Precedia/Small molecules/Pretomanid/Tox package

Pretomanid: what was done before first-in-human, and what came after?

pretomanid · Mycobacterial cell wall / respiration

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.”

✓ VerifiedFDA 2005: Estimating the Maximum Safe Starting Dose in Initial Clinical…, p. 7Source ↗

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)

Full method, every step sourced →

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.”

✓ VerifiedEMA assessment report, p. 22Source ↗

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.”

✓ VerifiedEMA assessment report, p. 22Source ↗

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”

✓ VerifiedFDA multi-discipline review, p. 39Source ↗

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.”

✓ VerifiedFDA multi-discipline review, p. 41Source ↗

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”

✓ VerifiedFDA multi-discipline review, p. 39Source ↗

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.”

✓ VerifiedUS prescribing informationSource ↗

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.”

✓ VerifiedUS prescribing informationSource ↗

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”

✓ VerifiedEMA assessment report, p. 32Source ↗

Summary across all 211 small molecules →

Pretomanid: what was done before first-in-human, and what came after?

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Same question, other small molecules