Utebzi (tebipenem pivoxil): what was done before first-in-human, and what came after?

Precedia/Small molecules/Utebzi/Tox package

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

tebipenem pivoxil · Penicillin-binding proteins

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 Utebzi 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: Rat NOAEL 1000 mg/kg/day (28-day GLP) and 300 mg/kg/day (90-day); low-grade stomach and heart findings (FDA integrated review, p. 211)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

13-week cynomolgus monkey (non-GLP) with 4-week recovery; longest GLP studies were 4-week rat and monkey

“Study # LJT 2561. A 13-Week Repeated Oral Dose Toxicity Study on LJC 11,084 Using Cynomolgus Monkeys With a 4-Week Recovery Segment”

✓ VerifiedFDA integrated review, p. 347Source ↗

Pivotal GLP studies

28-day GLP oral rat and monkey studies; supporting non-GLP 14-, 28- and 90-day rat and monkey studies

“oral administration of the proposed clinical formulation, tebipenem pivoxil hydrobromide has been studied in rats and monkeys in repeat dose 28-day GLP toxicology studies, while tebipenem pivoxil has been studied in rats and monkeys in non-GLP studies (i.e. 14-day, 28-day, and 90-day studies).”

✓ VerifiedFDA integrated review, p. 211Source ↗

DART package

Species: DART

Rat (fertility, EFD, pre/postnatal); mouse, rabbit and monkey (EFD)

“reproductive and developmental toxicity studies including fertility studies in male and female rats, embryo-fetal developmental studies in mice, rats, rabbits, and monkeys, and a peri- and post-natal developmental study in rats”

✓ VerifiedFDA integrated review, p. 290Source ↗

Reproductive & developmental

Mouse, rat and monkey EFD: no adverse developmental effects

“As noted in that review, no adverse developmental effects were noted in embryofetal development (EFD) studies following oral administration of tebipenem pivoxil to pregnant mice, rats and monkeys during periods of organogenesis.”

✓ VerifiedFDA integrated review, p. 213Source ↗

PPND / ePPND: when

Rat PPND completed and reviewed in the NDA; offspring effects secondary to maternal toxicity

“In the pre- and postnatal development (PPND) study in rats, oral administration of tebipenem pivoxil resulted in adverse findings in offspring (stillborn litters, reduced postnatal survival, and decreased body weights through postnatal day 4) that were considered secondary to maternal toxicity.”

✓ VerifiedFDA integrated review, p. 213Source ↗

Carcinogenicity

Species: carcinogenicity

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.

Carcinogenicity model

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.

Carcinogenicity timing

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.

Summary across all 211 small molecules →

Utebzi: 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