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

“Lefamulin did not elicit genotoxic potential in an in vivo rat bone marrow micronucleus assay for clastogenicity or in the in vitro Mouse Lymphoma Ly5178Y TK+/- mutation assay.”

“No carcinogenicity studies have been carried out, as the expected clinical use is of short duration.”

“Effects on embryo-foetal development were evaluated in rats and rabbits. Overall, a reduced live pup birth index in rats indicated an effect of lefamulin on embryo-foetal survival at high doses”

“The IC50 for lefamulin at the hERG channel is 27 µM in CHO cells and 47 µM in HEK-293 cells. In rabbit Purkinje fibres, the potential to prolong the duration of the action potential was observed.”

“Lefamulin did not exhibit genotoxic potential in a battery of standard genotoxicity assays. Cytotoxicity limited the concentrations that were used to evaluate the mutagenic potential of lefamulin in the Ames reverse mutation study.”

“Lefamulin did not elicit genotoxic potential in an in vivo rat bone marrow micronucleus assay for clastogenicity or in the in vitro Mouse Lymphoma Ly5178Y TK+/- mutation assay.”

“In an in-vivo micronucleus test in rats (≤100 mg/kg/day), there was no evidence of chromosomal damage with lefamulin (AUC0-8 ≤ 26.9 µg.h/mL).”

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

“Carcinogenicity studies were not carried out by the applicant. In line with guidance, carcinogenicity studies are not required if expected clinical use is for a short duration.”

“The IC50 for lefamulin at the hERG channel is 27 µM in CHO cells and 47 µM in HEK-293 cells. In rabbit Purkinje fibres, the potential to prolong the duration of the action potential was observed.”