Faculty of Medicine, Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
Division of Clinical and Experimental Pharmacology, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.
Epilepsia. 2021 Feb;62(2):285-302. doi: 10.1111/epi.16802. Epub 2021 Jan 10.
The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra-subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow-therapeutic-index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second-generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%-111%) applied to NTI drugs. Intra-subject variability for AUC was <10% for 53 (88%) of the 60 products for which this measure was reported. Many gabapentin generics showed broader, 90% CIs for bioequivalence estimates, and greater intra-subject variability, compared with generics of other ASMs. When interpreted within the context of other available data, these results suggest that any risk of non-bioequivalence between these individual generic products is small, and that switches across these products are not likely to result in clinically relevant changes in plasma drug exposure. The potential for variability in exposure when switching across generics is likely to be greatest for gabapentin.
抗癫痫药物（ASM）仿制药之间转换的安全性仍然是癫痫管理中的一个热门话题。主要关注的原因是不确定两种仿制药是否以及何时与同一品牌（参比）产品具有生物等效性，以及在仿制药之间转换是否会导致血浆 ASM 浓度发生临床显著变化。本文通过讨论生物等效性和统计学显著性检验之间的区别、解释生物等效性研究时个体内变异性的重要性、适用于窄治疗指数（NTI）药物的更严格的监管生物等效性要求以及目前可用的 ASM 仿制药在多大程度上符合这些标准来解决这些问题。基于对公开可获取的监管评估报告的审查，分析了在欧洲通过集中、互认或分散程序批准的第二代 ASM 的 117 种口服仿制药的数据。分析表明，对于 99%评估的仿制药（排除加巴喷丁产品后），AUC（药物浓度-时间曲线下面积）的测试/参比几何均数比值的 90%置信区间（90%CI）狭窄且完全包含于适用于 NTI 药物的接受区间（90%-111%）。对于报告了该指标的 60 种产品中的 53 种（88%），AUC 的个体内变异性<10%。与其他 ASM 的仿制药相比，许多加巴喷丁仿制药的生物等效性估计值的 90%CI 更宽，个体内变异性更大。从其他可用数据的角度来解释这些结果表明，这些个别仿制药之间非生物等效的风险很小，并且这些产品之间的转换不太可能导致血浆药物暴露的临床相关变化。在跨仿制药转换时，暴露变异性的可能性在加巴喷丁中最大。
