Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation.

Abstract

Velusetrag (TD-5108) is a potent, selective high intrinsic activity serotonin 5-HT(4) receptor agonist. We assessed effects of Velusetrag on gastrointestinal transit and compared its pharmacokinetics in healthy volunteers (HV) and chronic constipation (CC) patients. Sixty HV were randomly assigned, double-blind to placebo, 5, 15, 30 or 50 mg Velusetrag (single and 6-day dosing). Primary endpoints were colonic transit (geometric centre at 24 h, GC24) and ascending colon emptying (ACE) T(1/2) after first dose. Secondary endpoints included gastric emptying (GE) T(1/2) and colonic filling at 6 h (CF6). Single dose Velusetrag significantly accelerated GC24, ACE T(1/2), and CF6; 30 and 50 mg Velusetrag accelerated all three endpoints. With multiple doses, Velusetrag 30 mg accelerated GC24, and overall accelerated GE T(1/2) at 15-50 mg. Pharmacokinetics studies showed dose proportionality in health, and no significant differences between health and chronic constipation with a 15 mg oral dose of Velusetrag. Stimulation of bowel function after15 mg Velusetrag was similar in CC and controls. There were no serious adverse events; notable adverse events were the predictable gastrointestinal effects such as diarrhoea or altered bowel movements. Velusetrag significantly accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing. Further studies of its potential as a gastrointestinal and colonic prokinetic are warranted.

• Authors: M L Manini, M Camilleri, M Goldberg, S Sweetser, S McKinzie, D Burton, S Wong, M M Kitt, Y-P Li, A R Zinsmeister
• Journal: Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society (Neurogastroenterol Motil) Vol. 22 Issue 1 Pg. 42-9, e7-8 (Jan 2010) ISSN: 1365-2982 [Electronic] England
• PMID: 19691492 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• Azabicyclo Compounds
• Gastrointestinal Agents
• Placebos
• TD-5108

Topics

• Adolescent
• Adult
• Aged
• Azabicyclo Compounds (pharmacokinetics, pharmacology, therapeutic use)
• Constipation (drug therapy)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Gastrointestinal Agents (pharmacokinetics, pharmacology, therapeutic use)
• Gastrointestinal Motility (drug effects, physiology)
• Gastrointestinal Transit (drug effects, physiology)
• Humans
• Intestines (drug effects, physiology)
• Male
• Middle Aged
• Placebos (therapeutic use)
• Pregnancy
• Young Adult