Sohonos: which tox species, and why?

“A series of pharmacology, pharmacokinetics (PK)/absorption, distribution, metabolism, excretion (ADME), repeat dose general toxicology studies of up to 26- and 39-week duration in rats and dogs, respectively, as well as reproductive toxicology (male and female fertility and early embryonic development (FEED), single species (rat) embryofetal development EFD) and juvenile animal toxicity studies were conducted.”

“The in vivo metabolite profiles were similar in rats and dogs. No metabolites unique to humans were identified.”

“Groups of Wistar rats were given oral daily doses of vehicle (Miglyol 812 with 0.01% BHA and 0.01% BHT), or palovarotene at 0.3, 0.6 and 1 mg/kg/day for 26 weeks, including groups terminated after 13-weeks.”

“A series of pharmacology, pharmacokinetics (PK)/absorption, distribution, metabolism, excretion (ADME), repeat dose general toxicology studies of up to 26- and 39-week duration in rats and dogs, respectively, as well as reproductive toxicology (male and female fertility and early embryonic development (FEED), single species (rat) embryofetal development EFD) and juvenile animal toxicity studies were conducted.”

“The Agency agreed that there was no benefit in conducting an EFD study in pregnant animals of a second species, as palovarotene adversely affected fetal development in pregnant rats, which was consistent with the retinoid class known to carry fetal development risks.”

“The nonclinical review team in consultation with the CDER Executive Carcinogenicity Assessment Committee (ECAC) concluded that the carcinogenic potential of palovarotene in humans is uncertain and assessment in a 2-year rat carcinogenicity study, in addition to a mouse in vivo carcinogenicity study, would add value to the assessment of human carcinogenic risk.”

“Groups of Wistar rats were given oral daily doses of vehicle (Miglyol 812 with 0.01% BHA and 0.01% BHT), or palovarotene at 0.3, 0.6 and 1 mg/kg/day for 26 weeks, including groups terminated after 13-weeks.”