title: Pharmacokinetics of the novel PAR-1 antagonist vorapaxar in patients with hepatic impairment.
abstract: OBJECTIVE
  To determine whether hepatic impairment has an effect on the pharmacokinetics (PK) of vorapaxar or M20, its main pharmacologically active metabolite.
  
  
  METHODS
  This was an open-label study in which a single 40-mg oral dose of vorapaxar was administered to patients with mild (n = 6), moderate (n = 6), and severe (n = 4) hepatic impairment and healthy controls (n = 16) matched for age, gender, weight, and height. Blood samples for vorapaxar and M20 assay were collected predose and at frequent intervals up to 8 weeks postdose.
  
  
  RESULTS
  Plasma vorapaxar and M20 PK profiles were similar between patients with impaired liver function and healthy controls. Group mean values for vorapaxar C(max) and AUC(tf) were 206-279 ng/mL and 14,200-18,200 ng·h/mL, respectively, with the lowest values observed in patients with severe impairment. Vorapaxar median T(max) and mean t(1/2) values were 1.00-1.75 h and 298-366 h, respectively. There was no apparent correlation between vorapaxar or M20 exposure or t(1/2) values and disease severity. Vorapaxar was generally well tolerated; one serious adverse event (gastrointestinal bleeding secondary to ruptured esophageal varices) was reported in a patient with severe hepatic impairment.
  
  
  CONCLUSIONS
  Hepatic impairment had no clinically relevant effect on the PK of vorapaxar and M20. No dose or dosage adjustment of vorapaxar will be required in patients with mild to moderate hepatic impairment. Although systemic exposure to vorapaxar does not appear to increase in patients with severe hepatic impairment, administration of vorapaxar to such patients is not recommended given their bleeding diathesis.
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. paul.statkevich@merck.com
authors.forename: Paul
authors.initials: P
authors.lastname: Statkevich
authors.forename: Teddy
authors.initials: T
authors.lastname: Kosoglou
authors.forename: Richard A
authors.initials: RA
authors.lastname: Preston
authors.forename: Bharath
authors.initials: B
authors.lastname: Kumar
authors.forename: Fengjuan
authors.initials: F
authors.lastname: Xuan
authors.forename: Craig
authors.initials: C
authors.lastname: Trusley
authors.forename: James E
authors.initials: JE
authors.lastname: Schiller
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Langdon
authors.forename: David L
authors.initials: DL
authors.lastname: Cutler
mesh_terms: D000368:Aged; D001711:Biotransformation; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced; D006207:Half-Life; D048550:Hepatic Insufficiency / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007408:Intestinal Absorption; D007783:Lactones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D017093:Liver Failure / Q000097:blood / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D012720:Severity of Illness Index
chemical_list: D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D018179:Receptors, Thrombin; C530299:vorapaxar