title: 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: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Algorithme Pharma Inc, Laval, Quebec, Canada.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Paquette
authors.affiliation: Algorithme Pharma Inc, Laval, Quebec, Canada.
authors.forename: Marianne
authors.initials: M
authors.lastname: Rufiange
authors.affiliation: Algorithme Pharma Inc, Laval, Quebec, Canada.
authors.forename: Mirela
authors.initials: M
authors.lastname: Iovu Niculita
authors.affiliation: Algorithme Pharma Inc, Laval, Quebec, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Massicotte
authors.affiliation: Algorithme Pharma Inc, Laval, Quebec, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Lefebvre
authors.affiliation: gIcare Pharma Inc, Montreal, Quebec, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Colin
authors.affiliation: gIcare Pharma Inc, Montreal, Quebec, Canada.
authors.forename: Ariles
authors.initials: A
authors.lastname: Telmat
authors.affiliation: gIcare Pharma Inc, Montreal, Quebec, Canada. Electronic address: mrufiange@algopharm.com.
authors.forename: Maxime
authors.initials: M
authors.lastname: Ranger
mesh_terms: D000328:Adult; D000368:Aged; D000700:Analgesics / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003113:Colonoscopy; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy; D053719:Tandem Mass Spectrometry
chemical_list: D000700:Analgesics; D001557:Benzenesulfonates; C000605012:trimebutine 3-thiocarbamoylbenzenesulfonate
keywords: Phase I; colonoscopy; first in human; gastroenterology; sedation free