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

“Ganaxolone was negative for genotoxicity in in vitro (Ames and mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays. The major circulating human metabolite, oxy-dehydro-ganaxolone, was negative for mutagenicity in the in vitro Ames assay but positive for clastogenicity in an in vitro mammalian chromosomal aberration test in human peripheral blood lymphocytes.”

“Oral administration of ganaxolone (150, 500, and 1000 mg/kg/day in males and 100, 300, and 1000 mg/kg/day in females) to Tg.rasH2 mice for up to 26 weeks did not result in an increase in tumors. No carcinogenicity studies have been conducted with ganaxolone in rats.”

“In the EFD study in mouse, an increase in fetal malformations (external, visceral) was observed at all doses (0, 50, 175, and 300 mg/kg/day) in the absence of maternal toxicity.”

“GNX did not inhibit the hERG channel at a concentration of 10 μM (Study 1245-007) and there were no alterations in blood pressure, heart rate, or qualitative or quantitative ECG parameters in a CV safety pharmacology study in conscious, telemetered beagle dogs (Study 1245-008) up to the highest dose tested (15 mg/kg).”

“Ganaxolone was negative for genotoxicity in in vitro (Ames and mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays. The major circulating human metabolite, oxy-dehydro-ganaxolone, was negative for mutagenicity in the in vitro Ames assay”

“Ganaxolone was negative for genotoxicity in in vitro (Ames and mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays. The major circulating human metabolite, oxy-dehydro-ganaxolone, was negative for mutagenicity in the in vitro Ames assay but positive for clastogenicity in an in vitro mammalian chromosomal aberration test in human peripheral blood lymphocytes.”

“GNX was evaluated in a GLP-compliant Ames test, in vitro mouse lymphoma cell mutagenesis assay and in vivo micronucleus assay in rats dosed with GNX up to 140 mg/kg, and demonstrated no genotoxic potential.”

“Carcinogenicity studies in two species (26-week study in TgRasH2 mouse and 2-year study in rat) are to be conducted as post-marketing requirements (PMR)”

“Carcinogenicity studies in two species (26-week study in TgRasH2 mouse and 2-year study in rat) are to be conducted as post-marketing requirements (PMR)”

“In two GLP-compliant in vitro hERG inhibition studies, no significant hERG inhibition was observed with GNX at concentrations up to 10 µM, which is approximately 11-fold the total GNX concentration at the clinical Cmax of ~300 ng/ml.”