Is the demonstration of bioequivalence for clavulanic acid required in amoxicillin–clavulanic acid orally administered immediate‐release products?. (6th April 2018)

• Record Type: Journal Article
• Authors: Charoo, Naseem A.; Rahman, Ziyaur; Ali, Areeg Anwer
• Is Part Of: Journal of pharmacy and pharmacology. Volume 70:Number 7(2018)
• Page Start: 883
• Page End: 892
• Publication Date: 2018-04-06
• Subjects: absorption variability -- amoxicillin clavulanic acid -- bioequivalence -- minimum inhibitory concentration -- postβ‐lactamase inhibitor effect; Pharmacy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/jphp.12920
• Languages: English
• ISSNs: 0022-3573

Abstract

Abstract: Objectives: Bioequivalence (BE) criteria for amoxicillin–clavulanic acid (Co‐amoxiclav) oral formulations are based on 90% confidence interval for both amoxicillin and clavulanic acid. The aim of this work is to explore the relevance of demonstrating BE of clavulanic acid in Co‐amoxiclav oral formulations and also to assess the impact on safety and efficacy of product due to bioinequivalent clavulanic acid. Methods and key findings: The subtherapeutic levels of clavulanic acid would continue to exert their action against β‐lactamases due to postβ‐lactamase inhibitor effect. Additionally, only minute quantities are required to inhibit β‐lactamases. Majority of adverse effects associated with Co‐amoxiclav are of less serious nature, therefore, risk due to suprabioavailable clavulanic acid was determined to be low. 'Very rapid clavulanic acid release' in in vitro dissolution test would ensure that clinically significant differences between test and reference formulations if any are detected in advance. As an additional risk mitigation strategy, WHO recommends qualitative and quantitative composition similarity between test and reference formulations to ensure excipients do not adversely impact bioavailability. Conclusions: Co‐amoxiclav with non‐bioequivalent clavulanic acid, but bioequivalent amoxicillin would still achieve its therapeutic objectives without exposing patients to unwanted adverse effects. Therefore, the current regulatory criterion of demonstrating BE of clavulanic acid appears conservative.