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

“Sulopenem etzadroxil was negative for mutations in an in vitro Ames assay with and without metabolic activation but positive for chromosome aberrations with and without metabolic activation in vitro in peripheral human lymphocytes and Chinese hamster ovary cells. In vivo, sulopenem etzadroxil was negative for genetic toxicity in a bone marrow micronucleus assay in rats.”

“No carcinogenicity studies have been conducted for sulopenem etzadroxil or sulopenem.”

“Sulopenem etzadroxil did not inhibit fertility in male and female rats and was not associated with fetal malformations in embryo-fetal studies in rats and rabbits. However, in mice, a higher litter and fetal incidence of cleft palate in fetuses occurred at a sulopenem etzadroxil dose associated with sulopenem exposures approximately 46-times the mean clinical exposure”

“However, concern for inhibition of hERG potassium channels and possible QT prolongation in the clinic is minimal because the 2.64 µg/ml plasma Cmax for sulopenem associated with administration of a single bilayer tablet containing 500 mg sulopenem etzadroxil in fed patients is approximately 6-fold and 40-fold lower than the hERG IC50 values for sulopenem etzadroxil and sulopenem, respectively.”

“Both compounds were shown to be negative for mutagenicity in Ames assays and sulopenem was negative for mutagenicity in an in vitro CHO HGRPT forward mutation assay.”

“Sulopenem etzadroxil was negative for mutations in an in vitro Ames assay with and without metabolic activation but positive for chromosome aberrations with and without metabolic activation in vitro in peripheral human lymphocytes and Chinese hamster ovary cells.”

“These results were balanced by negative results for both compounds in vivo in micronucleus assays in bone marrow cells from rats (both compounds) and mice (sulopenem).”

“Carcinogenicity studies in animals have not been conducted with ORLYNVAH.”

“No carcinogenicity studies have been conducted for sulopenem etzadroxil or sulopenem.”

“However, concern for inhibition of hERG potassium channels and possible QT prolongation in the clinic is minimal because the 2.64 µg/ml plasma Cmax for sulopenem associated with administration of a single bilayer tablet containing 500 mg sulopenem etzadroxil in fed patients is approximately 6-fold and 40-fold lower than the hERG IC50 values for sulopenem etzadroxil and sulopenem, respectively.”