TGR5 is a bile acid receptor and a potential target for the treatment of type 2 diabetes (T2D). We report here the safety, pharmacokinetics, and pharmacodynamic effects of a selective TGR5 agonist, SB-756050, in patients with T2D. Fifty-one subjects were randomized to receive either placebo or one of four doses of SB-756050 for 6 days. A single 100 mg dose of sitagliptin was co-administered on Day 6 to all subjects. SB-756050 was well-tolerated; it was readily absorbed, exhibited nonlinear pharmacokinetics with a less than dose-proportional increase in plasma exposure above 100 mg, and demonstrated no significant changes in exposure when co-administered with sitagliptin. SB-756050 demonstrated highly variable pharmacodynamic effects both within dose groups and between doses, with increases in glucose seen at the two lowest doses and no reduction in glucose seen at the two highest doses. The glucose effects of SB-756050 + sitagliptin were comparable to those of sitagliptin alone, even though gut hormone plasma profiles were different. This study was registered at ClinicalTrials.gov (NCT00733577).

BackgroundThe promotility agents currently available to treat gastroparesis and feed intolerance in the critically ill are limited by adverse effects. The aim of this study was to assess the pharmacodynamic effects and pharmacokinetics of single doses of the novel gastric promotility agent motilin agonist camicinal (GSK962040) in critically ill feed-intolerant patients.MethodsA prospective, randomized, double-blind, parallel-group, placebo-controlled, study was performed in mechanically ventilated feed-intolerant patients [median age 55 (19–84), 73 % male, APACHE II score 18 (5–37) with a gastric residual volume ≥200 mL]. Gastric emptying and glucose absorption were measured both pre- and post-treatment after intragastric administration of 50 mg (n = 15) camicinal and placebo (n = 8) using the 13C-octanoic acid breath test (BTt1/2), acetaminophen concentrations, and 3-O-methyl glucose concentrations respectively.ResultsFollowing 50 mg enteral camicinal, there was a trend to accelerated gastric emptying [adjusted geometric means: pre-treatment BTt1/2 117 minutes vs. post- treatment 76 minutes; 95 % confidence intervals (CI; 0.39, 1.08) and increased glucose absorption (AUC240min pre-treatment: 28.63 mmol.min/L vs. post-treatment: 71.63 mmol.min/L; 95 % CI (1.68, 3.72)]. When two patients who did not have detectable plasma concentrations of camicinal were excluded from analysis, camicinal accelerated gastric emptying (adjusted geometric means: pre-treatment BTt1/2 121 minutes vs. post-treatment 65 minutes 95 % CI (0.32, 0.91) and increased glucose absorption (AUC240min pre-treatment: 33.04 mmol.min/L vs. post-treatment: 74.59 mmol.min/L; 95 % CI (1.478, 3.449). In those patients receiving placebo gastric emptying was similar pre- and post-treatment.ConclusionsWhen absorbed, a single enteral dose of camicinal (50 mg) accelerates gastric emptying and increases glucose absorption in feed-intolerant critically ill patients.Trial registrationThe study protocol was registered with the US NIH clinicaltrials.gov on 23 December 2009 (Identifier NCT01039805).

Background: The gut hormone motilin stimulates gastrointestinal motility by inducing