College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.
Mol Pharm. 2010 Aug 2;7(4):1235-43. doi: 10.1021/mp100053q.
The Biopharmaceutical Classification System (BCS) guidance issued by the FDA allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release (IR) solid oral dosage forms only for BCS class I drugs. However, a number of drugs within BCS class III have been proposed to be eligible for biowaivers. The World Health Organization (WHO) has shortened the requisite dissolution time of BCS class III drugs on their Essential Medicine List (EML) from 30 to 15 min for extended biowaivers; however, the impact of the shorter dissolution time on AUC(0-inf) and C(max) is unknown. The objectives of this investigation were to assess the ability of gastrointestinal simulation software to predict the oral absorption of the BCS class I drugs propranolol and metoprolol and the BCS class III drugs cimetidine, atenolol, and amoxicillin, and to perform in silico bioequivalence studies to assess the feasibility of extending biowaivers to BCS class III drugs. The drug absorption from the gastrointestinal tract was predicted using physicochemical and pharmacokinetic properties of test drugs provided by GastroPlus (version 6.0). Virtual trials with a 200 mL dose volume at different drug release rates (T(85%) = 15 to 180 min) were performed to predict the oral absorption (C(max) and AUC(0-inf)) of the above drugs. Both BCS class I drugs satisfied bioequivalence with regard to the release rates up to 120 min. The results with BCS class III drugs demonstrated bioequivalence using the prolonged release rate, T(85%) = 45 or 60 min, indicating that the dissolution standard for bioequivalence is dependent on the intestinal membrane permeability and permeability profile throughout the gastrointestinal tract. The results of GastroPlus simulations indicate that the dissolution rate of BCS class III drugs could be prolonged to the point where dissolution, rather than permeability, would control the overall absorption. For BCS class III drugs with intestinal absorption patterns similar to those of cimetidine, atenolol or amoxicillin, the dissolution criteria for extension of biowaivers to BCS class III drugs warrants further investigation.
美国食品和药物管理局（FDA）发布的生物药剂分类系统（BCS）指南允许对速释（IR）固体口服剂型的 I 类 BCS 药物豁免体内生物利用度和生物等效性研究。然而，已经提出了一些属于 III 类 BCS 的药物有资格获得生物豁免。世界卫生组织（WHO）在其基本药物清单（EML）上将 III 类 BCS 药物的必需溶出时间从 30 分钟缩短至 15 分钟，以延长生物豁免；然而，较短的溶解时间对 AUC（0-inf）和 C（max）的影响尚不清楚。本研究的目的是评估胃肠模拟软件预测 I 类 BCS 药物普萘洛尔和酒石酸美托洛尔以及 III 类 BCS 药物西咪替丁、阿替洛尔和阿莫西林口服吸收的能力，并进行计算机模拟生物等效性研究，以评估将生物豁免扩大到 III 类 BCS 药物的可行性。使用 GastroPlus（版本 6.0）提供的测试药物的物理化学和药代动力学特性预测药物从胃肠道的吸收。以不同药物释放速率（T（85%）= 15 至 180 分钟）进行 200 毫升剂量体积的虚拟试验，以预测上述药物的口服吸收（C（max）和 AUC（0-inf））。两种 I 类 BCS 药物在 120 分钟的释放速率范围内均符合生物等效性。III 类 BCS 药物的结果表明，延长释放速率（T（85%）= 45 或 60 分钟）具有生物等效性，表明生物等效性的溶解标准取决于肠膜通透性和整个胃肠道的通透性分布。GastroPlus 模拟结果表明，III 类 BCS 药物的溶解速率可以延长到溶解而不是渗透性控制整体吸收的程度。对于与西咪替丁、阿替洛尔或阿莫西林吸收模式相似的 III 类 BCS 药物，需要进一步研究将生物豁免扩展到 III 类 BCS 药物的溶解标准。
