以兰索拉唑肠溶胶囊为例探索模型引导的仿制药等效性替代方法

目的：本研究探索如何建立体内外相关性与生物等效性的替代方法，为药物日常质量控制及市场监管提供有效手段。方法：通过分析兰索拉唑体内吸收、分布、代谢、排泄（absorption,distribution,metabolism,excretion,ADME）过程，整合已有体外研究结果至生理药代动力学模型（physiological pharmacokinetics,PBPK）中，搭建兰索拉唑的体内药代动力学（pharmacokinetics,PK）模型，借助GastroPlus中的机制性口服吸收模型反推口服给药后在胃肠道内的释放与吸收曲线，进而构建兰索拉唑肠溶制剂的体内外相关性模型，分析现有体外溶出条件是否是与生物体相关的溶出方法。最后再通过软件开展虚拟生物等效性（bioequivalence,BE）的分析。结果：成功搭建了兰索拉唑口服给药的PK模型，模型能够较好地反映口服给药后兰索拉唑在体内的ADME过程，口服特点以及在体内的处置行为。目前法定的溶出方法与体内并非生物体相关，通过软件推测了可能生物体相关的溶出方法。同时虚拟评估了7家仿制药企业与参比制剂的生物等效性情况。结论：本研究建立了体...

Lansoprazole; pharmacokinetic model; In vitro and in vivo correlation; Virtual bioequivalence; Conformance evaluation of generic drugs

Objective: This study explored how to establish an alternative method for in vitro-in vivo correlation and bioequivalence, providing effective means for daily drug quality control and market supervision. Methods: By analyzing the absorption, distribution, metabolism, excretion(ADME) process of lansoprazole in vivo, and integrating the existing in vitro research results into the PBPK model, an in vivo pharmacokinetics(PK) model of lansoprazole was constructed. By using the mechanized oral absorption model in GastroPlus, the release and absorption curves in the gastrointestinal tracts after oral administration were retroactively deduced, so as to construct the in vivo-in vitro correlation model of lansopazole enteric formulations, and to analyze whether the existing in vitro dissolution conditions were biologically related. Finally, bioequivalence(BE) was virtually analyzed by the software. Results: The PK model for oral administration of lansoprazole was successfully established, and the model well reflected the ADME process, oral characteristics and disposition of lansoprazole in vivo after oral administration. Current statutory methods of dissolution are not in vivo related, and the possible in vivo related method of dissolution was speculated by the software. At the same time, the virtual BE study found that the generic drugs of Company A, B, F and G might be bioequivalent while the generic drugs of Company C, D and E might be biologically nonequivalent to the reference preparation of Tianjin Takeda. Conclutions: This project has established an alternative method to evaluate in vivo-in vitro correlation and bioequivalence, and provided a simple, convenient and regulatory measure for quality control and consistency evaluation of drugs.