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Comparative Pharmacokinetics/Pharmacodynamics of Clopidogrel Besylate and Clopidogrel Bisulfate in Healthy Korean Subjects

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Abstract

Background

Clopidogrel selectively inhibits platelet aggregation. Clopidogrel bisulfate (Plavix®) was first developed for atherothrombosis prevention and is commonly prescribed for this indication. A new clopidogrel formulation, clopidogrel besylate (KOVIX®), has recently been developed.

Objective

This study was designed to compare the multiple-dose pharmacokinetics/pharmacodynamics and tolerability of clopidogrel besylate with those of clopidogrel bisulfate in 40 healthy male subjects.

Methods

This was an open-label, randomized-sequence, multiple-dose, two-period, two-treatment crossover study. The subjects were randomly assigned to a sequence group that received two treatments: clopidogrel besylate 75 mg followed by clopidogrel bisulfate 75 mg, or vice versa. The subjects received a 300-mg loading dose on day 1 followed by 75 mg daily for the next 4 days. Serial blood samples were collected to determine the concentrations of clopidogrel and its carboxylic acid metabolite, SR26334. Platelet aggregation and bleeding times were measured. Tolerability was evaluated throughout the study.

Results

The clopidogrel plasma concentration–time profiles of the formulations were similar. The measured pharmacokinetic parameters did not differ significantly between the clopidogrel besylate and clopidogrel bisulfate groups. The geometric mean ratios of the clopidogrel besylate group to the clopidogrel bisulfate group with respect to the maximum plasma concentration (Cmax) and the area under the concentration–time curve (AUC) from time zero to the time of last measurable concentration (AUClast) were 0.96 (90 % confidence interval [CI] 0.82, 1.12) and 0.95 (0.81, 1.11), respectively. Moreover, the pharmacokinetic parameters of SR26334 did not differ significantly between the two treatment groups. Furthermore, the areas under the platelet aggregation inhibition-time curves (AUIC) and the maximum inhibitory effects (Imax) did not differ significantly between the two groups. The geometric mean ratios (clopidogrel besylate to clopidogrel bisulfate) were 1.01 (90 % CI 0.95, 1.08) for the Imax and 0.98 (0.89, 1.07) for the AUIC. Both formulations were well tolerated and exhibited comparable safety profiles.

Conclusion

This study demonstrated that the pharmacokinetic/pharmacodynamic profiles of clopidogrel besylate were not significantly different from those of clopidogrel bisulfate. Both formulations were well tolerated in healthy subjects.

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Acknowledgments

This study was sponsored by Kolon Pharmaceuticals, Seoul, Korea. The authors have indicated that they have no other conflicts of interest relevant to the content of this article. All of the co-authors were involved in the writing of the manuscript. The authors thank Ms SungHee Han (Clinical Trials Center at Seoul National University Hospital) for performing the platelet aggregation tests in this study. The manuscript was edited for English language by American Journal Experts (http://www.journalexperts.com/).

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Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehangno, Jongno-gu, Seoul, 110-744, Republic of Korea

    Bo-Hyung Kim, Kyoung Soo Lim, Hyun-Suk Shin, Seo Hyun Yoon, Joo-Youn Cho, In-Jin Jang, Sang-Goo Shin & Kyung-Sang Yu

  2. Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Republic of Korea

    Jung-Ryul Kim

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  1. Bo-Hyung Kim
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Correspondence to Kyung-Sang Yu.

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Kim, BH., Kim, JR., Lim, K.S. et al. Comparative Pharmacokinetics/Pharmacodynamics of Clopidogrel Besylate and Clopidogrel Bisulfate in Healthy Korean Subjects. Clin Drug Investig 32, 817–826 (2012). https://doi.org/10.1007/s40261-012-0007-3

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