Recarbrio (imipenem, cilastatin and relebactam): what was done before first-in-human, and what came after?

Precedia/Small molecules/Recarbrio/Tox package

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

imipenem, cilastatin and relebactam · Beta-lactamase (relebactam)

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 Recarbrio 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: CNS signs in rats at 450 mg/kg/day (~7x clinical exposure); rat NOAELs ~2-fold clinical exposure (FDA multi-discipline review, p. 41)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

12-week rat and monkey relebactam studies, no recovery phase

“Relebactam was evaluated in repeat-dose toxicity studies in rats (4 weeks with 4 weeks recovery, and 12 weeks with no recovery phase) and in monkeys (4 weeks with 4 weeks recovery, and 12 weeks with no recovery phase).”

✓ VerifiedEMA assessment report, p. 29Source ↗

Pivotal GLP studies

Up to 3-month rat and monkey studies of relebactam, plus a monkey combination study with imipenem/cilastatin

“The program includes repeat-dose studies up to 3 months exposure in rats and monkeys, and a repeat dose combination study with REL and imipenem/relebactam.”

✓ VerifiedEMA assessment report, p. 29Source ↗

DART package

Species: DART

CD1 mouse, Sprague Dawley rat and New Zealand White rabbit (EFD)

“The embryo foetal development studies were conducted in the CD1 mouse, Sprague Dawley rat, and New Zealand White rabbit.”

✓ VerifiedEMA assessment report, p. 29Source ↗

Reproductive & developmental

Mouse, rat and rabbit EFD: external/skeletal malformations (incl. cleft palate) in mice only; none in rats or rabbits

“In rats and rabbits, malformations and variations were not increased by relebactam above concurrent or historical control levels. However, in mice, increases in specificexternal and/or skeletal alterations were observed.”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

PPND / ePPND: when

PPND in rat (IV) completed before the marketing application

“Relebactam: The study report for a MK-7655 (relebactam) pre-postnatal study in rats is reviewed below.”

✓ VerifiedFDA multi-discipline review, p. 67Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted (non-genotoxic, short treatment duration)

“In the absence of genotoxicity, and as the proposed treatment duration is relatively short, no carcinogenicity tests have been conducted.”

✓ VerifiedEMA assessment report, p. 31Source ↗

Carcinogenicity model

Not conducted (non-genotoxic, short treatment duration)

“In the absence of genotoxicity, and as the proposed treatment duration is relatively short, no carcinogenicity tests have been conducted.”

✓ VerifiedEMA assessment report, p. 31Source ↗

Carcinogenicity timing

Not required (non-genotoxic, short treatment duration)

“In the absence of genotoxicity, and as the proposed treatment duration is relatively short, no carcinogenicity tests have been conducted.”

✓ VerifiedEMA assessment report, p. 31Source ↗

Summary across all 211 small molecules →

Recarbrio: 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