title: Comparative pharmacokinetics/pharmacodynamics of clopidogrel besylate and clopidogrel bisulfate in healthy Korean subjects.
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 (C(max)) and the area under the concentration-time curve (AUC) from time zero to the time of last measurable concentration (AUC(last)) 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 (I(max)) 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 I(max) and 0.98 (0.89, 1.07) for the AUIC. Both formulations were well tolerated and exhibited comparable safety profiles.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Jongno-gu, Seoul, Republic of Korea.
authors.forename: Bo-Hyung
authors.initials: BH
authors.lastname: Kim
authors.forename: Jung-Ryul
authors.initials: JR
authors.lastname: Kim
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Lim
authors.forename: Hyun-Suk
authors.initials: HS
authors.lastname: Shin
authors.forename: Seo Hyun
authors.initials: SH
authors.lastname: Yoon
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001760:Bleeding Time; D000077144:Clopidogrel; D018592:Cross-Over Studies; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D056910:Republic of Korea; D012492:Salts; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D010975:Platelet Aggregation Inhibitors; C521473:SR26334; D012492:Salts; D000077144:Clopidogrel; D013988:Ticlopidine