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.”
Species: general tox
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.”
Species: DART
Rat (IV) and mouse (SC) embryo-fetal development studies
“Developmental toxicity was not observed in rats at intravenous doses of up to 1000 mg/kg/day or mice at subcutaneous doses of up to 2000 mg/kg/day given during the period of organogenesis (gestation days 6-17 in rats and 6-15 in mice).”
Species: 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).”
Surrogate used in
No surrogate used; the clinical formulation 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).”
Genotox: Ames
Negative (S. typhimurium and E. coli reverse mutation)
“Cefiderocol was negative for genotoxicity in a reverse mutation test with S. typhimurium and E. coli and did not induce mutations in V79 Chinese hamster lung cells.”
Genotox: in vitro mammalian
Positive: chromosomal aberration in TK6 human lymphoblasts and mouse lymphoma L5178Y assay
“Cefiderocol was positive in a chromosomal aberration test in cultured TK6 human lymphoblasts and increased mutation frequency in L5178Y mouse lymphoma cells.”
Genotox: in vivo
Negative: rat micronucleus (2000 mg/kg/day) and rat comet assay (1500 mg/kg/day)
“Cefiderocol was negative in an in vivo rat micronucleus test and a rat comet assay at the highest doses of 2000 and 1500 mg/kg/day, respectively.”
Carcinogenicity model
Not conducted (dosing generally 14 days or less, not exceeding 21 days)
“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).”
Carcinogenicity timing
Not needed: dosing generally 14 days or less (not exceeding 21 days)
“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).”
hERG / QT
Minor hERG inhibition: 12% at 1.5 mg/mL, IC50 > 1.5 mg/mL
“The study conducted in HEK293 cells stably expressing hERG channels, indicate a dose related suppression of hERG, being 12 % at the highest dose (1.5 mg/mL) and hence an IC50 > 1.5 mg/mL.”
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.”
Anti-drug antibodies: animals
Guinea pig antigenicity: specific antibodies and anaphylaxis only with adjuvanted cefiderocol, none with cefiderocol sodium alone
“In an antigenicity study in Guinea pigs, anaphylactic reactions including the production of specific antibodies against cefiderocol were noted when adjuvated cefiderocol was used for immunization, but no such reactions were noted when immunization had been performed with cefiderocol sodium alone.”
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
- Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections
- Hypersensitivity Reactions
- Clostridioides difficile-associated Diarrhea (CDAD)
- Seizures and Other Central Nervous System (CNS) Adverse Reactions
- Development of Drug-Resistant Bacteria
InfectionsHypersensitivity & infusion reactionsGastrointestinalNeurotoxicity
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
IV Sprague-Dawley rat study (longest duration, as was the monkey study) with 4-week recovery in control and high-dose groups
“Satellite groups/ unique design: 5/sex in control and high dose groups for 4-week recovery; 4/group for TK”
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.”
DART package
Species: DART
Rat (IV) and mouse (SC) embryo-fetal development studies
“Developmental toxicity was not observed in rats at intravenous doses of up to 1000 mg/kg/day or mice at subcutaneous doses of up to 2000 mg/kg/day given during the period of organogenesis (gestation days 6-17 in rats and 6-15 in mice).”
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.”
PPND / ePPND: when
IV PPND in rat completed and reviewed with the marketing application; NOAEL 1000 mg/kg/day
“The NOAEL for parturition, maternal function, and pre-/postnatal development and viability of the pups was the high dose of 1000 mg/kg/day.”
Carcinogenicity
Species: 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).”
Carcinogenicity model
Not conducted (dosing generally 14 days or less, not exceeding 21 days)
“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).”
Carcinogenicity timing
Not needed: dosing generally 14 days or less (not exceeding 21 days)
“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).”
Safety marginopen answer page →
Safety margin at NOAEL
3-month monkey NOAEL 100 mg/kg/day: 0.3-fold human AUC (3-fold Cmax)
“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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Murine thigh and lung infection models with Gram-negative strains (dose-ranging, PK/PD target)
“Cefiderocol with ascending doses (0.3-30 mg/kg q3h) was tested in murine thigh and lung infection models for each tested strain to determine the effective dose and %fT > MIC required to achieve static effect and 1-log10 reduction in the number of viable cells compared to the mean of untreated baseline control group.”
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: stasis or 1-log10 reduction in animal infection models considered sufficient to translate to clinical efficacy for cUTI
“For cUTI indication, bacteriostasis or 1-log10 bacteria reduction from the animal infection models is thought to be sufficient to translate the preclinical drug activity to clinical efficacy.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesCriticised but acceptedBeyond the letter
Cynomolgus monkey used as non-rodent species for general toxicology without species justification
Why: Studies already completed in the monkey · Other reason
“While this is true, the use of Cynomolgus monkey should be reserved to situations where this species is the only relevant species.”
“CHMP agreed however that since the studies had already been completed in the monkey, this would not be further pursued.”
DARTAcceptedBeyond the letter
Mouse subcutaneous embryo-fetal study used instead of intravenous rabbit study
Why: Mouse is a well-characterised, relevant species for embryo-fetal studies · Other reason
“The Applicant decided to use an additional rodent model (CD-1 mouse) and subcutaneous administration instead of intravenously administered rabbits, because repeated-dosing with intravenous administration in mice is not feasible.”
“Overall the justifications for the species use in the general toxicology and EFD studies is considered acceptable.”
Safety marginVerdict not stated
3-month monkey NOAEL gives only 0.3-fold human AUC and 3-fold Cmax
“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.”
GLPAcceptedBeyond the letter
Toxicokinetic bioanalytical assays not run with GLP-validated methods
Why: High-quality standards of the bioanalytical methods · Other reason
“Even though the Guideline on bioanalytical method validation (EMEA/CHMP/EWP/192217/2009) states that all the bioassays should be conducted with GLP validated methods, CHMP agreed that the high-quality standards of the bioanalytical methods used here can be considered adequate for the non-clinical analyses.”
Safety pharmacologyCriticised but acceptedBeyond the letter
Secondary pharmacology screen run at a low concentration despite convulsions in rat repeat-dose studies
Why: No secondary targets identified in the screen; clinical safety profile to date · Human data · Weight of evidence
“However, this statement was not fully supported by CHMP, considering the low concentration tested and the applicant was asked to justify the concentration of cefiderocol used for the secondary pharmacology screen, also in the context of the convulsions seen in the repeat dose toxicity studies in rats.”
“Whilst using a higher concentration of the drug in the secondary pharmacology screen would seem to have been more appropriate, taking into account the absence of secondary pharmacology targets identified in the already conducted screen and the clinical safety profile to date, CHMP agreed that the issue did not need to be further pursued.”
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