Livmarli: which tox species, and why?

“repeat-dose oral toxicology studies in rats for up to 6 months and in dogs for up to 12 months”

“Maralixibat has to be characterised as a substance of very low bioavailability, with a local mode of action. Overall, the study programme appears to be appropriate and complete, justifying from pharmacokinetic point of view the species involved in toxicity testing.”

“In the 26-week rat toxicity study, maralixibat at 750 mg/kg/day in males and 2000 mg/kg/day in females caused deaths due to bleeding, which was attributed to vitamin K deficiency.”

“repeat-dose oral toxicology studies in rats for up to 6 months and in dogs for up to 12 months”

“Reproductive and developmental toxicology studies included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and post-natal development study in rats. Two juvenile animal toxicity studies were performed in rats.”

“Maralixibat chloride was not tumorigenic in a 2-year oral carcinogenicity study in rats with administration of up to 100 mg/kg/day (approximately 233 to 870 times the maximum recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice with doses of up to 25 (males) or 75 (females) mg/kg/day, no drug-related tumors were observed following administration of maralixibat chloride.”

“The ASBT transporter protein is highly conserved across species, with the human and mouse proteins showing 81% identity and 89% similarity at the amino acid level”