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

“Based on the weight of evidence from these studies, nifurtimox is considered to be genotoxic and the product label for Lampit will include a Warning for genotoxicity.”

“Because the proposed treatment duration of nifurtimox is less than 6 months, a carcinogenicity assessment is not required.”

“In preliminary embryo-fetal studies in rats and mice and a comprehensive study in rabbits, nifurtimox produced dose-related maternal and/or fetal toxicity in all test species as well as a fetal malformation in rabbits.”

“Nifurtimox at high concentrations was shown to inhibit hERG channels with an estimated IC50 value of 98 mcM (28.2 mcg/ml). In a cardiovascular study in conscious telemetered dogs, QTc intervals were slightly increased at a nifurtimox dose of 80 mg/kg.”

“In Ames assays, nifurtimox produced dose-dependent increases in the number of mutants with and without S9 activation, and, in an in vitro micronucleus assay, nifurtimox was clastogenic in human lymphocytes.”

“In Ames assays, nifurtimox produced dose-dependent increases in the number of mutants with and without S9 activation, and, in an in vitro micronucleus assay, nifurtimox was clastogenic in human lymphocytes.”

“In vivo, nifurtimox was shown to be positive for clastogenesis in a mouse micronucleus assay, a mouse sister chromatid exchange assay, and a chromosome aberration assay in Chagas patients.”

“Because the proposed treatment duration of nifurtimox is less than 6 months, a carcinogenicity assessment is not required. However, three carcinogenicity studies for nifurtimox were submitted in NDA 213464, two in limited brief study reports and one in a published manuscript.”

“Because the proposed treatment duration of nifurtimox is less than 6 months, a carcinogenicity assessment is not required.”

“The 28.2 mcg/ml IC50 value for nifurtimox inhibition of hERG channels is approximately 38-fold higher than the clinical Cmax value of 751 ng/ml measured in healthy human subjects administered a single dose of 15 mg/kg nifurtimox (Paulos et al. 1989).”