Pharmacokinetics and pharmacodynamics of the novel PAR-1 antagonist vorapaxar in patients with end-stage renal disease.

Purpose: To determine whether impaired renal function alters the pharmacokinetics (PK) of vorapaxar or its ability to inhibit thrombin receptor agonist peptide (TRAP)-induced platelet aggregation.
Methods: This was an open-label study in which 8 patients with end-stage renal disease (ESRD) on hemodialysis and 7 matched (based on age, gender, weight, and height) healthy controls were administered a single 10-mg oral dose of vorapaxar. Blood samples for vorapaxar PK and pharmacodynamic analysis were collected predose and at frequent intervals up to 6 weeks postdose.
Results: Mean vorapaxar bioavailability (based on area under the curve of plasma vorapaxar concentration over time) was identical in the two subject groups; the ESRD/healthy geometric mean ratio (GMR, expressed in percent) was 98. Mean maximum observed plasma concentration (77.4-98.2 ng/mL) was numerically lower in patients with ESRD compared with matched controls (GMR=76; 90% confidence interval=48 to 118). Median time of maximum observed plasma concentration was 2 h in both subject groups. The observed means for elimination half-life were 186 and 231 h in the ESRD and control groups, respectively. Inhibition of platelet aggregation was similar in the two groups. Four out of 15 (27%) subjects reported adverse events, all of which were characterized by the investigator as mild and unrelated to treatment.
Conclusions: ESRD had no clinically relevant effect on the PK profile of vorapaxar or its ability to inhibit TRAP-induced platelet aggregation.