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

“The Applicant did not conduct genotoxicity studies with lactitol and relied on the published literature. Lactitol was examined for potential mutagenicity in the Ames test, chromosome aberration test with cultured mammalian cells, and in vivo mouse micronucleus test. The results showed that lactitol has no mutagenicity potential”

“In a 2-year carcinogenicity study in rats, lactitol was not tumorigenic at daily oral doses up to 2 g/kg/day (about 0.93 times the recommended daily human dose based on body surface area). In a 6-month carcinogenicity study in Tg.rasH2 mice at daily oral doses of lactitol up to 2 g/kg/day (about 0.47 times the recommended daily human dose based on body surface area), there were no drug-related neoplasms.”

“In animal developmental studies, no effects on embryo-fetal development were observed with oral administration of lactitol to rats and rabbits during organogenesis at doses much higher than the maximum recommended human dosage.”

“Published studies (referenced in Section 5.5.1/General toxicology; additional studies) indicated that lactitol was negative in the Ames test, chromosome aberration test with cultured mammalian cells, and in vivo mouse micronucleus test.”

“Published studies (referenced in Section 5.5.1/General toxicology; additional studies) indicated that lactitol was negative in the Ames test, chromosome aberration test with cultured mammalian cells, and in vivo mouse micronucleus test.”

“Published studies (referenced in Section 5.5.1/General toxicology; additional studies) indicated that lactitol was negative in the Ames test, chromosome aberration test with cultured mammalian cells, and in vivo mouse micronucleus test.”

“In a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice at 225, 675 and 2000 mg/kg/day, there were no drug-related neoplasms in either males or females. The 104-week oral carcinogenicity study in rats was initiated in February 2017, and the study report will be submitted post approval, as per agreement with the Agency.”

“In a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice at 225, 675 and 2000 mg/kg/day, there were no drug-related neoplasms in either males or females. The 104-week oral carcinogenicity study in rats was initiated in February 2017, and the study report will be submitted post approval, as per agreement with the Agency.”

“The Applicant has not conducted a dedicated QT prolongation study. The ECG data from phase 3 studies BLI400-301 and BLI400-302 did not indicate clinically relevant effects of lactitol on the QT interval in CIC patients.”