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

“Zoliflodacin was not genotoxic in the mouse lymphoma assay (MLA) and rat in vivo micronucleus assay. In the Ames bacterial reverse mutation assay, zoliflodacin was mutagenic in the TA102 strain, consistent with its pharmacologic action as a bacterial topoisomerase II inhibitor.”

“Carcinogenicity studies have not been conducted with zoliflodacin.”

“In the mouse EFD study, exencephaly, a neural tube malformation, was present in litters in the 500 and 1000 mg/kg/day groups at levels above current and historical control rates.”

“In a safety pharmacology study in dogs, an oral 4-week repeat dose toxicity study in dogs, and an intravenous (IV) study in anesthetized guinea pigs, other reported cardiac effects included decreased blood pressure, increased heart rate, increase in cardiac contractility, and decreased cardiac relaxation. No arrhythmias or adverse QTc prolongation were detected in the IV-infusion safety pharmacology study in dogs.”

“AZ13420914 was mutagenic in S. typhimurium strain TA102 ± rat S9 under the conditions of this assay. Mutagenicity was not observed in TA98, TA100, TA1535 or TA1537.”

“Under the conditions of this assay, AZD0914 was not mutagenic or clastogenic to mouse lymphoma L5178Y cells regardless of metabolic activation with rat S9.”

“AZD0914 did not induce micronuclei in immature erythrocytes in the bone marrow of male Wistar Han rats after 2 daily consecutive oral doses up to 500 mg/kg/day and is therefore not clastogenic in vivo.”

“Carcinogenicity studies have not been conducted with zoliflodacin.”

“Carcinogenicity studies have not been conducted with zoliflodacin.”

“In an in vitro human ether-a-go-go related gene (hERG) study, zoliflodacin inhibited hERG currents in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 449µM, which is about 8-fold higher than the Cmax calculated from clinical studies.”