Fetroja
cefiderocol
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
“The clinical formulation of cefiderocol, was tested in the repeat-dose toxicology studies described below. Rats and monkeys were the primary rodent and nonrodent species used in toxicology testing of this drug product.”
Why that species
Monkey chosen as non-rodent because dogs vomited and were not expected to tolerate repeat dosing at 1000 mg/kg
“In the response, the Applicant explained that in exploratory single-dose studies in dog, vomiting was observed several times from during dosing to 1 hour after the end of dosing at 1000 mg/kg, reason for which the Applicant considered that dogs would not tolerate repeat-dosing at the 1000 mg/kg dose level.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The clinical formulation of cefiderocol, was tested in the repeat-dose toxicology studies described below.”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and monkey)
“This finding was not associated with renal degeneration in either species, even when the animals were treated for 3 months with up to 1500 mg/kg/day in rats and 1000 mg/kg/day in monkeys.”
Pivotal GLP studies
3-month rat and 3-month monkey studies, up to 1500 and 1000 mg/kg/day
“This finding was not associated with renal degeneration in either species, even when the animals were treated for 3 months with up to 1500 mg/kg/day in rats and 1000 mg/kg/day in monkeys.”
Route in tox
Intravenous (subcutaneous in mouse EFD and young juvenile rats)
“With a few notable exceptions (subcutaneous dosing of mice in a developmental toxicology study and very young rats in a juvenile toxicology study), most animal studies of cefiderocol were conducted using an intravenous route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; chromosomal aberrations in vitro; negative in vivo rat micronucleus and liver comet assays
“non-mutagenic in Ames test, increased chromosomal aberrations in vitro but not considered clastogenic in the in vivo rat micronucleus assay and did not induce DNA damage in the Comet assay in rat hepatocytes”
Carcinogenicity
Not conducted (short treatment duration, generally 14 days or less)
“Carcinogenicity studies were not conducted. CHMP agreed that carcinogenicity studies were not needed as the SmPC states that the duration of dosing will be generally 14 days or less (not exceeding 21 days).”
Reproductive & developmental
Mouse and rat EFD: no developmental toxicity up to 2000 (mouse, SC) and 1000 (rat, IV) mg/kg/day
“Cefiderocol did not cause developmental toxicity in mice when administered to dams at daily subcutaneous doses up to 2000 mg/kg/day (twice daily 1000 mg/kg doses) from GD 6-15. It did not cause developmental toxicity in rats when administered intravenously to dams at doses up to 1000 mg/kg/day from GD 6-17.”
Safety pharmacology
QTc prolongation in cynomolgus monkeys at 1000 mg/kg IV, in safety pharmacology and repeat-dose studies
“Prolongation of the QTc (Bazett) was observed in cynomolgus monkeys following a 1000 mg/kg dose given intravenously over 1 hour (observed in both a single dose safety pharmacology study and in repeat dose toxicology studies).”
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 Fetroja 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: 3-month monkey NOAEL 100 mg/kg/day, only 3-fold (Cmax) and 0.3-fold (AUC) human exposure; red blood cell decreases above it (EMA assessment report, p. 27)
NOAEL / key findings
3-month monkey NOAEL 100 mg/kg/day, only 3-fold (Cmax) and 0.3-fold (AUC) human exposure; red blood cell decreases above it
“It should however be noted that the margins to clinical exposure from NOAEL (100mg/kg/day in the 3- month monkey study) is only 3-fold and 0.3-fold of the Cmax and AUC-values in humans respectively.”
Risksopen answer page →
Immune & cytokine safety
Splenic germinal center development in 1- and 3-month rat studies, a response to weak antigenic stimulation; no anaphylaxis
“In the 1-month and 3-month repeat-dose toxicity studies in rats, development of germinal centers in the spleen, which suggested an enhanced antibody production, was observed. This change is considered to be an immune response possibly associated with the weak antigenic stimulation by cefiderocol, however, there was no evidence of anaphylaxis in either study.”
Biodistribution & persistence
Low, brief CNS exposure; tissue levels mostly below plasma; no preferential melanin binding
“CNS exposure was low and brief. Most tissue levels were lower than plasma levels. Binding to RBC was negligible. Preferential binding to melanin not observed.”
Modality-specific risk
Convulsions (rat) and QTc prolongation (monkey), at exposures >18-20-fold human Cmax
“Convulsions observed in rats occurred at blood levels >20-fold higher and QTc prolongation in monkeys occurred at blood levels >18-fold higher than the Cmax in healthy male volunteers.”