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”
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.”
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.”