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.
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.


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
ADX10059 decreased reflux episodes in healthy subjects. The MR formulation is suitable for longer-term treatment to evaluate symptom control in GERD patients.
Zerbib
F
F
Gastroenterology Department, Saint André Hospital, CHU Bordeaux, Bordeaux, France.
Keywood
C
C
Strabach
G
G
D000293:Adolescent; D000328:Adult; D000494:Allosteric Regulation / Q000502:physiology*; D000818:Animals; D004311:Double-Blind Method; D017097:Electric Impedance; D005764:Gastroesophageal Reflux / Q000188:drug therapy* / Q000503:physiopathology; D005765:Gastrointestinal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008365:Manometry / Q000379:methods*; D008875:Middle Aged; D010919:Placebos / Q000627:therapeutic use; D019518:Postprandial Period / Q000187:drug effects; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry*; D055815:Young Adult
D005765:Gastrointestinal Agents; D010919:Placebos; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate