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

“Serdexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mammalian cell micronucleus assay using human peripheral blood lymphocytes, in the in vivo rat bone barrow micronucleus assay, or in the in vivo rat alkaline comet assay.”

“Carcinogenicity studies were not conducted with SDX. The Applicant is relying upon the carcinogenicity data in the referenced product labeling.”

“In the embryo-fetal development study in rabbits, there were no findings of maternal or fetal development toxicity at exposures up to 49 times (400 mg/kg) the MRHD.”

“All findings for SDX were typical of a CNS stimulant (including dilated pupil, increased activity, increased heart rate and blood pressure, and increased respiratory rate) and all findings were generally comparable for SDX and a comparative dose of d-MPH. In the hERG assay, the IC50 for SDX was considered >25 µM.”

“SDX was negative for mutagenicity in bacterial cells in a valid Ames assay.”

“SDX was negative for clastogenicity in human lymphocytes in a valid in vitro micronucleus assay.”

“SDX was not clastogenic in a valid in vivo micronucleus assay and Comet assay up to a dose of 100 mg/kg.”

“In addition, carcinogenicity studies in mice or rats, fertility and early embryonic development in rats, embryofetal development in rats, and prenatal and postnatal development study in rats would not be informative because of species differences in pharmacokinetics for SDX”

“Therefore, considering the weight-of-evidence, we agree that carcinogenicity studies are not needed for SDX.”

“In the hERG assay, the IC50 for SDX was considered >25 µM.”