Skip to main content
Article
The effects of laropiprant, a selective prostaglandin D₂ receptor 1 antagonist, on the antiplatelet activity of clopidogrel or aspirin.
Department of Pharmacology and Experimental Therapeutics Faculty Papers
  • Aimee Dallob, Merck, Whitehouse Station, NJ
  • Wen-Lin Luo, Merck, Whitehouse Station, NJ
  • Julie Mabalot Luk, Merck, Whitehouse Station, NJ
  • Lisa Ratcliffe, Merck, Whitehouse Station, NJ
  • Amy O Johnson-Levonas, Merck, Whitehouse Station, NJ
  • Jules I Schwartz, Merck, Whitehouse Station, NJ
  • Victor Dishy, Daiichi-Sankyo Pharma Development, Edison, NJ
  • Walter K. Kraft, Thomas Jefferson University
  • Jan N De Hoon, Center for Clinical Pharmacology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium
  • Anne Van Hecken, Center for Clinical Pharmacology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium
  • Inge De Lepeleire, Merck, Brussels, Belgium
  • Waldemar Radziszewski, Merck, Whitehouse Station, NJ
  • John A Wagner, Merck, Whitehouse Station, NJ
  • Eseng Lai, Merck, Whitehouse Station, NJ
Document Type
Article
Publication Date
1-1-2011
Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Platelets

Volume 22, Issue 7, November 2011, Pages 495-503.

The published version is available at DOI: 10.3109/09537104.2011.565433 Copyright © Informa Healthcare

Abstract

Laropiprant (LRPT) is being developed in combination with Merck's extended-release niacin (ERN) formulation for the treatment of dyslipidemia. LRPT, an antagonist of the prostaglandin PGD₂ receptor DP1, reduces flushing symptoms associated with ERN. LRPT also has affinity for the thromboxane A₂ receptor TP (approximately 190-fold less potent at TP compared with DP1). Aspirin and clopidogrel are two frequently used anti-clotting agents with different mechanisms of action. Since LRPT may potentially be co-administered with either one of these agents, these studies were conducted to assess the effects of steady-state LRPT on the antiplatelet activity of steady-state clopidogrel or aspirin. Bleeding time at 24 h post-dose (trough) was pre-specified as the primary pharmacodynamic endpoint in both studies. Two separate, double-blind, randomized, placebo-controlled, crossover studies evaluated the effects of multiple-dose LRPT on the pharmacodynamics of multiple-dose clopidogrel or aspirin. Healthy subjects were randomized to once-daily oral doses of LRPT 40 mg or placebo to LRTP co-administered with clopidogrel 75 mg or aspirin 81 mg for 7 days with at least a 21-day washout between treatments. In both studies, bleeding time and platelet aggregation were assessed 4 and 24 hours post-dose on Day 7. Comparability was declared if the 90% confidence interval for the estimated geometric mean ratio ([LRPT+clopidogrel]/clopidogrel alone or [LRPT+aspirin]/aspirin alone) for bleeding time at 24 hours post-dose on Day 7 was contained within (0.66, 1.50). Concomitant daily administration of LRPT 40 mg with clopidogrel 75 mg or aspirin 81 mg resulted in an approximate 4-5% increase in bleeding time at 24 hours after the last dose vs. bleeding time after treatment with clopidogrel or aspirin alone, demonstrating that the treatments had comparable effects on bleeding time. Percent inhibition of platelet aggregation was not significantly different between LRPT co-administered with clopidogrel or aspirin vs. clopidogrel or aspirin alone at 24 hours post-dose at steady state. At 4 hours after the last dose, co-administration of LRPT 40 mg resulted in 3% and 41% increase in bleeding time vs. bleeding time after treatment with aspirin or clopidogrel alone, respectively. Co-administration of LPRT with clopidogrel or aspirin was generally well tolerated in healthy subjects. Co-administration of multiple doses of LRPT 40 mg and clopidogrel 75 mg or aspirin 81 mg had no clinically important effects on bleeding time or platelet aggregation.

Citation Information
Aimee Dallob, Wen-Lin Luo, Julie Mabalot Luk, Lisa Ratcliffe, et al.. "The effects of laropiprant, a selective prostaglandin D₂ receptor 1 antagonist, on the antiplatelet activity of clopidogrel or aspirin." (2011)
Available at: http://works.bepress.com/walter_kraft/3/