The Effect of Multiple Doses of Ketoconazole or Rifampin on the Single- and Multiple-Dose Pharmacokinetics of Vorapaxar

This randomized, open‐label, parallel‐group study evaluated the effects of multiple‐dose ketoconazole or rifampin on the single‐ and multiple‐dose pharmacokinetics of vorapaxar. Healthy subjects randomly received one of the following three treatments (N = 12/group): (1) ketoconazole 400 mg once daily (QD) for 28 days (Days 1–28) and single‐dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.5 mg QD for 21 days (Days 8–28); (2) rifampin 600 mg QD for 28 days (Days 1–28) and single‐dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.5 mg QD for 21 days (Days 8–28); and (3) placebo QD for 28 days (Days 1–28) and single‐dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.5 mg QD for 21 days (Days 8–28). Ketoconazole increased the steady‐state vorapaxar AUC0–24 h and Cmax by approximately twofold (GMR [90% CI]: 196% [173,222]; 193% [166,223], respectively), while rifampin decreased vorapaxar AUC0–24 h and Cmax by approximately 50% (GMR [90% CI]: 45.5% [40,52]; 61.4% [52,72], respectively) versus vorapaxar alone. Potent CYP3A4 inhibitors or inducers may cause moderate increases or decreases in vorapaxar exposure, respectively, which may have safety and/or efficacy implications; therefore, their concomitant use with vorapaxar is not recommended.