title: Vorapaxar, an oral PAR-1 receptor antagonist, does not affect the pharmacokinetics of rosiglitazone.
abstract: To evaluate the potential effects of vorapaxar on the pharmacokinetics and safety of rosiglitazone.
  
  
  
  This was an open-label, two-period, two-treatment, fixed-sequence study in 18 healthy subjects. On Day 1, Period 1, subjects received a single dose of rosiglitazone 8 mg. In Period 2, subjects received vorapaxar 40 mg on Day 1, vorapaxar 7.5 mg once-daily on Days 2-7, and a single dose of rosiglitazone 8 mg on Day 7. Rosiglitazone and N-desmethylrosiglitazone pharmacokinetics were assessed alone (Period 1) and after coadministration with vorapaxar (Period 2). Vorapaxar and its M20 metabolite pharmacokinetics were assessed on Day 7, Period 2. Safety and tolerability were assessed throughout the study.
  
  
  
  Coadministration of rosiglitazone with vorapaxar had no effect on rosiglitazone or N-desmethylrosiglitazone pharmacokinetics. The ratio of geometric means (GMR) and 90% confidence intervals (CI) of the coadministration versus monotherapy for Cmax (GMR 95; 90% CI 88, 103) and AUC0-24 h (GMR 103; 90% CI 98, 108) were within the 80-125% bioequivalence criteria. The metabolite-to-parent exposure ratio with and without vorapaxar was unaltered. Coadministration of vorapaxar with rosiglitazone was generally well tolerated.
  
  
  
  Coadministration of vorapaxar with rosiglitazone or drugs metabolized via CYP2C8 is unlikely to cause a significant pharmacokinetic interaction.
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: Teddy
authors.initials: T
authors.lastname: Kosoglou
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: Bharath
authors.initials: B
authors.lastname: Kumar
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Statkevich
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Schiller
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: Bhavna
authors.initials: B
authors.lastname: Kantesaria
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Hanson
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: Christine McCrary
authors.initials: CM
authors.lastname: Sisk
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Cutler
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation; D065727:Cytochrome P-450 CYP2C8 / Q000378:metabolism; D065687:Cytochrome P-450 CYP2C8 Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007783:Lactones / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009658:North Dakota; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D044463:Receptor, PAR-1 / Q000378:metabolism; D000077154:Rosiglitazone; D013810:Therapeutic Equivalency; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D065687:Cytochrome P-450 CYP2C8 Inhibitors; D007004:Hypoglycemic Agents; D007783:Lactones; C480687:N-desmethylrosiglitazone; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D044463:Receptor, PAR-1; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; C530299:vorapaxar
keywords: clinical therapy; oral antiplatelet therapy; pharmacokinetics; safety; vorapaxar