Xacduro
sulbactam and durlobactam
Sources:FDA integrated review ↗
Species
RatMouseDog
Longest study
4 wk
Genotox
Conducted Conducted
Carcinogenicity
Not stated Not stated
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog (mouse for embryo-fetal development)
“Pivotal nonclinical studies were conducted in rats, mice and dogs.”
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 compound was tested
“Repeated intravenous dosing of sulbactam-durlobactam in rats for 28 days resulted in reversible perivascular inflammation and thrombus at the injection site”
Species: general tox
Rats, mice and dogs (pivotal nonclinical studies)
“Pivotal nonclinical studies were conducted in rats, mice and dogs.”
Species: DART
Rat (fertility and EFD, durlobactam IV)
“ETX2514: Intravenous (Infusion) Study of Fertility and Embryo-Fetal Development in the Rat, Study PC2514-2017-0019”
Species: carcinogenicity
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.
Surrogate used in
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.
Study lengthopen answer page →
Longest pivotal study
4 (28-day dog)
“A 28-Day Study of ETX2514 by Intravenous Infusion in Beagle Dogs With a 28-Day Recovery Period.”
Pivotal GLP studies
28-day intravenous sulbactam-durlobactam study in rats
“Repeated intravenous dosing of sulbactam-durlobactam in rats for 28 days resulted in reversible perivascular inflammation and thrombus at the injection site”
Route in tox
Intravenous infusion
“Repeated intravenous dosing of sulbactam-durlobactam in rats for 28 days resulted in reversible perivascular inflammation and thrombus at the injection site”
Skipped studiesopen answer page →
Genotoxicity
Durlobactam negative in in vivo rat micronucleus assay up to 2000 mg/kg
“Durlobactam did not induce statistically significant increases in micronucleated PCEs at any test article dose up to 2000 mg/kg.”
Carcinogenicity
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.
Reproductive & developmental
Durlobactam rat fertility/EFD study: no toxicologically significant effects up to 3x clinical AUC
“At doses up to 3 times the maximum recommended dose based on AUC comparisons, there were no toxicologically significant drug-related effects of durlobactam in pups born to rats dosed for 2 weeks prior to pairing, during pairing, and up to gestation Day 17.”
Safety pharmacology
No safety signals in safety pharmacology studies; no potent secondary pharmacology activity
“There were no safety signals observed in safety pharmacology studies. Secondary pharmacology data did not reveal any potent activity among 192 pharmacology receptors/enzymes evaluated.”
Genotox: Ames
Durlobactam Ames invalid: toxicity precluded testing above 5 µg/plate
“The study is not considered to be a valid assessment of the mutagenicity of durlobactam, since toxicity precluded testing of the strains at doses above 5 μg/plate.”
Genotox: in vitro mammalian
Durlobactam human peripheral blood lymphocyte micronucleus: negative
“Durlobactam was negative for inducing micronuclei in cultured human peripheral blood lymphocytes with or without metabolic activation.”
Genotox: in vivo
Durlobactam rat bone marrow micronucleus: negative up to 2000 mg/kg
“Durlobactam did not induce statistically significant increases in micronucleated PCEs at any test article dose up to 2000 mg/kg.”
Carcinogenicity 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.
Carcinogenicity timing
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.
hERG / QT
Durlobactam caused <50% inhibition of hERG and other cardiac ion channels in vitro
“Durlobactam did not cause >50% mean inhibitory effect in any of these systems.”
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 Xacduro 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: Dog IV study: NOAEL not determined (prostate findings at lowest dose); prostate and testes weight changes did not reverse (FDA integrated review, p. 97)
NOAEL / key findings
Dog IV study: NOAEL not determined (prostate findings at lowest dose); prostate and testes weight changes did not reverse
“A no observed adverse effect level (NOAEL) could not be determined because of prostate findings at the lowest dose, but changes reversed by the end of dosing except for prostate and testes weights.”
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: low brain and spinal cord levels (tissue/blood <0.1); no blood-brain barrier penetration
“Concentrations in the brain and spinal cord were low throughout with tissue/blood ratios of <0.1, indicating that test material-related radioactivity had not penetrated the blood-brain barrier.”
Modality-specific risk
No specific or serious nonclinical safety concern identified
“No specific or serious safety concern was identified based on nonclinical data.”
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
- Hypersensitivity Reactions
- Clostridioides difficile-Associated Diarrhea (CDAD)
- Development of Drug-Resistant Bacteria
Hypersensitivity & infusion reactionsGastrointestinal
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 Xacduro 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: Dog IV study: NOAEL not determined (prostate findings at lowest dose); prostate and testes weight changes did not reverse (FDA integrated review, p. 97)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
28-day IV infusion dog study (durlobactam) with 28-day recovery; a 28-day rat study ties
“Study Title/Number: A 28-Day Study of ETX2514 by Intravenous Infusion in Beagle Dogs With a 28-Day Recovery Period. Study PC2514-2020-0001”
Pivotal GLP studies
28-day intravenous sulbactam-durlobactam study in rats
“Repeated intravenous dosing of sulbactam-durlobactam in rats for 28 days resulted in reversible perivascular inflammation and thrombus at the injection site”
DART package
Species: DART
Rat (fertility and EFD, durlobactam IV)
“ETX2514: Intravenous (Infusion) Study of Fertility and Embryo-Fetal Development in the Rat, Study PC2514-2017-0019”
Reproductive & developmental
Durlobactam rat fertility/EFD study: no toxicologically significant effects up to 3x clinical AUC
“At doses up to 3 times the maximum recommended dose based on AUC comparisons, there were no toxicologically significant drug-related effects of durlobactam in pups born to rats dosed for 2 weeks prior to pairing, during pairing, and up to gestation Day 17.”
PPND / ePPND: when
PPND in rat (durlobactam IV, GLP) completed before the marketing application
“Study Information for GLP Pre- and Post-Natal Development Study of ETX2514 by the Intravenous Route (2-Hour Infusion) in the Rat (Segment III), Study PC2514-2019-0004”
Carcinogenicity
Species: carcinogenicity
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.
Carcinogenicity 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.
Carcinogenicity timing
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.
Safety marginopen answer page →
Safety margin at NOAEL
Durlobactam rat male fertility study: NOAEL 1000 mg/kg/day ~3x clinical AUC
“The NOAEL for male fertility was 1000 mg/kg/day (1220 μg*h/mL), about 3 times the clinical exposure based on the area under the concentration-time curve (AUC)”
NOAEL / key findings
Dog IV study: NOAEL not determined (prostate findings at lowest dose); prostate and testes weight changes did not reverse
“A no observed adverse effect level (NOAEL) could not be determined because of prostate findings at the lowest dose, but changes reversed by the end of dosing except for prostate and testes weights.”
Efficacy evidenceopen answer page →
Efficacy evidence
Neutropenic murine thigh and lung (pneumonia) infection models with MDR A. baumannii
“The Applicant conducted several studies examining the nonclinical pharmacokinetics (PK)/ pharmacodynamics (PD) of sulbactam-durlobactam in murine thigh and pneumonia models of MDR ABC infection.”
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: PTA analyses using the PK/PD targets support the 1 g sulbactam/1 g durlobactam dose
“PTA analyses for both plasma and ELF exposures using these PK/PD targets support the clinical dose selection of 1g sulbactam and 1 g durlobactam.”
Flexibilityopen answer page →
Flexibility accepted
Juvenile toxAccepted with a conditionBeyond the letter
Repeat-dose juvenile toxicity study (to inform dosing from birth to under one year) still ongoing at approval; completion under a postmarketing commitment
Why: Pediatric studies deferred until adult efficacy and safety demonstrated · Other reason
“Also, a repeat dose juvenile toxicity study is ongoing to inform dosing in patients from birth to less than1 year of age. A postmarketing commitment for the study completion and final report submission dates will be issued upon approval.”
“The Applicant submitted a pediatric study plan along with a request for a deferral of pediatric studies in all age groups until efficacy and safety have been demonstrated in the adult population.”
OtherVerdict not stated
Limited in vivo nonclinical pharmacokinetic data for sulbactam
“Few details of in vivo nonclinical pharmacokinetics of sulbactam were provided.”
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