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

“Levacetylleucine was non-mutagenic in vitro (in bacterial cells) and non-clastogenic in vitro (in cultured human peripheral lymphocytes) and in vivo (in bone marrow cells of the CD rats).”

“We are requiring juvenile toxicity, fertility, and early embryonic development, pre- and postnatal development, and carcinogenicity studies to be conducted postapproval.”

“In pregnant rats, increases in resorptions, post-implantation loss, and skeletal malformation were seen due to exposure to levacetylleucine at doses of 600 mg/kg/day and at the human-equivalent dose of 97 mg/kg/day.”

“At the highest feasible concentration of 525μM, levacetylleucine inhibited hERG tail currents by less than 30%, therefore, half-maximal inhibitory concentration (IC50) could not be determined, as the concentration response curve was limited by solubility.”

“Levacetylleucine was non-mutagenic in vitro (in bacterial cells) and non-clastogenic in vitro (in cultured human peripheral lymphocytes) and in vivo (in bone marrow cells of the CD rats).”

“Levacetylleucine was non-mutagenic in vitro (in bacterial cells) and non-clastogenic in vitro (in cultured human peripheral lymphocytes) and in vivo (in bone marrow cells of the CD rats).”

“Indeed, levacetylleucine was tested in male CD rats and did not induce micronucleus in bone marrow cells, indicating no mutagenic effects (the in vivo negative results confirmed the two in vitro results).”

“Consequently, the Applicant committed to realize the 26-week carcinogenicity study in rasH2 mice and submit the results when available.”

“A 26-week carcinogenicity study in the transgenic rasH2 mouse will be required as a PMR, along with a 2-year rat carcinogenicity study.”

“At the highest feasible concentration of 525μM, levacetylleucine inhibited hERG tail currents by less than 30%, therefore, half-maximal inhibitory concentration (IC50) could not be determined, as the concentration response curve was limited by solubility.”