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 AUC(0-24 h) and C(max) by approximately twofold (GMR [90% CI]: 196% [173,222]; 193% [166,223], respectively), while rifampin decreased vorapaxar AUC(0-24 h) and C(max) 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.

Hepatic impairment had no clinically relevant effect on the PK of vorapaxar and M20. No dose or dosage adjustment of vorapaxar will be required in patients with mild to moderate hepatic impairment. Although systemic exposure to vorapaxar does not appear to increase in patients with severe hepatic impairment, administration of vorapaxar to such patients is not recommended given their bleeding diathesis.

ESRD had no clinically relevant effect on the PK profile of vorapaxar or its ability to inhibit TRAP-induced platelet aggregation.

The pharmacokinetic profiles of vorapaxar and M20 and the metabolite/parent ratios in healthy Chinese were generally comparable to those in a healthy Western population.

This randomized, open-label, parallel group study examined the effects of food, antacid, and age on the pharmacokinetics of vorapaxar. In total, 101 subjects were enrolled including 83 young adults (18-45 years) and 18 elderly subjects (>65 years). Subjects received single-dose vorapaxar 40 mg after a 10-hour fast (young and elderly) or with extra-strength antacid, food, or 1 or 2 hours after food (young only). Vorapaxar 40 mg was rapidly absorbed after a fast (median Tmax : 1 hour). Administration with food or 1 or 2 hours post-meal modestly increased vorapaxar mean area under the curve (AUC) and Cmax and prolonged median Tmax by 1 hour. Concomitant food modestly increased vorapaxar AUC from time zero to infinity [AUC(I)] and Cmax 43% and 31%, respectively. Antacid modestly decreased vorapaxar AUC(I) by 15% and Cmax by 38%, and increased median Tmax by 1 hour. Vorapaxar AUC(I) and Cmax were 41% and 29% higher, respectively, in elderly versus young subjects. Concomitant food and older age were associated with modest increases, and antacid was associated with a small decrease in vorapaxar exposure, which are not expected to affect the drug's safety or efficacy.