Ayvakit: genotox, carcinogenicity and repro: done or skipped?

“Avapritinib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). Avapritinib was positive in the in vitro chromosome aberration test in human peripheral blood lymphocytes but negative in the in vivo rat bone marrow micronucleus test, and overall non-genotoxic.”

“Avapritinib was not mutagenic in a 6-month transgenic mouse study up to the highest dose evaluated at 20 mg/kg/day.”

“Daily oral administration of avapritinib to pregnant rats resulted in decreased fetal body weights, post-implantation loss, and increases in visceral (hydrocephaly, septal defect, and stenosis of the pulmonary trunk) and skeletal (sternum) malformations at doses ≥ 10 mg/kg/day (a dose resulting in exposures approximately 2.7 times the exposure based on AUC at the 300 mg human dose).”

“There were no avapritinib-related adverse effects on pulmonary function or the cardiovascular system at single doses up to 45 mg/kg. Avapritinib blocked hERG channel potential with an IC50 of 2.4 μM; however, this IC50 is 1.5 times the free Cmax in humans at the 300 mg dose.”