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

“Tenapanor was negative in the Ames test, the in vitro mammalian chromosome aberration assay in human peripheral blood lymphocytes, and the in vivo micronucleus assay in mice following oral and IV administration in rats.”

“Tenapanor was not tumorigenic in 2-year rat and 6- month Tg rasH2 mouse carcinogenicity bioassays.”

“There were no tenapanor-related effects on female or male fertility at doses up to 50 mg/kg/day in female mice and up to 10 mg/kg/day in male rats. In an embryofetal developmental study in rats, tenapanor was administered orally at dose levels of 1, 10 and 30 mg/kg/day from Gestation Days 6 through 17. Dose levels of 10 and 30 mg/kg/day were not tolerated”

“Tenapanor showed a slight inhibition (16.1%) of hERG current (IKr) at a concentration 10µM (highest concentration tested) in an in vitro assay in HEK293 cells. However, oral administration of tenapanor to conscious telemetered male beagle dogs at doses up to 1000 mg/kg had no effect on cardiac and circulatory functions”

“AZD1722 was not mutagenic in the Ames bacterial reverse mutation assay, not clastogenic in an in vitro cultured human lymphocyte assay, and negative in the in vivo oral gavage mouse and intravenous rat micronucleus assays.”

“AZD1722 was not mutagenic in the Ames bacterial reverse mutation assay, not clastogenic in an in vitro cultured human lymphocyte assay, and negative in the in vivo oral gavage mouse and intravenous rat micronucleus assays.”

“AZD1722 was not mutagenic in the Ames bacterial reverse mutation assay, not clastogenic in an in vitro cultured human lymphocyte assay, and negative in the in vivo oral gavage mouse and intravenous rat micronucleus assays.”

“Tenapanor was not tumorigenic in 2-year rat and 6- month Tg rasH2 mouse carcinogenicity bioassays.”

“Tenapanor was not tumorigenic in 2-year rat and 6- month Tg rasH2 mouse carcinogenicity bioassays.”

“RDX5791 at 1μM had no effect (0%) on the hERG currents but at 3μM and 10μM caused slight inhibitions of hERG currents by 5% and 16.1%, respectively. The clinical exposures in humans at 50 mg BID were <0.5 ng/mL. The, 10μM concentration is >24300-fold higher than the clinical exposures at the proposed dose.”