title: No Pharmacokinetic Drug-Drug Interaction Between Prasugrel and Vorapaxar Following Multiple-Dose Administration in Healthy Volunteers.
abstract: Vorapaxar is a first-in-class antagonist of the protease-activated receptor-1, the primary thrombin receptor on human platelets, which mediates the downstream effects of thrombin in hemostasis and thrombosis. Prasugrel is a platelet inhibitor that acts as a P2Y12 receptor antagonist through an active metabolite, R-138727. This study investigated the interaction of these 2 platelet antagonists when coadministered. This was a randomized, open-label, multiple-dose study in 54 healthy volunteers consisting of a fixed-sequence crossover and a parallel group design. In sequence 1, 36 subjects received prasugrel 60 mg on day 1 and then prasugrel 10 mg once daily on days 2 to 7, followed by vorapaxar 40 mg and prasugrel 10 mg on day 8 and then vorapaxar 2.5 mg and prasugrel 10 mg orally once daily on days 9 to 28. In sequence 2, 18 subjects received vorapaxar 40 mg on day 1 and then vorapaxar 2.5 mg once daily on days 2 to 21. The geometric mean ratios (90% confidence intervals) for AUCτ and Cmaxof coadministration/monotherapy for vorapaxar (0.93 ng·h/mL[0.85-1.02 ng·h/mL] and 0.95 ng/mL [0.86-1.05 ng/mL]) and R-138727 (0.91 ng·h/mL [0.85- 0.99 ng·h/mL] and 1.02 ng/mL [0.89-1.17 ng/mL]) were within prespecified bounds, demonstrating the absence of a pharmacokinetic interaction between vorapaxar and prasugrel. There was no specific safety or tolerability risk associated with multiple-dose coadministration of vorapaxar and prasugrel. In conclusion, in this study in healthy volunteers, there was no pharmacokinetic drug-drug interaction between vorapaxar and prasugrel. Multiple-dose coadministration of the 2 drugs was generally well tolerated.
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Matt S
authors.initials: MS
authors.lastname: Anderson
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Teddy
authors.initials: T
authors.lastname: Kosoglou
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Statkevich
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rotonda
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Meehan
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Cutler
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000068799:Prasugrel Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D000068799:Prasugrel Hydrochloride; C530299:vorapaxar
keywords: PAR-1; drug-drug interaction; pharmacokinetics; prasugrel; thrombin receptor antagonist; vorapaxar