Safety, tolerability and pharmacokinetics of trimebutine 3-thiocarbamoylbenzenesulfonate (GIC-1001) in a randomized phase I integrated design study: single and multiple ascending doses and effect of food in healthy volunteers.

Abstract

PURPOSE:

Trimebutine 3-thiocarbamoylbenzenesulfonate (GIC-1001) is a new drug intended to be used for the management of visceral pain in patients undergoing sedation-free, full colonoscopy. The objectives of this Phase I, single-center, randomized, double-blinded, placebo-controlled, integrated study were to evaluate the safety and pharmacokinetics of GIC-1001 after single ascending doses (SAD) and multiple ascending doses (MAD) and to evaluate the influence of food on the pharmacokinetics in healthy volunteers.

METHODS:

GIC-1001 or placebo was orally administered to 80 healthy male and female subjects (non- or ex-smokers) aged 18 to 50 years with a body mass index between 18.5 and 30 kg/m(2). The SAD portion of the study consisted of 5 cohorts with dose levels of 125 to 1000 mg. The MAD portion included 4 cohorts in which subjects received TID doses of 125 to 500 mg over 7 days (19 consecutive doses). Subjects were randomized (6:2) to receive GIC-1001 or placebo. The third portion of the study included a single 375-mg dose of GIC-1001 in a randomized, 2-period, crossover design to assess the influence of food (n = 8 subjects). Safety was evaluated by using adverse events (AEs), vital signs, ECGs, physical examination, cardiac monitoring, and laboratory test results. The analytes were assayed by using validated HPLC-MS/MS methods. Pharmacokinetic parameters were evaluated by using a noncompartmental analysis, and regression models were used to assess dose linearity. To evaluate the effect of food, 90% CIs of the ratio of geometric least squares means from ln-transformed pharmacokinetic parameters were calculated.

FINDINGS:

The most frequently reported drug-related AEs were of nervous system and gastrointestinal origin. The most common AEs included headache, somnolence, and nausea. After single-dose administration, Tmax of trimebutine ranged from 1.0 to 1.5 hours. Cmax and AUCT were linear (nonlinearity P ≥ 0.05) and proportional (P < 0.05) over the studied dose range. Food increased the Cmax and AUC of trimebutine; the ratio of geometric least squares means (90% CI) were 140% (84-234) and 174% (138-221), respectively. In the MAD study portion, the Tmax of trimebutine ranged from 0.5 to 2 hours and AUCτ increased from 38 to 170 ng · h/mL. AUCτ and Cmax were linear and proportional over the studied dose range.

IMPLICATIONS:

GIC-1001 was well tolerated, and its safety profile was similar to that of placebo. Pharmacokinetics of GIC-1001 and its metabolites were mainly linear and proportional over the studied dose ranges. Steady state was generally considered to be reached after 3 days. Food consumption affected the pharmacokinetic profile of the analytes differently. (ClinicalTrials.gov identifier: NCT01738425.).

• Authors: Jean-Michel Paquette, Marianne Rufiange, Mirela Iovu Niculita, Julie Massicotte, Marc Lefebvre, Patrick Colin, Ariles Telmat, Maxime Ranger
• Journal: Clinical therapeutics (Clin Ther) Vol. 36 Issue 11 Pg. 1650-64 (Nov 01 2014) ISSN: 1879-114X [Electronic] United States
• PMID: 25224876 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Chemical References

• Analgesics
• Benzenesulfonates
• trimebutine 3-thiocarbamoylbenzenesulfonate

Topics

• Adult
• Aged
• Analgesics (pharmacokinetics)
• Area Under Curve
• Benzenesulfonates (pharmacokinetics)
• Chromatography, High Pressure Liquid
• Colonoscopy
• Cross-Over Studies
• Double-Blind Method
• Female
• Food-Drug Interactions
• Humans
• Least-Squares Analysis
• Male
• Middle Aged
• Pain (drug therapy)
• Tandem Mass Spectrometry