Tryvio: which tox species, and why?

“Repeat dose toxicology studies were conducted in rats (up to 26 weeks) and dogs (up to 39 weeks). These animal species were considered relevant for human risk assessment because pharmacodynamic (PD) and PK/ADME profiles are similar to those in humans.”

“Repeat dose toxicology studies were conducted in rats (up to 26 weeks) and dogs (up to 39 weeks). These animal species were considered relevant for human risk assessment because pharmacodynamic (PD) and PK/ADME profiles are similar to those in humans.”

“In the repeat-dose toxicology studies in male rats and dogs given aprocitentan for 26 weeks or 39 weeks, respectively, at doses up to 250 mg/kg/day, an increased incidence of tubular degeneration/atrophy was observed at 250 mg/kg/day in rats and at ≥25 mg/kg/day in dogs, representing approximately 41-fold and 53-fold, respectively, the exposure at the MRHD, based on AUC.”

“General toxicity studies were conducted for durations up to 26 weeks in rats and 39 weeks in dogs.”

“No embryo-fetal toxicity was observed in the EFD studies with aprocitentan alone at 5-fold and 29-fold the human exposure at the MRHD in rats and rabbits, respectively.”

“Two-year carcinogenicity studies with macitentan did not identify any carcinogenic potential at doses up to 100 mg/kg/day and 250 mg/kg/day in mice and rats, where aprocitentan exposures represented approximately 30-fold and 11-fold, respectively, the clinical aprocitentan exposure at the MRHD based on AUC.”

“In embryo-fetal developmental (EFD) toxicity studies, treatment with macitentan (for which aprocitentan is a major metabolite) in pregnant rats and rabbits revealed teratogenicity and developmental toxicity at all doses tested”