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The effects of ulimorelin, a ghrelin agonist, on liquid gastric emptying and colonic transit in humans
Author(s) -
James Joyce,
Mair Stuart,
Doll Walter,
Sandefer Erik,
Wurtman David,
Maurer Alan,
Deane Adam M,
Harris M. Scott
Publication year - 2020
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.13784
Subject(s) - gastric emptying , prokinetic agent , gastroparesis , medicine , pharmacokinetics , stomach , ghrelin , gastroenterology , dosing , agonist , metoclopramide , pharmacology , receptor , vomiting
Abstract Background Ulimorelin, a small molecule ghrelin agonist and prokinetic agent, was effective in animal models of gastroparesis and delayed transit. However, employing once daily administration, it failed in clinical trials of postoperative ileus (POI), a condition in which colonic motility recovers last. The aim of this study was to evaluate drug dosing and regional differences in drug activity between stomach and colon. Methods Gastric emptying was assessed by scintigraphy in healthy adults at single doses of 600‐1200 µg kg −1 and multiple doses of 80‐600 µg kg −1 Q8H for 7 days. Colonic motility was assessed by 7‐region scintigraphic analysis at a dose of 600 µg kg −1 for 2 days. The primary endpoints were percent change in time to 50% (∆ t 50 ) liquid gastric emptying on Days 1, 4, and 6 and the geometric mean center of colonic transit at 24 hours (GC 24 ). Plasma concentrations of free and total ulimorelin were measured for pharmacokinetic and exposure‐response modeling. Key Results Ulimorelin 150‐600 µg kg −1 every 8 hours resulted in statistically significant improvements (∆ t 50 = 23% to 46% ( P < .05)) in gastric emptying from baseline that were sustained through Day 6. However, no effects on GC 24 were observed. Pharmacokinetic analyses suggested that the free concentrations of ulimorelin achieved in POI trials and dosing frequency may have been inadequate. Conclusions and Inferences Ulimorelin is a potent gastric prokinetic but lacks evidence of activity in the human colon, pointing to the stomach as the predominant site of action of ghrelin in humans; ClinicalTrials.gov NCT02993055.