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

“Gepotidacin was positive in an in vitro micronucleus test in human peripheral blood lymphocytes and in an L5178Y mouse lymphoma assay, consistent with the known in vitro clastogenic effects of topoisomerase inhibitors in in vitro mammalian cell assays. Gepotidacin was negative in an in vivo micronucleus test or Comet assay in rat.”

“Long term carcinogenicity studies have not been conducted with gepotidacin.”

“In embryo‑fetal development studies in mice and rats, decreased fetal weights and increased fetal mortality (late resorptions) were observed at exposures less than the maximum recommended human dose (MRHD). In a mouse pre- and postnatal development study, there were no adverse developmental effects at exposures approximately equal to the MRHD”

“No arrhythmias or heart-rate corrected QT interval (QTc) prolongation were detected in an oral safety pharmacology study in dogs; however, gepotidacin was associated with increases in heart rate, mean arterial pressure, cardiac contractility, and cardiac load.”

“Gepotidacin was cytotoxic to Salmonella typhimurium and Escherichia coli and therefore an Ames assay was determined to not be a useful assay.”

“Gepotidacin was positive in an in vitro micronucleus test in human peripheral blood lymphocytes and in an L5178Y mouse lymphoma assay, consistent with the known in vitro clastogenic effects of topoisomerase inhibitors in in vitro mammalian cell assays.”

“An in vivo rat micronucleus assay and comet assay was negative for both endpoints.”

“Long term carcinogenicity studies have not been conducted with gepotidacin.”

“13.1.4.3. Carcinogenicity No studies were available.”

“In an in vitro human ether-a-go-go related gene (hERG) study, gepotidacin inhibited hERG currents in a concentration-dependent manner with an IC50 of 0.588 mg/mL, which is more than 100-fold higher than the maximum plasma concentration (Cmax) calculated from clinical studies.”