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Background: GSK2894512 is a topically delivered investigational drug being developed for treatment of atopic dermatitis and psoriasis., Objectives: To investigate, in a phase I clinical trial, the spatial biodistribution and residency of GSK2894512 within the epidermis and dermis of healthy human participants noninvasively using fluorescence lifetime imaging microscopy (FLIM)., Methods: Two topical drug formulations containing GSK2894512 1% were applied to the right and left forearms of six participants for seven consecutive days, followed by seven days of observation for residency. FLIM images were obtained daily throughout the study, approximately every 24 h. During the treatment phase of the study, images were collected from each participant pretreatment, reflecting the residual dose from the previous day. Three punch biopsies from each participant of one formulation was obtained from the treated region during the post-treatment follow-up period between days 8 and 14 for comparison with FLIM results., Results: Cellular and subcellular features associated with different epidermal and dermal layers were visualized noninvasively, down to a depth of 200 μm. Results yielded three-dimensional maps of GSK2894512 spatial distribution and residency over time. This fluorescence data provided a marker that was used as a monitor for day-to-day variance of drug presence and residency postapplication., Conclusions: The results suggest FLIM could be a viable alternative to skin biopsies without the usual patient discomfort and limitations, thereby enabling the direct measurement of skin distribution through longitudinal monitoring. These results are the first step in establishing the unique capabilities that multiphoton imaging could provide to patients through noninvasive drug detection., (© 2018 British Association of Dermatologists.)

Background: The gut hormone motilin stimulates gastrointestinal motility by inducing gastric phase III of the migrating motor complex (MMC) and enhancing the rate of gastric emptying. Camicinal (GSK962040), a small molecule motilin receptor agonist, has been shown to increase gastrointestinal motility., Methods: In this proof of concept study the effects of camicinal on MMC activity, esophageal and gastric pH was evaluated in eight healthy volunteers as a secondary endpoint. Doses of 50 and 150 mg were compared to placebo for a period of 24 hours in a double-blinded randomized crossover trial., Key Results: The 50 mg dose (n=4) of camicinal had no significant impact on gastroduodenal manometry or pH parameters. A single dose of 150 mg (n=4) induced a gastric phase III after 0:34 h (0:25-0:58), which was significantly faster compared to placebo (18:15 h (4:32-22:16); P=.03). Moreover, the high dose significantly increased the occurrence of gastric phase III contractions compared to placebo (12% vs 39%; P=.0003). This increase in gastric phase III contractions during a period of 24 hour was due to an increased occurrence of gastric phases III during the daytime (5% vs 50%; P=.0001). The same dose however did not affect small bowel manometry parameters or esophageal and gastric pH., Conclusions and Inferences: Considering its stimulating effect on the MMC and gastric emptying, camicinal is an attractive candidate for the treatment of gastroparesis and gastroesophageal reflux disease. This trial was registered at clinicaltrials.gov as NCT00562848., (© 2017 John Wiley & Sons Ltd.)

Background: The 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., Methods: A 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 (13)C-octanoic acid breath test (BTt1/2), acetaminophen concentrations, and 3-O-methyl glucose concentrations respectively., Results: Following 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., Conclusions: When absorbed, a single enteral dose of camicinal (50 mg) accelerates gastric emptying and increases glucose absorption in feed-intolerant critically ill patients., Trial Registration: The study protocol was registered with the US NIH clinicaltrials.gov on 23 December 2009 (Identifier NCT01039805 ).

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)., (© The Author(s) 2013.)