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

M. L. Manini, Michael Camilleri, M. Goldberg, S. Sweetser, S. McKinzie, D. Burton, S. Wong, M. M. Kitt, Y. P. Li, A. R. Zinsmeister

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Velusetrag (TD-5108) is a potent, selective high intrinsic activity serotonin 5-HT4 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) T1/2 after first dose. Secondary endpoints included gastric emptying (GE) T1/2 and colonic filling at 6 h (CF6). Single dose Velusetrag significantly accelerated GC24, ACE T1/2, and CF6; 30 and 50 mg Velusetrag accelerated all three endpoints. With multiple doses, Velusetrag 30 mg accelerated GC24, and overall accelerated GE T1/2 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.

Original languageEnglish (US)
JournalNeurogastroenterology and Motility
Volume22
Issue number1
DOIs
StatePublished - Jan 2010

Fingerprint

Gastrointestinal Transit
Constipation
Pharmacokinetics
Health
Gastric Emptying
Ascending Colon
Healthy Volunteers
Serotonin 5-HT4 Receptor Agonists
TD-5108
Diarrhea
Placebos

Keywords

  • 5-HT
  • Colon
  • Motility
  • Prokinetic
  • Serotonergic
  • TD5108
  • Velusetrag

ASJC Scopus subject areas

  • Endocrine and Autonomic Systems
  • Gastroenterology
  • Physiology

Cite this

Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation. / Manini, M. L.; Camilleri, Michael; Goldberg, M.; Sweetser, S.; McKinzie, S.; Burton, D.; Wong, S.; Kitt, M. M.; Li, Y. P.; Zinsmeister, A. R.

In: Neurogastroenterology and Motility, Vol. 22, No. 1, 01.2010.

Research output: Contribution to journalArticle

Manini, M. L. ; Camilleri, Michael ; Goldberg, M. ; Sweetser, S. ; McKinzie, S. ; Burton, D. ; Wong, S. ; Kitt, M. M. ; Li, Y. P. ; Zinsmeister, A. R. / Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation. In: Neurogastroenterology and Motility. 2010 ; Vol. 22, No. 1.
@article{f163bd9c1df849f690fc89ef5a037692,
title = "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-HT4 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) T1/2 after first dose. Secondary endpoints included gastric emptying (GE) T1/2 and colonic filling at 6 h (CF6). Single dose Velusetrag significantly accelerated GC24, ACE T1/2, and CF6; 30 and 50 mg Velusetrag accelerated all three endpoints. With multiple doses, Velusetrag 30 mg accelerated GC24, and overall accelerated GE T1/2 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.",
keywords = "5-HT, Colon, Motility, Prokinetic, Serotonergic, TD5108, Velusetrag",
author = "Manini, {M. L.} and Michael Camilleri and M. Goldberg and S. Sweetser and S. McKinzie and D. Burton and S. Wong and Kitt, {M. M.} and Li, {Y. P.} and Zinsmeister, {A. R.}",
year = "2010",
month = "1",
doi = "10.1111/j.1365-2982.2009.01378.x",
language = "English (US)",
volume = "22",
journal = "Neurogastroenterology and Motility",
issn = "1350-1925",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation

AU - Manini, M. L.

AU - Camilleri, Michael

AU - Goldberg, M.

AU - Sweetser, S.

AU - McKinzie, S.

AU - Burton, D.

AU - Wong, S.

AU - Kitt, M. M.

AU - Li, Y. P.

AU - Zinsmeister, A. R.

PY - 2010/1

Y1 - 2010/1

N2 - Velusetrag (TD-5108) is a potent, selective high intrinsic activity serotonin 5-HT4 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) T1/2 after first dose. Secondary endpoints included gastric emptying (GE) T1/2 and colonic filling at 6 h (CF6). Single dose Velusetrag significantly accelerated GC24, ACE T1/2, and CF6; 30 and 50 mg Velusetrag accelerated all three endpoints. With multiple doses, Velusetrag 30 mg accelerated GC24, and overall accelerated GE T1/2 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.

AB - Velusetrag (TD-5108) is a potent, selective high intrinsic activity serotonin 5-HT4 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) T1/2 after first dose. Secondary endpoints included gastric emptying (GE) T1/2 and colonic filling at 6 h (CF6). Single dose Velusetrag significantly accelerated GC24, ACE T1/2, and CF6; 30 and 50 mg Velusetrag accelerated all three endpoints. With multiple doses, Velusetrag 30 mg accelerated GC24, and overall accelerated GE T1/2 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.

KW - 5-HT

KW - Colon

KW - Motility

KW - Prokinetic

KW - Serotonergic

KW - TD5108

KW - Velusetrag

UR - http://www.scopus.com/inward/record.url?scp=72449143707&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=72449143707&partnerID=8YFLogxK

U2 - 10.1111/j.1365-2982.2009.01378.x

DO - 10.1111/j.1365-2982.2009.01378.x

M3 - Article

C2 - 19691492

AN - SCOPUS:72449143707

VL - 22

JO - Neurogastroenterology and Motility

JF - Neurogastroenterology and Motility

SN - 1350-1925

IS - 1

ER -