PBPK建模预测CYP3A5基因型对五酯胶囊和他克莫司药动相互作用的影响

Wuzhi capsule, which is composed of ethanolic extract of Schisandra sphenanthera Rehd.et Wils, has been reported to be co-medicated with tacrolimus to reduce the dosing amount of the immunosuppressant . However the factors contributing to the drug-drug interaction (DDI) between these two drugs have not been sufficiently elucidated, particularly the genetic polymorphism of CYP3A5, which plays an important role on the clinical DDI findings. The complex components of Chinese Traditional Medicine (TCM) make it extremely difficult to systematically investigate their DDI potential, especially to predict the in vivo TCM DDI possibility based on in vitro data and to further quantitatively determine the contribution of each individual component in TCM. The present project focuses on the study of the DDI between Wuzhi capsule and TAC using the most popular physiologically based pharmacokinetic (PBPK) modeling technology and the "knock-in/knock-out" strategy. Specifically, by utilizing the commercially available PBPK software-Simcyp and GastroPlus, the PBPK modeling is employed to evaluate and predict the exact contribution of 4 principal components in Wuzhi capsule to the overall DDI potential. Meanwhile these 4 components are knocked out to obtain the matrix components. Their individual contribution to DDI will be evaluated both in vitro and in vivo. Subsequently the quantitatively obtained influence of the 4 principal components will be scaled to calibrate and predict the systematic DDI potential of Wuzhi capsule in clinical settings. The rat model will be utilized to establish and optimize the PBPK strategy for humans. Finally the optimized human prediction model of DDI will be utilized to investigate the effect of CYP3A5 polymorphism and other factors on DDI between Wuzhi capsule and tacrolimus. The research investigation of this project will provide key insights into the rationales of future clinical research on this topic. The gained knowledge will also guide the optimal combination use of Wuzhi capsule and tacrolimus based on strong scientific foundations.

临床上常利用五酯胶囊（WZC）的保肝作用来缓解免疫抑制剂他克莫司（TAC）的肝毒性，并用来降低TAC剂量以节省费用。但是影响两者之间药物相互作用（DDI）个体差异的很多因素，特别是CYP3A5基因型，其影响还不清楚。因为中药的多组分，按传统思路系统研究中药和西药的相互作用非常困难，特别是如何利用体外数据定量预测体内的DDI和定量分析各组分的贡献。本项目试图应用生理药动学（PBPK）建模并结合主成分"敲除/敲入"思路来定量地预测WZC和TAC的药动学DDI。PBPK用于预测4个WZC主成分对DDI的贡献，而从整体上评价主成分敲除后其它成分对DDI的影响。用大鼠来帮助获取人PBPK模型建立和优化的策略，而从文献获取验证人模型的临床数据。最终利用建立的人预测模型替代临床试验考察CYP3A5基因型等因素对WZC和TAC的DDI的影响，为临床确定最佳安全合并用药方案或优化临床研究提供依据。

五酯胶囊和他克莫司经常在临床上联合用药，两者合用主要是因为五酯胶囊可以抑制他克莫司的代谢从而减少药量并节省费用。五酯胶囊也如其它中药，其成分复杂，并且含量很难保持恒定，因此它和他克莫司的药物相互作用（Drug-drug interaction，DDI）存在很大的个体差异。为了更精准地应用该联合用药，有必要明确五酯胶囊中决定药物相互作用的主要成分，并定量其对药物相互作用的贡献。但是中药的此类研究无法通过临床试验来进行，因此本项目创新地采用生理药动学（PBPK）建模技术，并结合体外酶动力学试验，来定量地考察五酯胶囊和他克莫司的药物相互作用，并首次考察他克莫司剂量的重要决定因素CYP3A5基因型对该药物相互作用的影响。（1）首先，本课题建立了他克莫司在不同CYP3A5基因型人群中的PBPK模型，并用临床数据验证了模型的可靠性，随后利用伏立康唑和他克莫司的临床DDI数据证明了模型预测DDI的可靠性；（2）随后开展了一系列体外和大鼠药动研究，获取五酯胶囊4个主成分五味子酯甲、甲素、醇甲和醇乙的PBPK建模参数和验证数据，在此基础上构建4成分的人体PBPK模型，考虑到中药单体无法获得人体药动数据来验证模型，我们也利用大鼠PBPK模型和体内药动数据验证了模型的可靠性；（3）利用不同基因型人肝微粒体，并结合CYP3A4的特异性抑制剂CYP3cide，获取了五酯胶囊4成分分别对CYP3A4或CYP3A5介导的他克莫司代谢抑制的动力学参数；（4）利用以上构建的PBPK模型和体外DDI参数，定量地预测了五酯胶囊4成分对DDI的贡献，发现其中五味子酯甲对DDI的影响最大，甲素次之，醇乙有一定影响，醇甲基本没有影响，并且导致代谢酶失活的机制性抑制影响最大，特别是多次给药后。CYP3A5对该药物相互作用影响不明显。本项目的发现为临床上精准联合应用五酯胶囊和他克莫司提供了新的理论依据，也为研究中药和西药的相互作用提供了一种全新的策略。