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 400mg once daily (QD) for 28 days (Days 128) and single-dose vorapaxar 20mg on Day 7 followed by vorapaxar 2.5mg QD for 21 days (Days 828); (2) rifampin 600mg QD for 28 days (Days 128) and single-dose vorapaxar 20mg on Day 7 followed by vorapaxar 2.5mg QD for 21 days (Days 828); and (3) placebo QD for 28 days (Days 128) and single-dose vorapaxar 20mg on Day 7 followed by vorapaxar 2.5mg QD for 21 days (Days 828). Ketoconazole increased the steady-state vorapaxar AUC024h and Cmax by approximately twofold (GMR [90% CI]: 196% [173,222]; 193% [166,223], respectively), while rifampin decreased vorapaxar AUC024h 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.