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

“No mutagenic or clastogenic effects were detected in conventional genotoxicity studies with pretomanid. A circulating metabolite of pretomanid, M50, was mutagenic in a bacterial reverse mutation assay.”

“No carcinogenic potential was revealed in a 6-month study in transgenic mice where this metabolite was produced. In a 2-year study in rats, there was no evidence of carcinogenic risk.”

“Reduced fertility was observed in male rats given daily oral pretomanid for 13 weeks at 30 mg/kg. At 100 mg/kg, pretomanid was associated with reduced body weight, and complete infertility, associated with testicular atrophy, lower sperm counts, reduced sperm motility, lower serum inhibin B concentration, and higher serum FSH concentration.”

“In vitro, pretomanid inhibited hERG current with an IC50 about 6.2 μg/mL. Since pretomanid is 82% protein bound and the IC50 was about 6 times the clinical Cmax, this hERG result does not indicate a risk to patients at the clinical dose. In monkeys, QT prolongation was inconsistently associated with pretomanid administration.”

“Pretomanid was negative for clastogenicity in a mouse bone marrow micronucleus assay. A metabolite of pretomanid was mutagenic in a bacterial reverse mutation assay.”

“No mutagenic or clastogenic effects were detected in both an in vitro bacterial reverse mutation assay and an in vitro mammalian chromosome aberrations assay using a Chinese hamster ovary cell line.”

“Pretomanid was negative for clastogenicity in a mouse bone marrow micronucleus assay.”

“No carcinogenic potential was revealed in a 6-month study in transgenic mice where this metabolite was produced. In a 2-year study in rats, there was no evidence of carcinogenic risk.”

“The applicant states that a 2-year oral carcinogenicity study in the rat is ongoing. A genotoxic concern based on the positive mutagenicity results of the M50 metabolite cannot at this point be excluded. However, based on the absence of pre-neoplastic or neoplastic findings in the chronic toxicity studies in the rat, or in the 26-week carcinogenicity study in transgenic mice”

“In vitro, pretomanid inhibited hERG current with an IC50 about 6.2 μg/mL. Since pretomanid is 82% protein bound and the IC50 was about 6 times the clinical Cmax, this hERG result does not indicate a risk to patients at the clinical dose.”