基于生理和疾病机制的肾移植患者麦考酚酸的PKPD研究

Mycophenolic acid (MPA) is a potent immunosuppressant, which is widely used to prevent allograft rejection after kidney and other solid organ transplantations. Currently, two different forms of MPA are available on the market: mycophenolate mofetil (MMF) and enteric-coated, delayed-release mycophenolate sodium (EC-MPS). MPA has high protein binding, enterohepatic circulation and shown large inter- and intra- individual variability in pharmacokinetics and pharmacodynamics (PK/PD). Therefore, therapeutic drug monitoring and individualized therapy of MPA are necessary. Previous established PK models cannot be well extrapolated to other clinical studies because all these models were mainly based on observed clinical data that represented different patient populations. This study will combine physiologically based pharmacokinetic (PBPK) and empirical population PK/PD analysis for the purpose of investigating the individual variability thoroughly. Firstly, PBPK/PD models in healthy volunteers will be developed based on physiology, drug’s absorption and metabolism as well as genetic polymorphisms. PK/PD behaviors of MMF and EC-MPS will be compared and connected to validate each other. Secondly, the established models in healthy volunteers will be extrapolated to renal transplant patients by incorporation of physiological and pathological changes, concurrent used medications, et al. Finally, physiologically based PK/PD with disease models will be developed step by step. This strategy provides a powerful tool to investigate the PK/PD behavior. The established PK/PD models have better extrapolation performance and clinical values and will provide quantitative evidence for optimizing individualized drug therapy of MPA.

麦考酚酸（MPA）是常用免疫制剂，广泛用于预防肾移植等实体器官移植术后的排斥反应。现有以MPA为活性成分的两大上市药物：吗替麦考酚酯（MMF）和麦考酚钠肠溶片（EC-MPS）。MPA的蛋白结合率高，具肠肝循环现象，药动学和药效学（PK/PD）的个体差异大，需要行治疗药物监测和个体化给药。既往研究因考察的患者人群存在异质性，不同研究的结果常有显著差异，且无法互推。本研究拟采用基于机制的生理药动学（PBPK）结合经验性的群体PK/PD的研究方法，深层次分析引起个体差异的原因。首先，结合生理、药物的吸收、代谢和遗传等相关因素，建立健康人中MPA的PBPK/PD模型，比较和桥接两种不同MPA药物的体内行为；然后，结合肾移植疾病进程、合并用药等因素外推至肾移植患者，逐步建立基于生理和疾病机制的PK/PD模型，以期获得更佳的外推性和临床应用价值，为精准设计MPA的个体化给药方案提供定量依据。

麦考酚酸（MPA）是常用的抗代谢类免疫抑制剂，常用于预防实体器官移植术后的排异反应。由于该药治疗窗窄，个体间和个体内的变异大，因此需要个体化给药。本项目首先建立了MPA作用靶点次黄嘌呤单核苷酸脱氢酶（IMPDH）活性的分析方法，并进行了方法验证。各项指标符合相关的技术规范，可作为MPA的药效学生物标志物的常规监测方法。其次，结合MPA的药动学研究，考察了肾移植患者中，服用MPA制剂（麦考酚酸钠和吗替麦考酚酯）后，MPA的药动学和药效学关系，建立了基于生理机制的总的MPA和游离MPA及其葡糖醛酸化代谢物（MPAG）的药动学肠肝循环模型，以及药效学标志物IMPDH的Emax链接模型，筛查了PK-PD的相关潜在影响因素，并对主要影响因素进行了敏感度分析。肠肝循环采用了含胆囊室的生理模型，描述MPA和MPAG的代谢和转运过程。结果表明了体内白蛋白以及合并用钙调磷酸酶抑制剂他克莫司或环孢素是最重要的影响因素。中国肾移植患者的药动学和药效学参数与白种人相比未见显著差异。此外，综合评价了既往发表的MPA制剂的群体药动学模型的外推适用性，包括预测误差为基础的评估、模拟为基础的评估和Bayes预测评估，探索模型预测性能的影响因素。结果表明既往模型的预测性能均不理想。另外，通过建立的基于生理机制的肠肝循环模型，针对进餐次数、首次进餐时间、进餐间隔、胆囊排空分数进行了系统考察。结果表明给药后的首次进餐时间是不同研究中采样方案差异的来源。另应用费雪信息矩阵法，针对肠肝循环进行了采样方案的考察和优化。结果表明首次进餐时间信息能有效改善有限采样方案（LSS）估算药时曲线下面积（AUC0-12h）的准确性，给药后的首次进餐时间是LSS方案差异的重要来源。最后，基于最大后验贝叶斯法，以及上述获得的优化采样方案和药动学药效学模型，开发了适于临床应用个体化给药计算软件，利于临床个体化给药方案的制定和实施。