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

“Zidesamtinib was genotoxic in the in vivo rat micronucleus assays. Zidesamtinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro assay in human lymphoblastoid TK6 cells.”

“Consistent with concepts described in the ICH S9 guidance (U.S. Food and Drug Administration, 2010), carcinogenicity studies were not conducted with zidesamtinib, nor were they warranted.”

“There was 100% post-implantation loss at ≥8 mg/kg/day (approximately 3.5 times the human exposure based on AUC at the recommended dose).”

“zidesamtinib inhibited in vitro human ether-à-go-go related gene (hERG) potassium channel current with an IC50 of 73.9 µM, which is approximately 161-fold higher than the human free steady-state Cmax. Additional cardiovascular safety pharmacology assessment identified an 11% increase in QTc prolongation in telemetered conscious dogs following a single oral administration of zidesamtinib at 30 mg/kg/day.”

“In the standard genotoxicity battery, zidesamtinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay in the presence or absence of microsomal S9 mix.”

“Zidesamtinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro assay in human lymphoblastoid TK6 cells.”

“However, zidesamtinib was genotoxic in vivo, inducing micronuclei formation in peripheral blood reticulocytes of rats following once daily oral administration for 2 or 4 days. A comet assay was negative for DNA damage in liver cells.”

“Consistent with concepts described in the ICH S9 guidance (U.S. Food and Drug Administration, 2010), carcinogenicity studies were not conducted with zidesamtinib, nor were they warranted.”

“Consistent with concepts described in the ICH S9 guidance (U.S. Food and Drug Administration, 2010), carcinogenicity studies were not conducted with zidesamtinib, nor were they warranted.”

“zidesamtinib inhibited in vitro human ether-à-go-go related gene (hERG) potassium channel current with an IC50 of 73.9 µM, which is approximately 161-fold higher than the human free steady-state Cmax. Additional cardiovascular safety pharmacology assessment identified an 11% increase in QTc prolongation in telemetered conscious dogs following a single oral administration of zidesamtinib at 30 mg/kg/day.”