Pharmacokinetics and pharmacodynamics of the novel  PAR-1 antagonist vorapaxar in patients with end-stage  renal disease.
OBJECTIVE
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.
Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. teddy.kosoglou2@merck.com
Teddy
T
Kosoglou
Walter K
WK
Kraft
Bharath
B
Kumar
Paul
P
Statkevich
Fengjuan
F
Xuan
Lei
L
Ma
Lisa K
LK
Jennings
James E
JE
Schiller
Ronald B
RB
Langdon
David L
DL
Cutler
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001682:Biological Availability; D003627:Data Interpretation, Statistical; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D007677:Kidney Function Tests; D007783:Lactones / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D006435:Renal Dialysis; D055815:Young Adult; D010975:Platelet Aggregation Inhibitors
D007783:Lactones; D011725:Pyridines; D018179:Receptors, Thrombin; C530299:vorapaxar; D010975:Platelet Aggregation Inhibitors