NONCLINICAL SAFETY EVALUATION OF A NOVEL HYPOGLYCEMIC AGENT PPAR-4; PARTIAL PPAR-γ AGONIST [ ]


The toxicity of PPAR-4; partial peroxisome proliferator activated receptor (PPAR) agonist, was evaluated in a comprehensive nonclinical toxicology program that included single-dose oral toxicity studies in mice and rats; repeat-dose toxicity studies in rats; a battery of in vitro and in vivo genetic toxicity studies; carcinogenicity studies in mice and rats; reproductive and developmental toxicity studies in rats. Pharmacologically mediated changes, similar to those observed with other PPARγ agonists, were observed following chronic administration and included subcutaneous edema, hematologic/hematopoietic and serum chemistry alterations, and morphologic findings in the heart and adipose tissue in rats. PPAR-4 was nongenotoxic in the standard battery of genotoxicity studies. Gallbladder adenomas in male mice and adipocyte neoplasms in male and female rats were seen at suprapharmacologic exposures, whereas urinary bladder tumors occurred in male rats at lower exposures. PPAR-4 had no effects on reproductive function in male and female rats at high systemic exposures, was not teratogenic in rats and demonstrated no selective developmental toxicity. Overall, there were no nonclinical findings that precluded the safe administration of PPAR-4 to humans.