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

Authors

• Teddy Kosoglou
• Walter K Kraft
• Bharath Kumar
• Paul Statkevich
• Fengjuan Xuan
• Lei Ma
• Lisa K Jennings
• James E Schiller
• Ronald B Langdon
• David L Cutler

Publication/Presentation Date

7-1-2012

Abstract

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.

Volume

68

Issue

7

First Page

1049

Last Page

1056

ISSN

1432-1041

Published In/Presented At

Kosoglou, T., Kraft, W. K., Kumar, B., Statkevich, P., Xuan, F., Ma, L., Jennings, L. K., Schiller, J. E., Langdon, R. B., & Cutler, D. L. (2012). Pharmacokinetics and pharmacodynamics of the novel PAR-1 antagonist vorapaxar in patients with end-stage renal disease. European journal of clinical pharmacology, 68(7), 1049–1056. https://doi.org/10.1007/s00228-012-1217-6

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

22315147

Department(s)

Administration and Leadership

Document Type

Article