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.”
Species: general tox
Rat (up to 6 months) and cynomolgus monkey (up to 9 months)
“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.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“fertility and pre- and post-natal developmental studies in rats; embryo-fetal developmental studies in rats and rabbits”
Species: carcinogenicity
Transgenic mouse (6-month) and rat (2-year)
“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.”
Surrogate used in
No surrogate used; pretomanid itself 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.”
Genotox: Ames
Negative for pretomanid; circulating metabolite M50 mutagenic in Ames
“Pretomanid was negative for clastogenicity in a mouse bone marrow micronucleus assay. A metabolite of pretomanid was mutagenic in a bacterial reverse mutation assay.”
Genotox: in vitro mammalian
Chromosomal aberration in CHO cells: negative
“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.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Pretomanid was negative for clastogenicity in a mouse bone marrow micronucleus assay.”
Carcinogenicity model
6-month transgenic mouse; 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.”
Carcinogenicity timing
26-week transgenic mouse completed; 2-year rat ongoing at the marketing application
“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”
hERG / QT
hERG IC50 ~6.2 µg/mL (~6x clinical Cmax); not considered a risk at clinical dose
“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.”
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.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Risks Associated with the Combination Treatment Regimen
- Hepatotoxicity
- Myelosuppression
- Peripheral and Optic Neuropathy
- QT Prolongation
- Drug Interactions
- Reproductive Effects
- Lactic Acidosis
HepatotoxicityCytopeniasNeurotoxicityCardiovascular
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) GLP cynomolgus monkey oral study with 3-month post-treatment recovery
“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. In the chronic studies, post-treatment assessments continued for 3 months to evaluate reversibility, progression, or delayed toxicity.”
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.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“fertility and pre- and post-natal developmental studies in rats; embryo-fetal developmental studies in rats and rabbits”
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.”
PPND / ePPND: when
Rat PPND completed and included in the NDA
“repeat dose toxicity studies (in mice, rats, and monkeys, for up to 39 weeks), fertility and pre- and post-natal developmental studies in rats; embryo-fetal developmental studies in rats and rabbits”
Carcinogenicity
Species: carcinogenicity
Transgenic mouse (6-month) and rat (2-year)
“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.”
Carcinogenicity model
6-month transgenic mouse; 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.”
Carcinogenicity timing
26-week transgenic mouse completed; 2-year rat ongoing at the marketing application
“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”
Safety marginopen answer page →
Safety margin at NOAEL
26-week rat: NOAEL exposure below predicted human exposure (testicular toxicity)
“In a 26-week study, exposures at the NOAEL were lower than predicted human exposures.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Acute, chronic and latent murine TB infection models (lung/spleen CFU, relapse)
“In vivo activity of pretomanid was evaluated in acute, chronic and latent TB murine models as monotherapy and in combination with a variety of first- and second-line TB drugs, including the compounds in clinical development.”
Why that model
Clinical monotherapy trials not ethical or feasible; component contribution shown in murine TB models
“Evaluation of drug monotherapies in TB clinical trials is not ethical nor feasible. The evidence for the contribution of the individual components to the BPaL regimen comes from the studies in the murine models of pulmonary tuberculosis,”
Reviewer's view of the efficacy data
FDA: murine models showed BPaL bactericidal and sterilizing activity superior to components and dual combinations
“in which the three-drug BPaL regimen demonstrated bactericidal as well as sterilizing activity superior to that of individual components and to the dual combinations of bedaquiline, pretomanid, and linezolid.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
2-year rat carcinogenicity study ongoing at approval and deferred post-marketing, despite mutagenic circulating metabolite M50
Why: No pre-neoplastic findings in chronic rat or transgenic mouse studies; severe drug-resistant tuberculosis; positive therapeutic effect · Weight of evidence · Serious disease
“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 combined with the severity of the indication (extensively drug resistant or treatment-intolerant/nonresponsive multidrug-resistant tuberculosis) and the observed positive therapeutic effect it is accepted that this study is submitted as a post marketing commitment.”
Safety marginAccepted with a conditionBeyond the letter
Rat testicular toxicity: NOAEL exposure in the 26-week study below predicted human exposure
Why: Human male fertility effects unknown; human semen analysis study required post-marketing
“In a 13-week study, exposures at the NOAEL were similar to or slightly higher than anticipated human exposures at the proposed dose. In a 26-week study, exposures at the NOAEL were lower than predicted human exposures.”
“The effects of pretomanid on human spermatogenesis and male fertility in humans are unknown at present. A human semen analysis study will be conducted as a postmarketing requirement (PMR) to investigate the effect of pretomanid on human male fertility.”
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