Efficacy, tolerability and pharmacokinetics of a modified release formulation of ADX10059, a negative allosteric modulator of metabotropic glutamate receptor 5: an esophageal pH-impedance study in healthy subjects

Neurogastroenterol Motil. 2010 Aug;22(8):859-65, e231. doi: 10.1111/j.1365-2982.2010.01484.x. Epub 2010 Mar 16.


Background: Animal studies show metabotropic glutamate receptor 5 inhibition reduces transient lower esophageal sphincter relaxations and increases lower esophageal sphincter tone. A preliminary, single-day study, demonstrated oral ADX10059 reduced 24-h esophageal acid exposure and clinical symptoms in gastro-esophageal reflux disease (GERD) patients, but had suboptimal tolerability, ascribable to the compound's rapid absorption. This study evaluated ADX10059 modified-release (MR) formulation pharmacokinetics, tolerability, and pharmacodynamics.

Methods: Randomized, double-blind placebo-controlled study. Three groups of eight healthy, male subjects received placebo (n = 2) or ADX10059 (n = 6) 50, 125 or 250 mg b.i.d. for 6 days. Esophageal pH-impedance was performed on day 1 and day 6 of treatment, for 1-h fasting and for 4 h post refluxogenic meal. Treatment effect was determined by Kruskall-Wallis test and placebo comparison by Wilcoxon rank sum.

Key results: Following placebo, reflux episodes increased from day 1 to day 6. Significant treatment effect was seen for total esophageal acid exposure (P = 0.048) and postprandial number of weakly acidic reflux episodes (P = 0.041). Significant differences from placebo were seen for 125 mg b.i.d.; 250 mg b.i.d. was not more effective than 125 mg b.i.d. Twice daily ADX10059 MR gave satisfactory 24-h exposure and good tolerability.

Conclusions & inferences: ADX10059 decreased reflux episodes in healthy subjects. The MR formulation is suitable for longer-term treatment to evaluate symptom control in GERD patients.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Allosteric Regulation / physiology*
  • Animals
  • Double-Blind Method
  • Electric Impedance
  • Gastroesophageal Reflux / drug therapy*
  • Gastroesophageal Reflux / physiopathology
  • Gastrointestinal Agents / pharmacokinetics*
  • Gastrointestinal Agents / pharmacology
  • Gastrointestinal Agents / therapeutic use*
  • Humans
  • Hydrogen-Ion Concentration*
  • Male
  • Manometry / methods*
  • Middle Aged
  • Placebos / therapeutic use
  • Postprandial Period / drug effects
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / chemistry*
  • Young Adult


  • Gastrointestinal Agents
  • Placebos
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate