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

Abstract

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