Pharmacodynamics and pharmacokinetics of the novel PAR-1 antagonist vorapaxar (formerly SCH 530348) in healthy subjects

Purpose The aim of our study was to evaluate the pharmacology of vorapaxar (SCH 530348), an oral PAR-1 antagonist, in healthy volunteers. Methods and results In two randomized, placebo-controlled studies, subjects received either single ascending doses of vorapaxar (0.25, 1, 5, 10, 20, or 40 mg; n = 50), multiple ascending doses of vorapaxar (1, 3, or 5 mg/day for 28 days; n = 36), a loading dose (10 or 20 mg) followed by daily maintenance doses (1 mg) for 6 days (n = 12), or placebo. Single 20- and 40-mg doses of vorapaxar completely inhibited thrombin receptor activating peptide (TRAP)-induced platelet aggregation (>80% inhibition) at 1 h and sustained this level of inhibition for >= 72 h. Multiple doses yielded complete inhibition on Day 1 (5 mg/day) and Day 7 (1 and 3 mg/day). Adverse events were generally mild, transient, and unrelated to dose. Conclusion Vorapaxar provided rapid and sustained dose-related inhibition of platelet aggregation without affecting bleeding or clotting times.