Pretomanid
pretomanid
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“GLP-compliant repeat-dose toxicity studies of 14 days, 3 months, and 6 months duration were conducted in rats and studies of 2 weeks, 3 months, and 9 months duration were conducted in cynomolgus monkeys.”
Why that species
All human circulating metabolites formed and qualified in rats and monkeys
“Rats and monkeys were chosen as target species for the toxicology studies. These species showed extensive metabolism and it has been shown that all human circulating extractable metabolites detected following a single oral dose of pretomanid were formed in the relevant toxicological animal species”
Surrogate molecule
No surrogate; the clinical compound was tested
“Oral administration of pretomanid to cynomolgus monkeys for 9 months at doses of 0, 25, 50, and 100 mg/kg/day was generally well tolerated.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“repeat dose toxicity studies (in mice, rats, and monkeys, for up to 39 weeks)”
Pivotal GLP studies
GLP 6-month rat and 9-month cynomolgus monkey oral/nasogastric gavage studies
“GLP-compliant repeat-dose toxicity studies of 14 days, 3 months, and 6 months duration were conducted in rats and studies of 2 weeks, 3 months, and 9 months duration were conducted in cynomolgus monkeys. In all studies, doses were administered daily by oral or nasogastric gavage corresponding to the proposed clinical oral dosing regimen.”
Route in tox
Oral or nasogastric gavage, daily
“In all studies, doses were administered daily by oral or nasogastric gavage corresponding to the proposed clinical oral dosing regimen.”
Skipped studiesopen answer page →
Genotoxicity
Negative in conventional genotoxicity battery; circulating metabolite M50 mutagenic in Ames
“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.”
Carcinogenicity
6-month transgenic mouse and 2-year rat: no carcinogenic potential
“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.”
Reproductive & developmental
Male rat fertility reduced at 30 mg/kg; complete infertility with testicular atrophy at 100 mg/kg
“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.”
Safety pharmacology
hERG IC50 ~6.2 µg/mL (~6x clinical Cmax); QT prolongation inconsistent in monkeys
“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.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Pretomanid don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: 26-week rat: irreversible late-onset cataracts at 100 mg/kg/day; testicular atrophy/degeneration at ≥30 mg/kg/day (EMA assessment report, p. 23)
NOAEL / key findings
26-week rat: irreversible late-onset cataracts at 100 mg/kg/day; testicular atrophy/degeneration at ≥30 mg/kg/day
“Pretomanid caused irreversible, late onset, cataracts at 100 mg/kg/day and testicular atrophy/degeneration at doses of 30 mg/kg/day and higher.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion (spleen, thymus, Peyer's patches, BALT) in all three species, at toxic doses
“Signs of immunotoxicity were seen in most of the repeat-dose toxicity studies and in all three species, such as lymphoid depletion in the spleen, thymus, Peyer’s patches and bronchial-associated lymphoid tissue in the lungs, and alterations in lymphoid organ weights.”
Biodistribution & persistence
Rat: highest in Harderian gland, liver, kidney, adrenal, lacrimal gland and spinal cord
“In a study of radiolabeled PA-824 in rats, the highest tissue concentrations were measured in the Harderian gland, liver, renal medulla, adrenal gland, kidney, renal cortex, exorbital lacrimal gland, and spinal cord.”
Modality-specific risk
Male reproductive (testicular) toxicity in rodents without safety margin
“Pretomanid shows clear signs of toxicological effects on male rodent reproductive organs without any safety margin.”