Comparison of effects of two different formulations of clopidogrel bisulfate tablets on platelet aggregation and bleeding time in healthy Korean volunteers: A single-dose, randomized, open-label, 1-week, two-period, phase IV crossover study.

摘要

Background: Clopidogel bisulfate, an oral antiplatelet agent that works by inhibiting adenosine diphosphate-induced platelet aggregation, is used in the treatment of coronary artery disease, peripheral vascular disease, and cerebrovascular disease. The newly developed generic version of Clopidogrel bisulfate has a mechanism of action comparable to the reference formulation. Objective: The aim of this study was to assess and compare the pharmacodynamic effects and safety profile of these 2 formulations of Clopidogrel bisulfate in healthy volunteers. Methods: This was a single-dose, randomized, openlabel, 1-week, 2-period, Phase IV crossover study conducted from July 2008 to February 2009. Healthy volunteers were randomly assigned to receive a 1-week course of the test formulation followed by a 1-week course of the reference formulation (each, 300 mg on day 1, then 75 mg for 6 days), or the reverse sequence, separated by a 2-week washout period. Inhibition of platelet aggregation and the effect on bleeding time were used to evaluate pharmacodynamic effects. Variables included the mean maximal activity (E(max)) of the percent inhibition of platelet aggregation and bleeding time. Blood was sampled at screening, on the morning before each first drug administration (days 1 and 21), the day after the completion of each 7-day treatment course (days 8 and 28), and 7 days after completion of each 7-day treatment course (days 14 and 34). The bioequivalence of the 2 pharmaceutical formulations was tested. The safety profiles included assessment of vital signs, laboratory test results, and the incidence of adverse events and adverse drug reactions. Results: Two of the original 32 healthy Korean volunteers were excluded because of screening failure or withdrawal of consent. Therefore, 30 volunteers (16 males; mean [SD] age, 28.6 [8.0] years; age range, 19-51 years; mean weight, 62.4 [9.5] kg; weight range, 45-78 kg) were recruited into the study. E(max) and bleeding time did not differ significantly between the 2 groups. The mean change in E(max) was 44.1% (22.5%) and 44.3% (24.2%) and the mean change in bleeding time was 4.8 (3.7) and 4.6 (3.8) minutes after 7 days' administration of the test formulation and the reference formulation, respectively. The geometric mean ratio (90% CI) was 99.5 (82.9-116.2) and was within the bioequivalence acceptance range of 80% to 120%. Vital signs and platelet and neutrophil counts were within normal limits. None of the volunteers experienced any adverse events or adverse drug reactions. Conclusion: In this study of healthy volunteers, there were no significant differences between the 2 tablet formulations of Clopidogrel bisulfate in pharmacodynamic effects or safety profile.