Pharmacodynamics, pharmacokinetics, and safety of AM211: a novel and potent antagonist of the prostaglandin D2 receptor type 2

J Clin Pharmacol. 2012 Oct;52(10):1482-93. doi: 10.1177/0091270011421912. Epub 2011 Nov 22.

Abstract

The prostaglandin D(2) receptor type 2 (DP2) and its ligand, PGD(2), have been implicated in the development of asthma and other inflammatory diseases. The authors evaluated the pharmacodynamics, pharmacokinetics and safety of [2'-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl]-acetic acid sodium salt (AM211), a novel and potent DP2 antagonist, in healthy participants. Single and multiple doses of AM211 demonstrated dose-dependent inhibition of eosinophil shape change in blood with near-complete inhibition observed at trough after dosing 200 mg once daily for 7 days. Maximum plasma concentrations and exposures of AM211 increased in a greater-than-dose-proportional manner after single and multiple dosing. After multiple dosing, the exposures on day 7 were higher than on day 1 with accumulation ratio values ranging from 1.4 to 1.5. Mean terminal half-life values ranged from 14 to 25 hours across the dose range of 100 to 600 mg. AM211 was well tolerated at all doses in both the single- and multiple-dose cohorts. These data support additional clinical studies to evaluate AM211 in asthma and other inflammatory diseases.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Area Under Curve
  • Double-Blind Method
  • Eosinophils / cytology
  • Eosinophils / drug effects
  • Female
  • Humans
  • Male
  • Methylurea Compounds / administration & dosage*
  • Methylurea Compounds / adverse effects
  • Methylurea Compounds / pharmacokinetics
  • Middle Aged
  • Phenylacetates / administration & dosage*
  • Phenylacetates / adverse effects
  • Phenylacetates / pharmacokinetics
  • Prostaglandin D2 / pharmacology
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Immunologic / metabolism
  • Receptors, Prostaglandin / antagonists & inhibitors*
  • Receptors, Prostaglandin / metabolism
  • Young Adult

Substances

  • (2'-(3-benzyl-1-ethylureidomethyl)-6-methoxy-4'-trifluoromethylbiphenyl-3-yl)acetic acid
  • Methylurea Compounds
  • Phenylacetates
  • Receptors, Immunologic
  • Receptors, Prostaglandin
  • Prostaglandin D2
  • prostaglandin D2 receptor