Comparative Pharmacokinetics/Pharmacodynamics of Clopidogrel Besylate and Clopidogrel Bisulfate in Healthy Korean Subjec
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ORIGINAL RESEARCH ARTICLE
Comparative Pharmacokinetics/Pharmacodynamics of Clopidogrel Besylate and Clopidogrel Bisulfate in Healthy Korean Subjects Bo-Hyung Kim • Jung-Ryul Kim • Kyoung Soo Lim Hyun-Suk Shin • Seo Hyun Yoon • Joo-Youn Cho • In-Jin Jang • Sang-Goo Shin • Kyung-Sang Yu
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Published online: 2 October 2012 Ó Springer International Publishing Switzerland 2012
Abstract Background Clopidogrel selectively inhibits platelet aggregation. Clopidogrel bisulfate (PlavixÒ) was first developed for atherothrombosis prevention and is commonly prescribed for this indication. A new clopidogrel formulation, clopidogrel besylate (KOVIXÒ), 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
B.-H. Kim K. S. Lim H.-S. Shin S. H. Yoon J.-Y. Cho I.-J. Jang S.-G. Shin K.-S. Yu (&) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehangno, Jongno-gu, Seoul 110-744, Republic of Korea e-mail: [email protected] J.-R. Kim Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Republic of Korea
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 pharm
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