基于PBPK模型预测不同晶型利福平的生物等效性  

Prediction of the bioequivalence of different crystal forms of rifampicin based on physiologically based pharmacokinetic model

作　　者：蔡其霖 黎文星 严真 尹莉芳 CAI Qilin;LI Wenxing;YAN Zhen;YIN Lifang(Department of Pharmaceutics,School of Pharmacy,China Pharmaceutical University,Nanjing 210009;Engineering Research Center for Development and Evaluation of Sustained-Release Intelligent Preparations and Key Functional Excipients of Jiangsu Province,Nanjing 210009,China)

机构地区：[1]中国药科大学药学院药剂系,南京210009 [2]江苏省缓释智能制剂及关键功能性辅料开发与评价工程研究中心,南京210009

出　　处：《中国药科大学学报》2022年第2期207-214,共8页Journal of China Pharmaceutical University

基　　金：江苏高校优势学科三期资助项目——“颠覆性理论与技术创新团队”;中国药科大学“重大科技成果转化”项目(高端缓控释制剂产业化研究)。

摘　　要：通过基于生理学的药动学(physiologically based pharmacokinetic,PBPK)建模策略预测晶型Ⅰ与晶型Ⅱ利福平在人体内的药动学行为,判断两者是否生物等效。对两种晶型利福平进行体外研究后,以大鼠静脉给药的药动学数据为基础,构建大鼠PBPK模型,再通过大鼠口服给药的药动学数据进行模型优化,种属外推至健康人体,利用外推模型预测两种晶型的利福平在健康人体内的血药浓度-时间曲线、吸收部位及吸收量等药动学行为。健康人体模型预测结果显示,晶型Ⅰ与晶型Ⅱ利福平的c_(max)分别为8.42和10.35μg/mL,t_(max)分别为0.40和0.32 h,AUC_(0-t)均为62.90μg·h/mL。根据吸收情况预测结果,晶型Ⅰ与晶型Ⅱ利福平在胃部均不被吸收,但在肠道被完全吸收,两者吸收部位及吸收量基本一致。晶型Ⅰ与晶型Ⅱ利福平的药动学参数十分接近,预测两者具有生物等效性。The physiologically based pharmacokinetic(PBPK)modeling strategy was adopted to predict the pharmacokinetic behavior of crystal forms Ⅰ and Ⅱ of rifampicin in humans,which was used to determine whether the two were bioequivalent.After conducting studies in vitro of the two crystal forms,a rat PBPK model was established based on the pharmacokinetic data of intravenous administration in rats.The model was optimized by the pharmacokinetic data of oral administration in rats.Species were extrapolated to healthy humans,and the extrapolation model was used to predict such pharmacokinetic behaviors as the drug-time curve,absorption site,and absorption amount of the two crystal forms of rifampicin in healthy humans.The prediction results of the healthy human model showed that the c_(max)of form Ⅰ and form Ⅱ rifampicin were 8.42 and 10.35μg/m L,t_(max)were 0.40 and 0.32 h,and AUC_(0-t)were both 62.90μg·h/m L.According to the prediction results of absorption,neither crystal form I nor crystal form II rifampicin was absorbed in the stomach,yet both were completely absorbed in the intestinal tract,with both the absorption site and the absorption amount were basically the same.The pharmacokinetic parameters of both crystal forms I and II of rifampicin were very close,which could indicate bioequivalence.

关 键 词：利福平 晶型 GastroPlus 基于生理学的药动学模型 种属外推 

分 类 号：R945[医药卫生—微生物与生化药学]