Abstract：
Currently, Biopharmaceutics Classification System (BCS) classes I and III are the only biological exemptions of immediate-release solid oral dosage forms eligible for regulatory approval. However, through virtual bioequivalence (VBE) studies, BCS class II drugs may qualify for biological exemptions if reliable and validated modeling is used. Here, we sought to establish physiologically based pharmacokinetic (PBPK) models, in vitro-in vivo relationship (IVIVR), and VBE models for enteric-coated omeprazole capsules, to establish a clinically-relevant dissolution specification (CRDS) for screening BE and non-BE batches, and to ultimately develop evaluation criteria for generic omeprazole enteric-coated capsules. To establish omeprazole\'s IVIVR based on the PBPK model, we explored its in vitro dissolution conditions and then combined in vitro dissolution profile studies with in vivo clinical trials. The predicted omeprazole pharmacokinetics (PK) profiles and parameters closely matched the observed PK data. Based on the VBE results, the bioequivalence study of omeprazole enteric-coated capsules required at least 48 healthy Chinese subjects. Based on the CRDS, the capsules\' in vitro dissolution should not be < 28%-54%, < 52%, or < 80% after two, three, and six hours, respectively. Failure to meet these dissolution criteria may result in non-bioequivalence. Here, PBPK modeling and IVIVR methods were used to bridge the in vitro dissolution of the drug with in vivo PK to establish the BE safety space of omeprazole enteric-coated capsules. The strategy used in this study can be applied in BE studies of other BCS II generics to obtain biological exemptions and accelerate drug development.
摘要：
目前,生物制药分类系统(BCS)I类和III类是唯一有资格获得监管部门批准的立即释放固体口服剂型的生物豁免。然而,通过虚拟生物等效性(VBE)研究，如果使用可靠且经过验证的建模，BCSII类药物可能有资格获得生物豁免。这里,我们试图建立基于生理的药代动力学（PBPK）模型，体外-体内关系（IVIVR），和肠溶奥美拉唑胶囊的VBE模型，建立临床相关的溶出规范（CRDS），用于筛选BE和非BE批次，并最终制定通用奥美拉唑肠溶胶囊的评价标准。建立基于PBPK模型的奥美拉唑IVIVR,我们探索了其体外溶出条件，然后将体外溶出曲线研究与体内临床试验相结合。预测的奥美拉唑药代动力学(PK)曲线和参数与观察到的PK数据紧密匹配。根据VBE结果，奥美拉唑肠溶胶囊的生物等效性研究需要至少48名健康中国受试者。基于CRDS,胶囊的体外溶出度不应<28%-54%，<52%,或<80%后两个，三,六个小时,分别。不满足这些溶出标准可能导致非生物等效性。这里,使用PBPK建模和IVIVR方法将药物的体外溶出与体内PK桥接，以建立奥美拉唑肠溶胶囊的BE安全空间。本研究中使用的策略可用于其他BCSII仿制药的BE研究，以获得生物豁免并加速药物开发。
