Exblifep
cefepime and enmetazobactam
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 and dog
“general toxicology studies (28-day IV-dose studies in rats and dogs, a 28-day combination toxicology study with cefepime and enmetazobactam in rats, and a 13-week combination toxicology study with cefepime and enmetazobactam in dogs)”
Why that species
Metabolic profiles in rats, dogs and rabbits similar to humans
“The metabolic profiles of enmetazobactam in rats, dogs, rabbits and humans were similar which supports the selection of these animal species as the primary toxicology species.”
Surrogate molecule
No surrogate; the clinical compounds were tested alone and in combination
“Enmetazobactam given alone to rats at doses of 125, 250 and 500 mg/kg/day and at doses of 60, 120 and 240 mg/kg/day to dogs was in general well tolerated.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week dog combination study)
“general toxicology studies (28-day IV-dose studies in rats and dogs, a 28-day combination toxicology study with cefepime and enmetazobactam in rats, and a 13-week combination toxicology study with cefepime and enmetazobactam in dogs)”
Pivotal GLP studies
28-day IV enmetazobactam rat and dog studies; 28-day rat and 13-week dog cefepime-enmetazobactam combination studies
“general toxicology studies (28-day IV-dose studies in rats and dogs, a 28-day combination toxicology study with cefepime and enmetazobactam in rats, and a 13-week combination toxicology study with cefepime and enmetazobactam in dogs)”
Route in tox
Intravenous, once daily
“All studies used once daily IV administration and included a recovery phase.”
Skipped studiesopen answer page →
Genotoxicity
Enmetazobactam negative in Ames, CHO chromosomal aberration and mouse bone marrow micronucleus assays
“Enmetazobactam was negative for genetic toxicity in vitro in a bacterial reverse mutation assay and a chromosomal aberration assay in Chinese Hamster ovary cells, and in vivo in a mouse micronucleus assay in bone marrow cells.”
Carcinogenicity
Not conducted (intended duration of therapy ≤14 days)
“Carcinogenicity studies of enmetazobactam have not been conducted and are not planned based on the intended duration of therapy (≤ 14 days).”
Reproductive & developmental
Rat and rabbit EFD: no malformations; reduced maternal weight gain and fetal body weights
“In embryo-fetal development (EFD) studies in rats and rabbits, enmetazobactam was not associated with fetal malformations, but did cause maternal toxicity in the form of reduced body weight gain and fetal toxicity as reduced fetal body weights in both studies.”
Safety pharmacology
hERG IC50 1,254.22 µg/mL (63-fold over MRHD Cmax); low QT risk
“The hERG study revealed an IC50 -value of 1,254.22 µg/mL, corresponding to 3,990.30 μM, for enmetazobactam which translates into a 63-fold safety margin compared to the Cmax level of 19.8 µg/ml at the MRHD. Thereby, the potential risk for QT prolongation in humans is low.”
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 Exblifep 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: Liver target: enzyme increases with single-hepatocyte necrosis (28-day dog) and hepatocellular inclusions (combination study) (FDA integrated review, p. 42)
NOAEL / key findings
Liver target: enzyme increases with single-hepatocyte necrosis (28-day dog) and hepatocellular inclusions (combination study)
“In the 28-day study in dogs, the increased liver enzymes correlated with microscopic evidence of single-hepatocyte necrosis, and in the combination toxicology study, liver enzyme increases correlated with granular hepatocellular inclusions.”
Risksopen answer page →
Immune & cytokine safety
Guinea pig maximization test: no skin sensitization
“At 24 and 48 hours after the challenge patch removal, the guinea pigs induced and challenged with AAI101 did not exhibit any skin responses and received the same Magnusson and Kligman grades (0% positive reaction) as the vehicle control group.”
Biodistribution & persistence
No melanin binding; no preferential retention in skin, eye or uveal tract
“There was no preferential distribution to or retention in the skin, the eye or the uveal tract, i.e., no specific binding of [14C]-enmetazobactam and drug related radioactivity to melanin was indicated.”
Modality-specific risk
Hepatotoxicity (liver primary target of enmetazobactam)
“Based on the 28-day Repeated Dose Toxicity (RDT) studies of enmetazobactam and the 28-day and 13-week combination studies in rats and dogs, the liver appears to be a primary target of toxicity for enmetazobactam.”