Preclinical toxicity evaluation of JD5037, a peripherally restricted CB₁ receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis.

ABSTRACT: JD5037 is a novel peripherally restricted CB₁ receptor (CB₁R) inverse agonist being developed for the treatment of visceral obesity and its metabolic complications, including nonalcoholic fatty liver disease and dyslipidemia. JD5037 was administered by oral gavage at 10, 40, and 150?mg/kg/day dose levels for up to 34 days to Sprague Dawley rats, and at 5, 20, and 75?mg/kg/day dose levels for 28 consecutive days to Beagle dogs. In rats, higher incidences of stereotypic behaviors were observed in 10?mg/kg females and 40?mg/kg males, and slower responses for reflex and sensory tests were observed only in males at 10 and 40?mg/kg during neurobehavioral testing. Sporadic minimal incidences of decreased activity (males) and seizures (both sexes) were observed in rats during daily clinical observations, without any clear dose-relationship. Male dogs at 75?mg/kg during treatment period, but not recovery period, had an increased incidence of gut associated lymphoid tissue hyperplasia and inflammation in the intestine. In both species, highest dose resulted in lower AUCs indicative of non-linear kinetics. Free access to food increased the plasma AUC_? by ~4.5-fold at 20?mg/kg in dogs, suggesting presence of food may help in systemic absorption of JD5037 in dogs. Based on the study results, 150?mg/kg/day in rats, and 20 and 75?mg/kg/day doses in male and female dogs, respectively, were determined to be the no-observed-adverse-effect-levels (NOAELs).

SUBMITTER: Kale VP 

PROVIDER: S-EPMC7017916 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature