Nonclinical safety evaluation of muraglitazar, a novel PPARalpha/gamma agonist.
The toxicity of muraglitazar, an oxybenzylglycine, nonthiazolidinedione peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, was evaluated in a comprehensive nonclinical toxicology program that included single-dose oral toxicity studies in mice, rats, and monkeys; repeat-dose toxicity studies in rats, dogs, and monkeys; a battery of in vitro and in vivo genetic toxicity studies; carcinogenicity studies in mice and rats; reproductive and developmental toxicity studies in rats and rabbits; and studies to investigate species-specific findings. Pharmacologically mediated changes, similar to those observed with other PPARgamma 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 and monkeys. In dogs, a species highly sensitive to PPARgamma agonists, muraglitazar caused pronounced species-specific clinical toxicity and degenerative changes in the brain, spinal cord, and testes at high doses and exposures. Muraglitazar 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. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Muraglitazar had no effects on reproductive function in male and female rats at high systemic exposures, was not teratogenic in rats or rabbits, and demonstrated no selective developmental toxicity. Overall, there were no nonclinical findings that precluded the safe administration of muraglitazar to humans.
Waites
Crystal R
CR
Bristol-Myers Squibb Research and Development, Drug Safety Evaluation, Mount Vernon, Indiana 47620, USA.
Dominick
Mark A
MA
Sanderson
Thomas P
TP
Schilling
Beth E
BE
D000284:Administration, Oral; D000818:Animals; D015197:Carcinogenicity Tests; D003257:Consumer Product Safety; D004285:Dogs; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000633:toxicity*; D007928:Lethal Dose 50; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010080:Oxazoles / Q000008:administration & dosage / Q000633:toxicity*; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013045:Species Specificity; D036401:Toxicity Tests, Chronic; D015533:Transcriptional Activation / Q000187:drug effects
D007004:Hypoglycemic Agents; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D005998:Glycine; C500085:muraglitazar