Onishi Motoki, Tagawa Kozo, Jiko Maiko, Koike Kayo, Maruyama Masato, Hashizume Hidetoshi, Imagaki Kazuhide, Higaki Kazutaka
Medical Analysis Research Department, Pharmaceutical Research & Technology Division, Towa Pharmaceutical Co., Ltd, Kyoto Research Park KISTIC #202, 134, Chudoji Minami-machi, Shimogyo-ku, Kyoto, Japan.
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama, 700-8530, Japan.
Pharm Res. 2022 Sep;39(9):2203-2216. doi: 10.1007/s11095-022-03337-4. Epub 2022 Jul 14.
The pharmaceutical bioequivalence of generic medicines must be confirmed with corresponding original drugs. Although the in vitro dissolution tests are required, results of the mandatory in vitro study do not necessarily reflect the in vivo performance after oral administration. Then, we have tried to develop the novel "Dissolution-Absorption Prediction (DAP) workflow" to evaluate the in vivo performance of generic medicines.
The DAP workflow consists of an "In vitro two-cell connected dissolution (TCCD) system" mimicking the changes in the luminal pH associated with gastrointestinal transit of medicines, "Evaluation of pharmacokinetics of active pharmaceutical ingredient (API)" and "Prediction of plasma concentration-time profile". TCCD system-evaluated dissolution kinetics of APIs from generic formulations and pharmacokinetic parameters based on human data regarding the original drugs were used to calculate the plasma concentration-time profiles of APIs after the oral administration of generic medicines.
The mandatory in vitro dissolution tests indicated that the dissolution properties of valsartan (BCS class II) and fexofenadine (BCS class III/IV) in generic formulations did not coincide with those in the corresponding original formulations. The TCCD system provided the very similar dissolution kinetics for the generic and original formulations for the two APIs. Plasma concentration-time profiles evaluated utilizing the dissolution profiles obtained by the TCCD system were in good agreement with the observed profiles for both the generic and original formulations for each API.
The DAP workflow would be valuable for estimating the in vivo performance of generic formulation and deducing their bioequivalence with the original formulation.
仿制药的药学等效性必须与相应的原研药进行确认。尽管需要进行体外溶出试验，但强制性体外研究的结果不一定能反映口服给药后的体内性能。因此，我们试图开发一种新型的“溶出-吸收预测（DAP）工作流程”来评估仿制药的体内性能。
DAP工作流程包括一个“体外双细胞连接溶出（TCCD）系统”，该系统模拟与药物胃肠道转运相关的管腔pH值变化、“活性药物成分（API）的药代动力学评估”以及“血浆浓度-时间曲线预测”。基于原研药的人体数据，利用TCCD系统评估仿制药制剂中API的溶出动力学和药代动力学参数，以计算口服仿制药后API的血浆浓度-时间曲线。
强制性体外溶出试验表明，缬沙坦（BCS II类）和非索非那定（BCS III/IV类）在仿制药制剂中的溶出特性与相应原研制剂不一致。TCCD系统为两种API的仿制药和原研制剂提供了非常相似的溶出动力学。利用TCCD系统获得的溶出曲线评估的血浆浓度-时间曲线与每种API的仿制药和原研制剂的观察曲线高度一致。
DAP工作流程对于估计仿制药制剂的体内性能以及推断其与原研制剂的生物等效性具有重要价值。
