Recarbrio
imipenem, cilastatin and relebactam
Species
MonkeyRat
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and monkey
“In 1- and 3-month repeated-dose toxicology studies, relebactam produced only limited toxicity. Two dose-dependent toxicities with clinical relevance were CNS toxicity primarily in rats and minimal kidney toxicity primarily in monkeys.”
Why that species
In vitro and in vivo metabolic profiles and satisfactory pharmacokinetics; monkey previously used for imipenem/cilastatin
“The selection was based on the in vitro and in vivo metabolic profiles and the demonstration of satisfactory pharmacokinetics in these species. The monkey had previously been used as the non-rodent species for the assessment of toxicological profile of imipenem/cilastatin including the evaluation of renal toxicity caused by imipenem.”
Surrogate molecule
No surrogate; relebactam itself was tested, alone and with imipenem/cilastatin
“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).”
Species: general tox
Wistar Han rat and cynomolgus monkey
“The Wistar Han rat and cynomolgus monkey were selected as the main rodent and non-rodent species in the general toxicity studies.”
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.”
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.”
Surrogate used in
No surrogate used; relebactam tested alone and with imipenem/cilastatin
“Relebactam in combination with imipenem and cilastatin was evaluated in a repeat-dose toxicity study in monkey (4 weeks with no recovery phase).”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and monkey)
“In 1- and 3-month repeated-dose toxicology studies, relebactam produced only limited toxicity.”
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.”
Route in tox
Intravenous
“The intravenous (IV) route of administration was utilized in all toxicology studies (except in the first phase of the juvenile study in rat and the EFD study in mouse) to match the intended clinical administration route.”
Skipped studiesopen answer page →
Genotoxicity
Relebactam negative in Ames, chromosomal aberration and rat bone marrow micronucleus assays
“Relebactam was shown to be negative for mutagenicity and/or clastogeniceffects in an Ames assay, a chromosomal aberration study, and in vivo in a rat bone marrow micronucleus assay.”
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.”
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.”
Safety pharmacology
Monkey telemetry: no effects on blood pressure, heart rate, ECG/QTc, respiration or body temperature
“No MK-7655-related changes compared to vehicle control values were observed for blood pressure measurements, heart rate, electrocardiogram parameters including QTc intervals, respiratory parameters, or body temperature.”
Genotox: Ames
Relebactam: negative
“The genotoxic potential of relebactam was characterized by the Ames test, a chromosome aberration test in CHO-cells, and an in-vivo rat bone marrow erythrocyte micronucleus test. The outcome of the studies was negative, thus, there were no indication that relebactam is genotoxic.”
Genotox: in vitro mammalian
Relebactam chromosome aberration in CHO cells: negative
“The genotoxic potential of relebactam was characterized by the Ames test, a chromosome aberration test in CHO-cells, and an in-vivo rat bone marrow erythrocyte micronucleus test. The outcome of the studies was negative, thus, there were no indication that relebactam is genotoxic.”
Genotox: in vivo
Relebactam rat bone marrow micronucleus: negative
“The genotoxic potential of relebactam was characterized by the Ames test, a chromosome aberration test in CHO-cells, and an in-vivo rat bone marrow erythrocyte micronucleus test. The outcome of the studies was negative, thus, there were no indication that relebactam is genotoxic.”
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.”
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.”
hERG / QT
Relebactam: no significant hERG effect at 318 µM (~8-fold clinical free Cmax)
“In a whole-cell voltage-clamping of CHO cells stably expressing hERG, REL had no significant effect on hERG current relative to time-dependent changes observed in the vehicle control, at a maximal testable actual concentration of 318 μM (~8-fold clinical free fraction Cmax, 38 µM).”
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 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.”
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)
NOAEL / key findings
CNS signs in rats at 450 mg/kg/day (~7x clinical exposure); rat NOAELs ~2-fold clinical exposure
“In the rat studies, the 450 mg/kg/day relebactam dose associated with neurological clinical signs produced plasma relebactam exposures approximately 7 times higher than the expected clinical exposures, but NOAEL doses in the rat studies were about 2-fold higher than the expected clinical exposures.”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Low brain, lens and bone levels in rat QWBA; relebactam not prone to cross the blood-brain barrier
“Brain, seminal vesicles, eye lens and bone were among the tissues with lowest concentrations of radioactivity (<1.5 μg equiv/g at Tmax). The low levels of radioactivity in the brain suggests REL is not prone to pass the blood brain barrier.”
Modality-specific risk
CNS toxicity (rat) and renal toxicity (monkey), possibly additive with imipenem
“Because nonclinical studies with relebactam revealed a potential for CNS toxicity in rats and renal toxicity in monkeys, it may be important to determine if an additive or synergisticpotential for these toxicities can occur when imipenem/cilastatin are clinically administered concomitantly with relebactam.”
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 evaluated; no immunogenicity evaluations conducted
“No immunogenicity/antigenicity evaluations were conducted as part of this development program.”
Label warnings
- Hypersensitivity Reactions
- Seizures and Other Central Nervous System (CNS) Adverse Reactions
- Increased Seizure Potential Due to Interaction with Valproic Acid
- Clostridioides difficile-Associated Diarrhea (CDAD)
- Development of Drug-resistant Bacteria
Hypersensitivity & infusion reactionsNeurotoxicityGastrointestinal
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 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.”
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)
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).”
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.”
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.”
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.”
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.”
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.”
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.”
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.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat NOAEL ~2x expected clinical relebactam exposure
“In the rat studies, the 450 mg/kg/day relebactam dose associated with neurological clinical signs produced plasma relebactam exposures approximately 7 times higher than the expected clinical exposures, but NOAEL doses in the rat studies were about 2-fold higher than the expected clinical exposures.”
NOAEL / key findings
CNS signs in rats at 450 mg/kg/day (~7x clinical exposure); rat NOAELs ~2-fold clinical exposure
“In the rat studies, the 450 mg/kg/day relebactam dose associated with neurological clinical signs produced plasma relebactam exposures approximately 7 times higher than the expected clinical exposures, but NOAEL doses in the rat studies were about 2-fold higher than the expected clinical exposures.”
Efficacy evidenceopen answer page →
Efficacy evidence
Neutropenic mouse infection models with relebactam plus imipenem
“Several animal models of infection in neutropenic mice were utilized for determining the in vivo efficacy of REL co-administered with IMI.”
Why that 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.
Reviewer's view of the efficacy data
FDA: relebactam restores imipenem activity in vivo against non-susceptible isolates and penetrates pulmonary ELF
“Consistent with the in vitro studies, REL has the ability to restore the antibacterial activity of imipenem in vivo against isolates that are not susceptible to imipenem. In vivo models also suggest that REL penetrates pulmonary ELF.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityVerdict not stated
No carcinogenicity studies with relebactam or imipenem/cilastatin
Why: Relebactam not genotoxic and treatment duration relatively short · Within the guideline · Pharmacology or kinetics
“In the absence of genotoxicity, and as the proposed treatment duration is relatively short, no carcinogenicity tests have been conducted.”
Safety pharmacologyAcceptedBeyond the letter
Cardiovascular and CNS GLP safety pharmacology studies used males only
Why: No substantial gender differences in repeat-dose toxicology studies · Weight of evidence
“For relebactam it was noted only males were used in the CV and CNS GLP-studies. However, since no substantial gender differences were observed in the repeat dose toxicology studies, this is considered acceptable.”
Impurity or metaboliteAcceptedBeyond the letter
No in vivo metabolism studies in rabbit or monkey, the species used for reproductive and repeat-dose toxicity
Why: No major relebactam metabolites identified in humans · Pharmacology or kinetics · Human data
“It is noted that no studies on in vivo metabolism of REL have been carried out in rabbit or monkey that were used in reproductive toxicity or CV and repeat dose toxicity studies, respectively. However, since no major REL metabolites have been identified in humans, this is considered acceptable by CHMP.”
SpeciesCriticised but acceptedBeyond the letter
Monkey chosen as non-rodent species without full 3Rs justification
Why: Animal models considered relevant
“With respect to the 3Rs principles the selection of the monkey should have been further justified. However, the animal models are considered relevant.”
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