Tsakiridou Georgia, Papanastasiou Antigoni Maria, Efentakis Panagiotis, Angelerou Maria Faidra Galini, Kalantzi Lida
Pharmathen SA, 31 Spartis Str., 14452 Metamorfosi Attica, Greece.
Pharmaceutics. 2025 Jun 27;17(7):839. doi: 10.3390/pharmaceutics17070839.
Locally acting gastrointestinal (GI) drugs present challenges for generic drug development because traditional bioequivalence measures, which rely on systemic drug levels, do not reflect local efficacy. This review examines regulatory guidelines for establishing therapeutic equivalence for such drugs, using rifaximin-a minimally absorbed, gut-localized antibiotic-as a case study. We reviewed bioequivalence guidelines from the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA), along with the literature on rifaximin's biopharmaceutical and clinical properties, to identify strategies and challenges for establishing equivalence for locally acting GI drugs. Rifaximin exemplifies the limitations of standard bioequivalence methods: as a Biopharmaceutics Classification System (BCS) class IV drug with minimal absorption and low solubility, in vitro dissolution may not predict local drug availability. Clinical endpoint trials (e.g., traveler's diarrhea, hepatic encephalopathy, IBS-D) are resource-intensive and insensitive to formulation differences. Pharmacokinetic (PK) studies in healthy volunteers show low, variable plasma levels, which may inaccurately discriminate between formulations. The EMA requires evidence of non-saturable absorption to accept PK data, a difficult-to-establish but potentially irrelevant criterion. Differences between FDA and EMA approaches highlight a lack of harmonization, complicating global generic development. A tailored, multifaceted approach is needed to demonstrate bioequivalence for GI-localized drugs like rifaximin. This case underscores the need for more sensitive surrogate methods (e.g. advanced in vitro or pharmacodynamic models) and flexible regulatory criteria. Harmonization across international guidelines and innovative bioequivalence study designs are key to facilitating the approval of safe and effective generic alternatives in this drug class.
局部作用的胃肠道（GI）药物在仿制药开发方面面临挑战，因为依赖全身药物水平的传统生物等效性衡量标准无法反映局部疗效。本综述以利福昔明（一种吸收极少、作用于肠道局部的抗生素）为例，研究了此类药物建立治疗等效性的监管指南。我们回顾了美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）的生物等效性指南，以及有关利福昔明生物制药和临床特性的文献，以确定建立局部作用GI药物等效性的策略和挑战。利福昔明体现了标准生物等效性方法的局限性：作为生物药剂学分类系统（BCS）IV类药物，其吸收极少且溶解度低，体外溶出可能无法预测局部药物可及性。临床终点试验（如旅行者腹泻、肝性脑病、腹泻型肠易激综合征）资源密集且对剂型差异不敏感。健康志愿者的药代动力学（PK）研究显示血浆水平低且变化不定，这可能无法准确区分不同剂型。EMA要求有非饱和吸收的证据才能接受PK数据，这一标准难以确立且可能无关紧要。FDA和EMA方法的差异凸显了缺乏协调性，使全球仿制药开发复杂化。对于利福昔明这类作用于胃肠道局部的药物，需要一种量身定制的多方面方法来证明生物等效性。这个案例强调了需要更敏感的替代方法（如先进的体外或药效学模型）和灵活的监管标准。国际指南的协调统一和创新的生物等效性研究设计是促进这类药物安全有效的仿制药获批的关键。
