No Pharmacokinetic Drug–Drug Interaction Between Prasugrel and Vorapaxar Following Multiple‐Dose Administration in Healthy Volunteers

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 Cmax of 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.