Bioequivalence Study Comparing Fixed-Dose Combination of Clopidogrel and Aspirin with Coadministration of Individual Formulations in Chinese Subjects Under Fed Conditions: A Phase I, Open-Label, Randomized, Crossover Study

Abstract

Introduction: Simultaneous administration of acetylsalicylic acid (ASA) and clopidogrel has demonstrated efficacy in the treatment of acute coronary syndrome. Clopidogrel ? ASA in a fixed-dose combination (FDC) provides a pharmaceutical option to enhance adherence to the coadministration of dual antiplatelet therapy (DAPT). Herein, we evaluate the bioequivalence of enteric ASA and clopidogrel in an FDC compared with simultaneous administration of the individual formulations. Methods: This study is a randomized, single-center, open-label, three-sequence, three-period, twotreatment, crossover study conducted in healthy Chinese male and female subjects under fed conditions. Subjects were randomized to receive, in each period, a single dose of (1) a combination tablet containing 75-mg clopidogrel and 100-mg enteric ASA (test formulation) or (2) coadministration of one 75-mg clopidogrel tablet and one 100-mg enteric-coated ASA tablet (reference formulations) under fed conditions. Plasma samples were analyzed for ASA, salicylic acid, clopidogrel, and the clopidogrel metabolite SR26334. For ASA, the reference-scaled average bioequivalence (RSABE) analysis was conducted for C max of ASA because within-subject standard deviation (SD W) was C 0.294 for log-transformed C max. Results: The point estimate (test/reference geometric mean ratio) was between 0.80 and 1.25, and the upper one-sided 95% confidence interval (CI) for the scaled average bioequivalence metric was B 0 (-0.08). AUC of ASA as SD W was \ 0.294 for log-transformed AUC last and AUC. Estimates of 90% CIs for log-transformed AUC last and AUC ratios were within the bioequivalence range of 0.80 to 1.25 (0.98-1.08 and 1.00-1.10, respectively). For clopidogrel, the 90% CIs for the ratios comparing log-transformed C max , AUC last , and AUC ratios of clopidogrel following administration of test versus reference formulation were calculated using the Digital Features To view digital features for this article go to

Use of combination pills with acetylsalicylic acid and clopidogrel in coronary artery disease. Efficacy and assessment of adherence to treatment: Kobra Study

“…Уже в первых исследованиях выявлено, что через 1 мес больные с ОКС реже отказывались от приема комбинированного препарата АСК и клопидогрела, чем при назначении отдельных лекарственных средств (7% против 17% соответственно) [13]. После этого стали появляться сходные воспроизведенные аналоги такой комбинации и проведены исследования их эквивалентности оригинальной форме и приверженности [14,15]. В 2017 г. в России также появился воспроизведенный препарат с фиксированной комбинацией АСК и клопидогрела Плагрил® А компании «Д-р Редди'с Лабораторис Лтд» (Индия).…”