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

“Daprodustat was negative for mutagenic or clastogenic potential in the in vitro bacterial reverse mutation assay, the in vitro human lymphocyte chromosomal aberration assay, and the in vivo rat bone marrow micronucleus assay.”

“Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males) / 7 mg/kg/day (females) in rats (up to 3 times the MRHD based on body surface area) and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”

“Daprodustat administered orally to pregnant rats and rabbits during the period of organogenesis was associated with adverse fetal outcomes, including embryonic and fetal loss and reduced fetal weight, at doses that caused maternal toxicity and polycythemia ( see Data ).”

“Daprodustat had no effect on hERG channel activity (up to 47.66µM), neurobehavioral, and respiratory activity (up to 20 mg/kg).”

“Daprodustat was not mutagenic in the bacterial mutation assay, when tested in either the presence or absence of S9-mix”

“Daprodustat was negative for mutagenic or clastogenic potential in the in vitro bacterial reverse mutation assay, the in vitro human lymphocyte chromosomal aberration assay, and the in vivo rat bone marrow micronucleus assay.”

“The result was positive, but it is not considered to be a direct genotoxic response based on the small magnitude of the response and the mechanism of action of GSK1278863A which can contribute to the positive result.”

“Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males) / 7 mg/kg/day (females) in rats (up to 3 times the MRHD based on body surface area) and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”

“Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males)/ 7 mg/kg/day (females) in rats and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”

“Daprodustat had no effect on hERG channel activity (up to 47.66µM), neurobehavioral, and respiratory activity (up to 20 mg/kg).”