Pharmacokinetics, Pharmacodynamics, and Safety of a Prostaglandin D2 Receptor Antagonist

doi:doi:10.1038/sj.clpt.6100345

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Clinical Pharmacology & Therapeutics (2008); 83, 6, 840–847 doi:10.1038/sj.clpt.6100345

Pharmacokinetics, Pharmacodynamics, and Safety of a Prostaglandin D₂ Receptor Antagonist

E Lai¹, LA Wenning¹, TM Crumley¹, I De Lepeleire², F Liu¹, JN de Hoon³, A Van Hecken³, M Depré³, D Hilliard¹, H Greenberg⁴, G O'Neill⁵, K Metters⁵, KG Gottesdiener¹ and JA Wagner¹

¹Merck Research Laboratories, Rahway, New Jersey and West Point, Pennsylvania, USA
²Merck Research Laboratories, Brussels, Belgium
³UZ Gasthuisberg, Center for Clinical Pharmacology, Leuven, Belgium
⁴Department of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
⁵Merck Frosst Canada, Montreal, Quebec, Canada

Correspondence: E Lai, (eseng_lai@merck.com)

Received 21 February 2007; Accepted 28 June 2007; Published online 19 September 2007.

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Abstract

Laropiprant is a selective antagonist of the prostaglandin D₂ (PGD₂) receptor subtype 1 (DP1). Three double-blind, randomized, placebo-controlled studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of laropiprant in healthy male volunteers. Single doses up to 900 mg and multiple doses up to 450 mg were generally well tolerated. Laropiprant exhibited dose-proportional pharmacokinetics. Oral absorption is rapid (T_max=0.8–2.0 h) and the terminal half-life is approximately 12–18 h. The pharmacokinetics of laropiprant was not affected by food. Single doses of 6 mg and higher were effective in suppressing PGD₂-induced cyclic AMP accumulation in platelets, demonstrating laropiprant target engagement with DP1. Laropiprant has detectable off-target antagonist effects at the thromboxane A₂ receptor but no clinically significant effect on collagen-induced platelet aggregation or bleeding times with multiple doses up to 200 mg.