Koselugo: which tox species, and why?

“The Applicant evaluated the toxicity profile of selumetinib in rats, mice, and monkeys in GLP-compliant studies with durations of up to 3 months (rats) and 26 weeks (mice and monkeys).”

“The Applicant chose the mouse as the rodent species for the long-term toxicology and developmental studies due to detectable levels of the active N-desmethyl metabolite in this species that allowed for toxicological coverage;”

“Administration of selumetinib to monkeys for up to 26 weeks was associated with loose/liquid feces, seen at 1.5 mg/kg BID in females and 4 mg/kg BID in males.”

“The Applicant evaluated the toxicity profile of selumetinib in rats, mice, and monkeys in GLP-compliant studies with durations of up to 3 months (rats) and 26 weeks (mice and monkeys).”

“The Applicant assessed the effects of selumetinib on reproduction and development using mice, as mice, unlike rats, make the active N-desmethyl AZD6244 metabolite at detectable levels.”

“Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice and in 2-year carcinogenicity study in rats at exposures ≥ 15 times the human exposure (AUC) at the clinical dose of 25 mg/m 2 .”

“The Applicant evaluated the toxicity profile of selumetinib in rats, mice, and monkeys in GLP-compliant studies with durations of up to 3 months (rats) and 26 weeks (mice and monkeys).”