title: Vorapaxar, an oral PAR-1 receptor antagonist, does not affect the pharmacokinetics and pharmacodynamics of warfarin.
abstract: OBJECTIVE
  Vorapaxar is an orally active protease-activated receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet aggregation. This open-label study assessed the pharmacokinetics and pharmacodynamics of single-dose warfarin in the presence/absence of multiple-dose vorapaxar in 12 healthy men.
  
  
  METHODS
  Subjects received two treatments separated by ≥ 7-day washout: Treatment A warfarin 25 mg (Day 1); Treatment B vorapaxar 2.5 mg/day on Days 1-6 and vorapaxar 40 mg coadministered with warfarin 25 mg (Day 7). R-warfarin, S-warfarin, and prothrombin time (PT) were assayed predose and up to 120 h postdose.
  
  
  RESULTS
  The geometric mean ratio (GMR) as a percentage (warfarin + vorapaxar/warfarin) was calculated. The GMR (90 % CIs) estimates of C(max) were 105 (99, 111) and 105 (99, 112) for R- and S-warfarin, respectively. The GMR (90 % CIs) estimates of AUC(0-∞) were 108 (101, 116) and 105 (96, 115) for R- and S-warfarin, respectively. The GMR (95 % CIs) estimates of AUC(0-120 h) for PT and INR were 97 (95, 98) and 96 (94, 98), respectively.
  
  
  CONCLUSIONS
  Results of this study indicate that vorapaxar has no meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin, suggesting that the coadministration of these two drugs or vorapaxar coadministered with other CYP2C9/CYP2C19 substrates is unlikely to cause a clinically significant pharmacokinetic drug interaction.
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. teddy.kosoglou2@merck.com
authors.forename: Teddy
authors.initials: T
authors.lastname: Kosoglou
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhu
authors.forename: Fengjuan
authors.initials: F
authors.lastname: Xuan
authors.forename: Laura
authors.initials: L
authors.lastname: Black
authors.forename: Amy O
authors.initials: AO
authors.lastname: Johnson-Levonas
authors.forename: Monika
authors.initials: M
authors.lastname: Martinho
authors.forename: Paul
authors.initials: P
authors.lastname: Statkevich
authors.forename: David L
authors.initials: DL
authors.lastname: Cutler
mesh_terms: D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D004347:Drug Interactions; D016903:Drug Monitoring; D006207:Half-Life; D006801:Humans; D019934:International Normalized Ratio; D007783:Lactones / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D011517:Prothrombin Time; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology*; D013223:Statistics as Topic; D013237:Stereoisomerism; D014859:Warfarin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D014859:Warfarin; C530299:vorapaxar