PMID- 25224876 OWN - NLM STAT- MEDLINE DCOM- 20160219 LR - 20190318 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 36 IP - 11 DP - 2014 Nov 1 TI - 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. PG - 1650-64 LID - S0149-2918(14)00536-0 [pii] LID - 10.1016/j.clinthera.2014.08.005 [doi] AB - 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 AUCtau increased from 38 to 170 ng . h/mL. AUCtau 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.). CI - Copyright (c) 2014 Elsevier HS Journals, Inc. All rights reserved. FAU - Paquette, Jean-Michel AU - Paquette JM AD - Algorithme Pharma Inc, Laval, Quebec, Canada. FAU - Rufiange, Marianne AU - Rufiange M AD - Algorithme Pharma Inc, Laval, Quebec, Canada. FAU - Iovu Niculita, Mirela AU - Iovu Niculita M AD - Algorithme Pharma Inc, Laval, Quebec, Canada. FAU - Massicotte, Julie AU - Massicotte J AD - Algorithme Pharma Inc, Laval, Quebec, Canada. FAU - Lefebvre, Marc AU - Lefebvre M AD - Algorithme Pharma Inc, Laval, Quebec, Canada. FAU - Colin, Patrick AU - Colin P AD - gIcare Pharma Inc, Montreal, Quebec, Canada. FAU - Telmat, Ariles AU - Telmat A AD - gIcare Pharma Inc, Montreal, Quebec, Canada. FAU - Ranger, Maxime AU - Ranger M AD - gIcare Pharma Inc, Montreal, Quebec, Canada. Electronic address: mrufiange@algopharm.com. LA - eng SI - ClinicalTrials.gov/NCT01738425 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20140915 PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Analgesics) RN - 0 (Benzenesulfonates) RN - 5O1CF9IS48 (trimebutine 3-thiocarbamoylbenzenesulfonate) SB - IM MH - Adult MH - Aged MH - Analgesics/*pharmacokinetics MH - Area Under Curve MH - Benzenesulfonates/*pharmacokinetics MH - Chromatography, High Pressure Liquid MH - Colonoscopy MH - Cross-Over Studies MH - Double-Blind Method MH - Female MH - *Food-Drug Interactions MH - Humans MH - Least-Squares Analysis MH - Male MH - Middle Aged MH - Pain/drug therapy MH - Tandem Mass Spectrometry OTO - NOTNLM OT - Phase I OT - colonoscopy OT - first in human OT - gastroenterology OT - sedation free EDAT- 2014/09/17 06:00 MHDA- 2016/02/20 06:00 CRDT- 2014/09/17 06:00 PHST- 2014/06/03 00:00 [received] PHST- 2014/07/28 00:00 [revised] PHST- 2014/08/11 00:00 [accepted] PHST- 2014/09/17 06:00 [entrez] PHST- 2014/09/17 06:00 [pubmed] PHST- 2016/02/20 06:00 [medline] AID - S0149-2918(14)00536-0 [pii] AID - 10.1016/j.clinthera.2014.08.005 [doi] PST - ppublish SO - Clin Ther. 2014 Nov 1;36(11):1650-64. doi: 10.1016/j.clinthera.2014.08.005. Epub 2014 Sep 15.