)), where CYP3A5 was 1 for CYP3A5*3/*3, Wuzhi Capsule (WZC) was 1 when patients took tacrolimus combined with WZC, otherwise it was 0, corticosteroids (COR) was 1 when patients take tacrolimus combined with COR, otherwise, it was 0, POD was the post-operative day. Visual inspection and bootstrap indicated that the final model was stable and robust. In this study, we developed the first tacrolimus population PK model in Chinese adult liver transplant patients. We first determined the influence of WZC on tacrolimus in these people, which could provide useful PK information for the drug combination of tacrolimus and WZC. We also revealed the influence of genetic polymorphism of CYP3A5, POD, and a combination of COR on tacrolimus PK. Therefore, these significant factors should be taken into consideration in optimizing dosage regimens.