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, two-treatment, 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 ≥ 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 ≤ 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 ABE method and were well within the acceptable range of 0.80 to 1.25 (1.02-1.12, 0.92-0.99, and 0.92-0.98, respectively).

Conclusion: FDC of ASA and clopidogrel was bioequivalent to the simultaneous administration of the individual formulations in healthy Chinese subjects under fed conditions.

Trial registration: CTR20190376.

Keywords: ASA; Bioequivalence; Clopidogrel; Fixed dose combination; RSABE.