title: Bioequivalence and tolerability of two clopidogrel salt preparations, besylate and bisulfate: a randomized, open-label, crossover study in healthy Korean male subjects.
abstract: BACKGROUND
  Clopidogrel, a potent antiplatelet agent, reduces the risk for thrombotic events in patients with atherothrombotic diseases. Clopidogrel is marketed primarily as a bisulfate salt. A different salt preparation of clopidogrel, clopidogrel besylate, has been developed and might provide an additional treatment option for patients.
  
  
  OBJECTIVE
  The aim of this study was to compare the pharmacokinetic, pharmacodynamic, and tolerability profiles of clopidogrel besylate with those of clopidogrel bisulfate to determine bioequivalence for the purposes of marketing approval.
  
  
  METHODS
  A randomized, open-label, 2-period, single- and multiple-dose, comparative crossover study was conducted in healthy Korean male subjects. The subjects received either clopidogrel bisulfate or clopidogrel besylate as a single 300-mg oral loading dose (day 1) followed by a 75-mg/d (once daily) maintenance dose on days 2 to 6. After a 15-day washout period, subjects were administered the alternative salt preparation according to the same protocol. The plasma concentrations of clopidogrel and its primary metabolite (SR26334) were assessed using high-performance liquid chromatography/tandem mass spectrometry after administration of the loading dose. The platelet aggregation response to 10-mumol/L adenosine diphosphate was measured using turbidometric aggregometry during the single- and multiple-dosing periods and at steady state (day 6). Tolerability was monitored using physical examination, including vital sign measurements, and laboratory analysis.
  
  
  RESULTS
  Forty-four subjects were enrolled and completed the study (mean [SD] age, 24.3 [2.7] years; weight, 70.0 [8.2] kg). The mean values for C(max), T(max), and AUC(0-t) with clopidogrel (parent drug) of clopidogrel besylate (5.2 ng/mL, 0.9 hour, and 10.1 ng/mL/h, respectively) were similar to those with clopidogrel bisulfate (5.4 ng/mL, 0.9 hour, and 10.3 ng/mL/h). The mean values for Cmax, AUC(0-t), and AUC(0-infinity) with the SR26334 of clopidogrel besylate (10.9 microg/mL, 38.8 microg/mL/h, and 43.0 microg/mL/h, respectively) were not significantly different from those with the SR26334 of clopidogrel bisulfate (11.9 microg/mL, 40.6 microg/mL/h, and 43.8 microg/mL/h). The mean values for maximal antiplatelet effect (Emax) and area under the time-effect curve (AUEC) with the 2 clopidogrel salt preparations were as follows: clopidogrel besylate, 58.8 h . % and 4299.1 h . % inhibition, respectively; and clopidogrel bisulfate, 61.7 h . % and 4406.9 h . % inhibition; these differences were not statistically significant. The 90% CIs for the ratios of the log-transformed C(max), AUC, E(max), and AUEC values were within the predetermined bioequivalence range of 80% to 125%. Three adverse events (6.8%) were reported during the study and included abdominal discomfort (1 subject [2.3%] in the group that received clopidogrel bisulfate), easy fatigability (1 subject [2.3%] immediately before administration of loading dose of clopidogrel besylate), and thrombocytopenia (1 subject [2.3%] in the group receiving the clopidogrel bisulfate). All adverse events were transient and mild.
  
  
  CONCLUSIONS
  In these healthy Korean male subjects, the differences in the pharmacokinetic and pharmacodynamic properties between the 2 clopidogrel salt preparations did not reach statistical significance and met the regulatory requirements for bioequivalence. Both preparations were well tolerated.
authors.affiliation: Clinical Trial Center, Kyungpook National University Hospital, Jung-gu, Daegu, Republic of Korea.
authors.forename: Sung-Doo
authors.initials: SD
authors.lastname: Kim
authors.forename: Wonku
authors.initials: W
authors.lastname: Kang
authors.forename: Hae Won
authors.initials: HW
authors.lastname: Lee
authors.forename: Dae Jin
authors.initials: DJ
authors.lastname: Park
authors.forename: Ju Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Kim
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Kim
authors.forename: Sung Wuk
authors.initials: SW
authors.lastname: Kim
authors.forename: Hee Sook
authors.initials: HS
authors.lastname: Nam
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Na
authors.forename: Young-Ran
authors.initials: YR
authors.lastname: Yoon
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D000077144:Clopidogrel; D018592:Cross-Over Studies; D006801:Humans; D007723:Korea; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012492:Salts / Q000737:chemistry; D053719:Tandem Mass Spectrometry / Q000379:methods; D013810:Therapeutic Equivalency; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D010975:Platelet Aggregation Inhibitors; C521473:SR26334; D012492:Salts; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine