Jesduvroq: which tox species, and why?

“General toxicology studies of 4- and 13-weeks duration were conducted in Sprague Dawley rats and Beagle Dogs with rats receiving daily oral doses by gavage and dogs by capsule. A 13-week toxicity study was also conducted in the cynomolgus monkey with daily dosing by oral gavage.”

“The 3 major circulating human metabolites (M2, M3, and M13) were present in rabbit and monkey plasma with an animal:human AUC ratio of at least 1X in monkeys (comparing the 50 mg/kg MTD dose in the 39-week toxicity study and human exposure at the 48 mg three times a week (TIW) human dose).”

“Title/ Study No.: GSK1278863A: A 26-week Oral (Gavage) Toxicity Study in the Rat/ 2011N126130”

“General toxicology studies of 4- and 13-weeks duration were conducted in Sprague Dawley rats and Beagle Dogs with rats receiving daily oral doses by gavage and dogs by capsule. A 13-week toxicity study was also conducted in the cynomolgus monkey with daily dosing by oral gavage.”

“Daprodustat administered orally to pregnant rats and rabbits during the period of organogenesis was associated with adverse fetal outcomes, including embryonic and fetal loss and reduced fetal weight, at doses that caused maternal toxicity and polycythemia”

“Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males) / 7 mg/kg/day (females) in rats (up to 3 times the MRHD based on body surface area) and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”

“The metabolites were not detected in mouse, rat, or dog plasma, and were administered SC as a metabolite cocktail to mice and rats in a mouse carcinogenicity study and rat pre-and post-natal development study to achieve at least 1X human exposure.”