Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
Food and Drug Administration, Office of Generic Drugs, Silver Spring, MD, USA.
J Clin Pharmacol. 2019 Sep;59(9):1252-1263. doi: 10.1002/jcph.1017. Epub 2019 May 14.
The University of Florida Center for Pharmacometrics and Systems Pharmacology and the Food and Drug Administration Office of Generic Drugs have collaborated on a research project to develop a mechanism- and risk-based strategy that systematically investigates postmarketing reports of therapeutic inequivalence following the switch between brand and generic drug products. In this study we developed and qualified a physiologically based pharmacokinetic model to systematically investigate the influence of drug- and formulation-related properties on the oral absorption and bioequivalence of modified-release products using metoprolol as an example. Our findings show that the properties of the release-controlling polymer are the critical attributes for in vitro dissolution, in vivo absorption, and systemic exposure (ie, pharmacokinetics) and, thus, the bioequivalence of metoprolol extended-release products rather than the properties of the drug itself. Differences in dissolution rate can result in significant differences in maximum plasma concentration but not in area under the concentration-time curve.
佛罗里达大学药物代谢动力学和系统药理学中心与美国食品和药物管理局仿制药办公室合作开展了一项研究项目，以制定一种基于机制和风险的策略，系统地调查品牌药和仿制药转换后治疗等效性方面的上市后报告。在这项研究中，我们开发并验证了一个生理药物代谢动力学模型，以使用美托洛尔作为示例，系统地研究药物和制剂相关特性对控释产品口服吸收和生物等效性的影响。我们的研究结果表明，释放控制聚合物的特性是体外溶出度、体内吸收和全身暴露（即药代动力学）以及美托洛尔缓释产品生物等效性的关键属性，而不是药物本身的特性。溶出速率的差异可能导致最大血浆浓度有显著差异，但对浓度-时间曲线下面积没有影响。
