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首页> 外文期刊>Molecular pharmaceutics >The biowaiver extension for BCS class III drugs: the effect of dissolution rate on the bioequivalence of BCS class III immediate-release drugs predicted by computer simulation.
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The biowaiver extension for BCS class III drugs: the effect of dissolution rate on the bioequivalence of BCS class III immediate-release drugs predicted by computer simulation.

机译：BCS III类药物的生物豁免范围：计算机模拟预测的溶出速率对BCS III类即时释放药物生物等效性的影响。

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摘要

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.
机译：FDA颁布的《生物制药分类系统（BCS）指南》允许仅针对BCS I类药物的即时释放（IR）固体口服剂型免除体内生物利用度和生物等效性研究。但是，已经提出了BCS III类中的许多药物有资格获得生物豁免。世界卫生组织（WHO）已将其基本药物清单（EML）中BCS III类药物的必需溶出时间从30分钟缩短为15分钟以延长生物豁免期;但是，较短的溶解时间对AUC（0-inf）和C（max）的影响尚不清楚。这项研究的目的是评估胃肠道模拟软件预测BCS I类药物普萘洛尔和美托洛尔以及BCS III类药物西咪替丁，阿替洛尔和阿莫西林的口服吸收能力，并进行计算机生物等效性研究以评估将生物豁免扩大到BCS III类药物的可行性。使用GastroPlus（6.0版）提供的测试药物的理化和药代动力学特性，可以预测胃肠道的药物吸收。进行了以200 mL剂量体积在不同药物释放速率下（T（85％）= 15至180分钟）进行的虚拟试验，以预测上述药物的口服吸收（C（max）和AUC（0-inf））。两种BCS I类药物在长达120分钟的释放速率方面都具有生物等效性。使用BCS III类药物的结果证明了使用延长的释放速率（T（85％）= 45或60分钟）的生物等效性，表明生物等效性的溶出度标准取决于整个胃肠道的肠膜通透性和通透性。 GastroPlus模拟的结果表明，BCS III类药物的溶出速率可以延长到溶出而不是渗透性将控制总吸收的程度。对于肠吸收模式与西咪替丁，阿替洛尔或阿莫西林相似的BCS III类药物，将生物豁免扩展至BCS III类药物的溶出标准值得进一步研究。

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