title: A Randomized Study of the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Clopidogrel in Three Different CYP2C19 Genotype Groups of Healthy Japanese Subjects.
abstract: OBJECTIVE
  We investigated the safety of 600/150 mg regimen of clopidogrel and the pharmacodynamics and pharmacokinetics of both 300/75 mg regimen and 600/150 mg regimen of clopidogrel in 72 Japanese subjects.
  
  
  METHODS
  A randomized study was conducted in healthy Japanese male subjects. Eligible subjects were stratified by dose regimen (300 mg loading dose of clopidogrel on day 1 followed by a 75 mg maintenance dose from days 2 to 7 or a 600 mg loading dose of clopidogrel on day 1 followed by a 150 mg maintenance dose from days 2 to 7) and CYP2C19 metabolizer group [extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs)]. Platelet aggregation and platelet reactivity were evaluated by measuring the maximum platelet aggregation intensity (MAI) induced by 5 and 20 μM ADP, phosphorylation of vasodilator-stimulated phosphoprotein (VASP), and P2Y12 reaction units (PRU) using the VerifyNow system, respectively. We also measured the plasma concentrations of clopidogrel and its active metabolite H4.
  
  
  RESULTS
  No treatment emergent adverse events in the 300/75 mg and 600/150 mg regimen were observed in EMs, IMs, and PMs. All CYP metabolizer groups exhibited a lower MAI (%) induced by ADP in the 300/75 mg and 600/150 mg clopidogrel regimens, and MAI (%) in IM group was equipotent to EM irrespective of the clopidogrel dosage. The double dose regimen decreased MAI in the PM group as equipotent to the IM group receiving the standard dose regimen without the extension of bleeding time. No clear relationship of exposure to clopidogrel and CYP2C19 function was observed, whereas active metabolite H4 exposure was likely to be related to CYP2C19 function.
  
  
  CONCLUSIONS
  Clopidogrel in the 600/150 mg regimen was well tolerated. All CYP metabolizer groups exhibited a lower MAI (%) induced by ADP and anti-platelet activities analyzed by VASP and VerifyNow test in the 300/75 mg and 600/150 mg regimens in healthy Japanese subjects.
authors.affiliation: Therapeutic Strategy Unit Asia Pacific R&D, Sanofi K.K.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kajiwara
authors.forename: Setsuo
authors.initials: S
authors.lastname: Hasegawa
mesh_terms: D000328:Adult; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004311:Double-Blind Method; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D007564:Japan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D011110:Polymorphism, Genetic / Q000235:genetics*; D012449:Safety; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine