Zevtera
ceftobiprole medocaril
Species
RatDog
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, marmoset and dog
“In 2- 4- and 13-week studies in rats, marmosets, and dogs, injection site findings included thrombus formation, accumulation of inflammatory cells, thickening of the vascular wall in the periphery of the dosing catheter, granulomas, edema/hemorrhage and/or necrosis of tissues around the catheter.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical prodrug ceftobiprole medocaril was tested
“The nonclinical safety profile of ceftobiprole medocaril sodium has been explored in single and repeat-dose studies in mice, rats, dogs, rabbits and monkeys for up to 3 months duration”
Species: general tox
Rat, marmoset and dog
“In 2- 4- and 13-week studies in rats, marmosets, and dogs, injection site findings included thrombus formation, accumulation of inflammatory cells, thickening of the vascular wall in the periphery of the dosing catheter, granulomas, edema/hemorrhage and/or necrosis of tissues around the catheter.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and monkey (EFD)
“fertility studies in male and female rats, embryofetal developmental studies in rats and monkeys, and pre- and post-natal developmental toxicity study in rats”
Species: carcinogenicity
Not conducted (not warranted)
“No animal studies have been performed to evaluate the carcinogenic potential of ZEVTERA as none were warranted.”
Surrogate used in
No surrogate used; ceftobiprole medocaril sodium tested directly
“The nonclinical safety profile of ceftobiprole medocaril sodium has been explored in single and repeat-dose studies in mice, rats, dogs, rabbits and monkeys for up to 3 months duration”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat, marmoset and dog)
“In 2- 4- and 13-week studies in rats, marmosets, and dogs, injection site findings included thrombus formation, accumulation of inflammatory cells, thickening of the vascular wall in the periphery of the dosing catheter, granulomas, edema/hemorrhage and/or necrosis of tissues around the catheter.”
Pivotal GLP studies
13-week rat, marmoset and dog studies (plus 2- and 4-week studies)
“In 2- 4- and 13-week studies in rats, marmosets, and dogs, injection site findings included thrombus formation, accumulation of inflammatory cells, thickening of the vascular wall in the periphery of the dosing catheter, granulomas, edema/hemorrhage and/or necrosis of tissues around the catheter.”
Route in tox
Intravenous
“Nearly all studies have been conducted via the intravenous route, except for juvenile toxicology study conducted in rats by the subcutaneous route.”
Skipped studiesopen answer page →
Genotoxicity
Negative in vivo (micronucleus and rat liver UDS), reducing concern over clastogenic signals in vitro
“However, in vivo ceftobiprole medocaril sodium was negative in both the micronucleus assay and rat liver unscheduled DNA synthesis reducing concern for potential clastogenic activity.”
Carcinogenicity
Not conducted; not warranted for short treatment duration
“No studies were available and none are warranted for this relatively short treatment duration.”
Reproductive & developmental
Rat and monkey EFD: no adverse fetal developmental outcomes at ~1.4x and 0.9x MRHD
“Intravenous administration of ceftobiprole medocaril sodium to pregnant rats and monkeys during organogenesis showed no evidence of adverse fetal developmental outcomes at doses approximately 1.4 times and 0.9 times the MRHD, respectively, based on BSA comparison.”
Safety pharmacology
Mouse CNS study: convulsions are a primary CNS effect of ceftobiprole, not secondary to kidney damage
“Ro 63-9141-induced convulsion appears to be a primary effect and not secondary to kidney damage as convulsions were seen with direct injection into the brain.”
Genotox: Ames
Negative, but test limited by bactericidal activity
“Ceftobiprole medocaril was negative in a standard bacterial reverse mutation test, however, the test was limited by bactericidal activity.”
Genotox: in vitro mammalian
Positive: mouse lymphoma assay and chromosomal aberration assays (pro-drug and active metabolite); forward mutation assay negative
“The genotoxicity profile of ceftobiprole medocaril sodium was mixed including a negative Ames assay, a positive mouse lymphoma assay, a negative forward mutation assay, and positive chromosomal assays for both the pro-drug and active metabolite suggesting clastogenic potential.”
Genotox: in vivo
Negative: mouse micronucleus and rat liver unscheduled DNA synthesis
“However, in vivo ceftobiprole medocaril sodium was negative in both the micronucleus assay and rat liver unscheduled DNA synthesis reducing concern for potential clastogenic activity.”
Carcinogenicity model
Not conducted (not warranted for relatively short treatment duration)
“No studies were available and none are warranted for this relatively short treatment duration.”
Carcinogenicity timing
Not required for the short treatment duration
“No studies were available and none are warranted for this relatively short treatment duration.”
hERG / QT
No difference in hERG tail current vs vehicle for ceftobiprole (BAL9141)
“There were no differences in HERG tail current between the BAL9141 and control vehicle.”
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 Zevtera 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: 13-week studies: convulsions and mortality at ≥50 mg/kg (marmoset, 0.2x MRHD) and ≥250 mg/kg (rat, 0.94x MRHD) (FDA integrated review, p. 125)
NOAEL / key findings
13-week studies: convulsions and mortality at ≥50 mg/kg (marmoset, 0.2x MRHD) and ≥250 mg/kg (rat, 0.94x MRHD)
“However, in the 13-week studies in the rats and marmosets at similar doses to those used in shorter term studies, convulsions and mortality were observed (≥50 mg/kg in marmosets, 0.2 times the MRHD; ≥250 mg/kg in rats, 0.94 times the MRHD, based on BSA comparisons).”
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
Rat QWBA: radioactivity in all tissues with low overall distribution
“In a rat exploratory quantitative whole body autoradiography study following a single intravenous administration of 14C radiolabeled ceftobiprole medocaril sodium (20 mg/kg), quantifiable levels of radioactivity (>0.29 mcg-equiv/g) were detected in all tissues with a low overall distribution into most organs and tissues.”
Modality-specific risk
Convulsions and thrombi/emboli with dosing longer than one month
“Both rats and marmosets showed convulsions and thrombi and/or emboli with dosing durations greater than one month.”
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
- Increased Mortality with Unapproved Use in Ventilator-Associated Bacterial Pneumonia Patients
- Hypersensitivity Reactions
- Seizures and Other Central Nervous System Reactions
- Clostridioides difficile-Associated Diarrhea
- 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 Zevtera 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: 13-week studies: convulsions and mortality at ≥50 mg/kg (marmoset, 0.2x MRHD) and ≥250 mg/kg (rat, 0.94x MRHD) (FDA integrated review, p. 125)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week IV infusion studies in rats, marmosets and dogs
“In 2- 4- and 13-week studies in rats, marmosets, and dogs, injection site findings included thrombus formation, accumulation of inflammatory cells, thickening of the vascular wall in the periphery of the dosing catheter, granulomas, edema/hemorrhage and/or necrosis of tissues around the catheter.”
Pivotal GLP studies
13-week rat, marmoset and dog studies (plus 2- and 4-week studies)
“In 2- 4- and 13-week studies in rats, marmosets, and dogs, injection site findings included thrombus formation, accumulation of inflammatory cells, thickening of the vascular wall in the periphery of the dosing catheter, granulomas, edema/hemorrhage and/or necrosis of tissues around the catheter.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and monkey (EFD)
“fertility studies in male and female rats, embryofetal developmental studies in rats and monkeys, and pre- and post-natal developmental toxicity study in rats”
Reproductive & developmental
Rat and monkey EFD: no adverse fetal developmental outcomes at ~1.4x and 0.9x MRHD
“Intravenous administration of ceftobiprole medocaril sodium to pregnant rats and monkeys during organogenesis showed no evidence of adverse fetal developmental outcomes at doses approximately 1.4 times and 0.9 times the MRHD, respectively, based on BSA comparison.”
PPND / ePPND: when
Rat PPND (IV infusion) completed and reviewed with the marketing application
“BAP00640/ Study for Effects of BAL5788 (Prodrug of BAL9141) on Pre- and Postnatal Development Including Maternal Function by Intravenous Infusion in Rats”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted)
“No animal studies have been performed to evaluate the carcinogenic potential of ZEVTERA as none were warranted.”
Carcinogenicity model
Not conducted (not warranted for relatively short treatment duration)
“No studies were available and none are warranted for this relatively short treatment duration.”
Carcinogenicity timing
Not required for the short treatment duration
“No studies were available and none are warranted for this relatively short treatment duration.”
Safety marginopen answer page →
Safety margin at NOAEL
13-week dog NOAEL 8 mg/kg/day, ~0.1-fold the maximum human dose
“Study NOAEL was considered at 8 mg/kg/day (approximately 0.1-fold of the maximum human dose)”
NOAEL / key findings
13-week studies: convulsions and mortality at ≥50 mg/kg (marmoset, 0.2x MRHD) and ≥250 mg/kg (rat, 0.94x MRHD)
“However, in the 13-week studies in the rats and marmosets at similar doses to those used in shorter term studies, convulsions and mortality were observed (≥50 mg/kg in marmosets, 0.2 times the MRHD; ≥250 mg/kg in rats, 0.94 times the MRHD, based on BSA comparisons).”
Efficacy evidenceopen answer page →
Efficacy evidence
Infection models: murine septicemia and acute pneumonia, rat/rabbit endocarditis and osteomyelitis (MSSA, MRSA, S. pneumoniae)
“In summary, ceftobiprole was shown to be active against MSSA and MRSA in the murine septicemia model and rat and rabbit endocarditis and osteomyelitis models. Ceftobiprole was active against S. pneumoniae, including penicillin resistant strains in the murine septicemia and the murine acute pneumonia models.”
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: in rat and rabbit endocarditis models ceftobiprole reduced MRSA vegetations but did not sterilize
“In both a rat and rabbit model of endocarditis, ceftobiprole did not sterilize but was effective in reducing cardiac vegetations of MRSA including a vancomycin intermediate strain.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAcceptedBeyond the letter
Animal data support only up to one month of dosing, while clinical treatment up to six weeks was permitted
Why: Longer treatment duration supported by clinical data · Human data
“The animal data supports safety of ceftobiprole medocaril sodium for up to 1 month duration, however, based on clinical data treatments for up to six weeks were permitted. We deferred to the clinical review team on the safety of ceftobiprole medocaril sodium administered for this extended duration.”
GenotoxicityAcceptedBeyond the letter
Positive in vitro mouse lymphoma and chromosomal assays (clastogenic potential); negative in vivo micronucleus and rat liver UDS
Why: Negative in vivo micronucleus and rat liver unscheduled DNA synthesis assays reduce the concern · Weight of evidence
“The genotoxicity profile of ceftobiprole medocaril sodium was mixed including a negative Ames assay, a positive mouse lymphoma assay, a negative forward mutation assay, and positive chromosomal assays for both the pro-drug and active metabolite suggesting clastogenic potential.”
“However, in vivo ceftobiprole medocaril sodium was negative in both the micronucleus assay and rat liver unscheduled DNA synthesis reducing concern for potential clastogenic activity.”
Impurity or metaboliteAcceptedBeyond the letter
Several drug substance and drug product impurities not adequately qualified in toxicology studies
Why: Impurity levels considered acceptable despite qualification limitations; no further safety evaluation warranted · Other reason
“The impurity qualification review indicates that the select individual impurities in the DS and DP are not adequately qualified based on the toxicology studies considered.”
“Although there are limitations in the qualification of impurities based on toxicological studies, the levels of impurities in ceftobiprole medocaril sodium are considered acceptable and no further evaluations of impurities for safety is warranted.”
Safety marginVerdict not stated
Convulsions and mortality in 13-week rat and marmoset studies at doses below the MRHD (0.2 times in marmosets)
“However, in the 13-week studies in the rats and marmosets at similar doses to those used in shorter term studies, convulsions and mortality were observed (≥50 mg/kg in marmosets, 0.2 times the MRHD; ≥250 mg/kg in rats, 0.94 times the MRHD, based on BSA comparisons).”
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