gIcare Pharma | Date: 2013-03-11
Cenac N.,French Institute of Health and Medical Research |
Cenac N.,French National Center for Scientific Research |
Cenac N.,University Paul Sabatier |
Castro M.,French Institute of Health and Medical Research |
And 14 more authors.
European Journal of Pain (United Kingdom)
Background Trimebutine maleate, a noncompetitive spasmolytic agent with some affinity for peripheral μ- and κ-opioid receptors has been evaluated as a treatment in a limited number of patients undergoing sedation-free full colonoscopy. The efficiency of such treatment was comparable to sedation-based colonoscopies to relieve from pain and discomfort. Methods A new and improved trimebutine salt capable of releasing in vivo hydrogen sulphide (H2S), a gaseous mediator known to reduce nociception, has been developed. This drug salt (GIC-1001) is composed of trimebutine bearing a H2S-releasing counterion (3-thiocarbamoylbenzoate, 3TCB), the latter having the ability to release H2S. GIC-1001 has been tested here in a mouse model of colorectal distension. Results In mice, while orally given trimebutine (the maleate salt, non-H2S-releaser) only slightly reduced the nociceptive response to increasing pressures of colorectal distension, oral administration of GIC-1001 (the H2S-releaser) was able to significantly reduce nociceptive response to all noxious stimuli, in a dose-dependent manner. This effect of GIC-1001 was significantly better than the effects of its parent compound trimebutine administered at equimolar doses. Conclusions Taken together, these results demonstrated increased antinociceptive properties for GIC-1001 compared to trimebutine, suggesting that this compound would be a better option to relieve from visceral pain and discomfort induced by lumenal distension. © 2015 European Pain Federation - EFIC®. Source
Montpetit H.,Algorithme Pharma Inc. |
Ranger M.,gIcare Pharma |
Colin P.,gIcare Pharma |
Furtado M.,Algorithme Pharma Inc. |
Garofolo F.,Algorithme Pharma Inc.
Hélène Montpetit has a Bachelor of Science in Biochemistry from the University du Québec at Montreal. For the past 15 years, she has worked in the bioanalysis field in CROs environment as well as in a big Pharma. She currently holds a position as scientific reviewer in the method development group at Algorithme Pharma. Background: A failure in incurred sample reanalysis (ISR) for N-desmethyltrimebutine (NDMT), during the analysis of a trimebutine-containing drug GIC-1001 Phase I study, led to the discovery of a never-before reported metabolite of trimebutine. Results: A positive bias for NDMT during the ISR and post-reconstitution stability evaluations indicated the presence of an unstable metabolite of NDMT. Precursor ion scans performed on freshly extracted samples enabled the identification of this metabolite to be the NDMT glucuronide conjugate and its fragmentation pattern suggested that the glucuronide moiety was attached at the N-terminal of NDMT. Conclusions: An acidification step was introduced in the extraction procedure to completely hydrolyze the glucuronide and measure the total NDMT in plasma, rendering this method a successful fit-for-purpose assay. © 2015 Future Science Ltd. Source
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
Paquette J.-M.,Algorithme Pharma Inc. |
Rufiange M.,Algorithme Pharma Inc. |
Niculita M.I.,Algorithme Pharma Inc. |
Massicotte J.,Algorithme Pharma Inc. |
And 4 more authors.
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 exsmokers) aged 18 to 50 years with a body mass index between 18.5 and 30 kg/m2. 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. © 2014 Elsevier HS Journals, Inc. All rights reserved. Source