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

“CBM was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays.”

“A 26-week study in transgenic RasH2 mice and a 2-year study in Sprague-Dawley rats were conducted. The executive carcinogenicity assessment committee concluded that the studies were adequate and that there were no drug-related neoplasms in either study.”

“Oral administration of CBM to pregnant rats throughout organogenesis at doses of up to 60 mg/kg/day resulted in increased embryofetal mortality, reduced fetal body weights, and incomplete fetal skeletal ossification at the highest dose tested, which was associated with maternal toxicity.”

“CBM produced concentration-dependent inhibition of hERG-mediated potassium currents; the IC50 was estimated as 1869 μM, which is 11X higher than the clinical steady state Cmax after daily dosing at the MRHD of 400 mg (45.5 μg/mL; 169 μM).”