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

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• 作者：Chi Young Shim ; Sungha Park ; Jae Woo Song ; Sang-Hak Lee ; Jung-Sun Kim ; Namsik Chung
• 关键词：clopidogrel ; antiplatelet ; effect ; safety
• 刊名：Clinical Therapeutics
• 出版年：2010
• 出版时间：August 2010
• 年：2010
• 卷：32
• 期：9
• 页码：1664-1673
• 全文大小：1513 K

文摘

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.