The Influence of Multiple-Dose Vorapaxar, an Oral PAR-1 Receptor Antagonist, on the Single-Dose Pharmacokinetics and Pharmacodynamics of Digoxin

Vorapaxar is a novel orally active thrombin receptor antagonist selective for the PAR-1 receptor. This open-label, single-center, fixed-sequence, 2-period, 2-treatment study assessed the pharmacokinetics and pharmacodynamics of single-dose digoxin in the presence/absence of multiple-dose vorapaxar. Eighteen healthy adult subjects received two treatments in a fixed sequence separated by ≥8-day washout: (A) digoxin 0.5 mg (Day 1); (B) vorapaxar 2.5 mg/day Days 1–6 and single-dose vorapaxar 40 mg administered with single-dose digoxin 0.5 mg Day 7. The geometric mean ratio (%; GMR) for the two treatments (digoxin alone and digoxin plus vorapaxar) and 90% confidence intervals (CIs) for and AUCtf and Cmax of digoxin were calculated. Pharmacodynamics of digoxin was assessed by measuring changes in electrocardiogram (ECG) parameters. The GMR (90% CIs) estimates for digoxin AUCtf and Cmax were 105% (91, 121) and 154% (130, 181), respectively. Except for differences in peak plasma concentrations, the pharmacokinetics of digoxin were similar between the two treatments. Coadministration of vorapaxar plus digoxin had no effect on digoxin Tmax or ECG parameters. The results of this study suggest that the coadministration of vorapaxar and digoxin is unlikely to cause a clinically significant drug–drug interaction.