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

“Capivasertib induced a statistically significant increase in the incidence of micronucleated immature erythrocytes at 150 mg/kg in the in vivo rat bone marrow micronucleus assay through an aneugenic mode of action.”

“Carcinogenicity studies with capivasertib were not warranted to support this NDA, as the proposed indication is for advanced cancer.”

“Administration of capivasertib to rats prior to implantation until Day 16 of gestation resulted in minor fetal visceral variations, an increase in post-implantation loss, and reduced gravid uterine and fetal weights at 150 mg/kg/day.”

“In safety pharmacology studies, single oral administration of capivasertib at 5, 30 and 40 mg/kg induced decreased heart rate for up to 8 hours, peak decreases in systolic and diastolic blood pressure with recovery within 4 hours, sustained prolongation of QTcR and increases in LVdP/dt+ along with elevation of both glucose and insulin levels in dogs.”

“Capivasertib was genotoxic in the in vivo rat bone marrow micronucleus assay through an aneugenic mechanism. Capivasertib was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay or mouse lymphoma gene mutation assay.”

“Capivasertib was genotoxic in the in vivo rat bone marrow micronucleus assay through an aneugenic mechanism. Capivasertib was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay or mouse lymphoma gene mutation assay.”

“Capivasertib induced a statistically significant increase in the incidence of micronucleated immature erythrocytes at 150 mg/kg in the in vivo rat bone marrow micronucleus assay through an aneugenic mode of action. In a Comet assay, capivasertib did not induce DNA damage in the liver of Wistar Han rats at doses up to 150 mg/kg.”

“In a 2-year rat carcinogenicity study, rats received oral doses up to 30 mg/kg/day in males and 75 mg/kg/day in females (approximately 0.2 times and 0.4 times the human exposure at the recommended dose based on AUC, respectively).”

“Carcinogenicity studies with capivasertib were not warranted to support this NDA, as the proposed indication is for advanced cancer.”

“Capivasertib exerted concentration-dependent hERG channel activity with the IC50 value of 73.0 μM. This is more than 100-fold of the unbound clinical Cmax. In male Beagle dogs, oral dosing of 30 and 40 mg/kg capivasertib led to a reversible reduction in systolic and diastolic blood pressure and heart rate and caused a sustained statistically significant prolongation of the QT interval.”