Clinical Therapeutics/Volume 32, Number 9, 2010

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, i-Week, Two-Period, Phase IV Crossover Study
Chi Young Shim, MD, PhD'; Sungha Park, MD, PhD'; jae Woo Song, MD, PhD2;
Sang-Hak Lee, MD, PhD'; Jung-Sun Kim, MD, PhD'; and Namsik Chung, MD, PhD'
lCardiology Division, Yonsei Cardiovascular Center, Yonsei University College ofMedicine) Seoul) Republic of
Korea; and 2Department of Laboratory Medicine) Yonsei University College ofMedicine) Seoul) Republic ofKorea

ABSTRACT withdrawal of consent.Therefore, 30 volunteers (16 males;

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 ge-
neric 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, open-
label, 1-week, 2-period, Phase IV crossover study con-
ducted 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 (Emax ) 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 bioequiva-
lence 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 vol-
unteers were excluded because of screening failure or
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. Emax and bleeding time
did not differ significantly between the 2 groups. The
mean change in Emax 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 pharmacody-
namic effects or safety profile. (Clin Ther. 2010;32:1664-
1673) © 2010 Excerpta Medica Inc.
Key words: clopidogrel, antiplatelet, effect, safety.
INTRODUCTION
Clopidogrel bisulfate is an oral antiplatelet agent used
in the treatment of coronary artery disease, peripheral
vascular disease, and cerebrovascular disease.' It is also
used, along with aspirin, for the prevention of throm-
boembolism after the placement of intracoronary stents
and other invasive operations in the cardiovascular
Accepted forpubtication june 15,2010.
doi:l 0.1016/j.clinthera.201 0.08.001
0149-2918/$ - see front matter
© 2010 Excerpta Medica Inc. All rights reserved.

1664 Volume 32 Number 9