Pharmaceutical Research and Technology Labs, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan; School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Fraunhofer Institute for Translational Medicine and Pharmacology, Theodor Stern Kai 7, 60596 Frankfurt am Main, Germany.
J Pharm Sci. 2022 Jan;111(1):135-145. doi: 10.1016/j.xphs.2021.08.008. Epub 2021 Aug 12.
The objective of the present study was to develop a physiologically based biopharmaceutics (PBBM) approach to predict the bioequivalence of dosage forms containing poorly soluble drugs. Aripiprazole and enzalutamide were used as model drugs. Variations in the gastrointestinal (GI) physiological parameters of fasted humans were taken into consideration in in vitro biorelevant dissolution testing and in an in silico PBBM simulations. To estimate bioequivalence between dosage forms, the inter-individual variabilities in their performance in virtual human subjects were predicted from the in vitro studies and variability in e.g. gastric emptying and fluid volume in the stomach was also taken into account. Formulations with different in vitro dissolution performance, a solution and a tablet formulation, were used in order to evaluate the accuracy of bioequivalence prediction using the PBBM approach. The bioequivalence parameters, i.e. geometric mean ratio and 90% confidence interval, for both drugs were predicted well in the virtual studies. In order to achieve even more precise predictions, it will be important to continue characterizing GI physiological parameters, along with their variabilities, on both an inter-subject and inter-occasion basis.
本研究旨在开发一种基于生理的生物药剂学（PBBM）方法，以预测含有难溶性药物的剂型的生物等效性。阿立哌唑和恩扎鲁胺被用作模型药物。在体外生物相关溶解试验和体内 PBBM 模拟中，考虑了空腹人体胃肠道（GI）生理参数的变化。为了估计剂型之间的生物等效性，从体外研究预测了其在虚拟人体受试者中的性能的个体间变异性，并且还考虑了例如胃排空和胃内液体量的变异性。使用具有不同体外溶解性能的制剂，即溶液和片剂制剂，以评估使用 PBBM 方法预测生物等效性的准确性。在虚拟研究中，两种药物的生物等效性参数（即几何均数比和 90%置信区间）均得到了很好的预测。为了实现更精确的预测，重要的是要继续在个体间和个体间的基础上表征 GI 生理参数及其变异性。
