Zaynich
cefepime and zidebactam
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
“The nonclinical safety profile of intravenous zidebactam was extensively explored in single- and repeated-dose toxicology studies (a 1-month toxicology study in rats, a 1-month combination toxicology study in dogs and a 13-week toxicology study in 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; zidebactam was tested alone and with cefepime
“WCK 5107-related liver enzyme increases were not exacerbated by coadministration with cefepime.”
Species: general tox
Rat (1-month) and dog (1-month combination with cefepime; 13-week), zidebactam IV
“The nonclinical safety profile of intravenous zidebactam was extensively explored in single- and repeated-dose toxicology studies (a 1-month toxicology study in rats, a 1-month combination toxicology study in dogs and a 13-week toxicology study in dogs)”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD), zidebactam
“reproductive and developmental toxicity studies including fertility studies in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre-postnatal developmental toxicity study in rats”
Species: carcinogenicity
Not conducted
“Long-term carcinogenicity studies have not been performed with cefepime or zidebactam.”
Surrogate used in
No surrogate used; zidebactam tested alone and with cefepime
“WCK 5107-related liver enzyme increases were not exacerbated by coadministration with cefepime.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week dog)
“13-Week Repeat Intravenous Dose Toxicity and Toxicokinetic Study of Zidebactam (WCK 5107) with a 4-Week Recovery Period in Beagle Dogs”
Pivotal GLP studies
1-month rat, 1-month dog combination (with cefepime) and 13-week dog studies of zidebactam
“The nonclinical safety profile of intravenous zidebactam was extensively explored in single- and repeated-dose toxicology studies (a 1-month toxicology study in rats, a 1-month combination toxicology study in dogs and a 13-week toxicology study in dogs)”
Route in tox
Intravenous
“Route of administration: Intravenous Formulation/Vehicle: 0.9% sodium chloride solution”
Skipped studiesopen answer page →
Genotoxicity
Zidebactam negative in mouse lymphoma, human lymphocyte chromosomal aberration and mouse micronucleus assays
“Zidebactam was negative for genetic toxicity in vitro in a mutagenicity assay in mouse lymphoma cells, and a chromosomal aberration assay in human peripheral blood lymphocytes, and in vivo in a mouse micronucleus assay in bone marrow cells.”
Carcinogenicity
Not conducted for cefepime or zidebactam
“Long-term carcinogenicity studies have not been performed with cefepime or zidebactam.”
Reproductive & developmental
Zidebactam rabbit EFD: late resorptions and fetal loss at 600 mg/kg/day; distended fetal bladder at ≥300 mg/kg/day (about 3 times RHD)
“In pregnant rabbits, intravenous administration of zidebactam during organogenesis was associated with increased late fetal resorptions and total fetal loss in two litters at a dose of 600 mg/kg/day (approximately 5 times the RHD) and distended bladder, a fetal anomaly, at zidebactam doses greater than or equal to 300 mg/kg/day (approximately 3 times the RHD).”
Safety pharmacology
Telemetered dogs: no heart rate, blood pressure or ECG interval changes at 300 mg/kg zidebactam alone or with cefepime
“None of the infusions of 300 mg/kg WCK 5107 (zidebactam), 300 mg/kg cefepime, or the combination doses of cefepime plus WCK 5107 (300 mg/kg cefepime + 300 mg/kg WCK 5107 and 300 mg/kg cefepime + 150 mg/kg WCK 5107) induced changes in heart rate or arterial blood pressure or changes in any of the cardiac intervals compared to the control group in conscious male and female Beagle dogs.”
Genotox: Ames
Zidebactam not mutagenic at the low concentrations testable (antibacterial activity limited concentrations)
“WCK 5107 was not mutagenic in the test assay conditions with and without metabolic activation in concentrations of 0.015 mg/ml for TA98, 0.05 mg/ml for TA100, 0.015 mg/ml for TA1535, and 14.9 mg/ml for the TA1537 and WP2 uvrA strains.”
Genotox: in vitro mammalian
Zidebactam: mouse lymphoma mutation and human lymphocyte chromosomal aberration assays negative
“Zidebactam was negative for genetic toxicity in vitro in a mutagenicity assay in mouse lymphoma cells, and a chromosomal aberration assay in human peripheral blood lymphocytes, and in vivo in a mouse micronucleus assay in bone marrow cells.”
Genotox: in vivo
Zidebactam: mouse bone marrow micronucleus negative
“Zidebactam was negative for genetic toxicity in vitro in a mutagenicity assay in mouse lymphoma cells, and a chromosomal aberration assay in human peripheral blood lymphocytes, and in vivo in a mouse micronucleus assay in bone marrow cells.”
Carcinogenicity model
Not conducted for cefepime or zidebactam
“Long-term carcinogenicity studies have not been performed with cefepime or zidebactam.”
Carcinogenicity timing
Not conducted for cefepime or zidebactam; no reason given
“Long-term carcinogenicity studies have not been performed with cefepime or zidebactam.”
hERG / QT
Zidebactam hERG IC50 >1461 µM (<10% inhibition); no additive inhibition with cefepime
“However, none of the tested concentrations of WCK 5107 including the high concentration of 1461 mcM produced greater than 10% channel inhibition. Consequently, the IC50 value could only be estimated to be > 1461 mcM WCK 5107.”
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 Zaynich 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: Minimal kidney proximal tubule necrosis/regeneration in dogs at 500 and 1000 mg/kg/day (FDA integrated review, p. 257)
NOAEL / key findings
Minimal kidney proximal tubule necrosis/regeneration in dogs at 500 and 1000 mg/kg/day
“Minimal necrosis and/or regeneration in kidney proximal tubule cells was observed in mid- and high-dose males and female dogs receiving 500 and 1000 mg/kg/day WCK 5107 (zidebactam).”
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: highest concentrations in kidney, plasma and urinary bladder wall
“Distribution: 100 mg/kg [14C]-WCK 5107, administered intravenously, distributed in the highest concentrations (> 200 to 4420 mcg equivalents/g tissue) to kidney (medulla and inner and outer cortex), plasma, and urinary bladder wall.”
Modality-specific risk
Renal tubular toxicity, with exposure margins of 2.7 (males) and 2.3 (females) in dogs
“The exposure margins for the lowest zidebactam dose associated with renal tubular histopathology relative to the recommended clinical dose of zidebactam (1 g administered every 8 hours) are 2.7 and 2.3 for male and female dogs respectively based on plasma AUC exposure (Table 1).”
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
- Neurotoxicity
- Clostridioides difficileInfection
- Positive Direct Coombs’ Tests
- Prolonged Prothrombin Time
- Development of Drug-Resistant Bacteria
- Interactions with Urine Glucose Testing
Hypersensitivity & infusion reactionsNeurotoxicityInfections
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; first-in-human single ascending dose study of zidebactam alone and with cefepime in healthy volunteers
“The study was a phase 1, first-in-human, randomized, placebo-controlled, double-blinded, single-site, sequential Cohort design in healthy subjects.”
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 Zaynich 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: Minimal kidney proximal tubule necrosis/regeneration in dogs at 500 and 1000 mg/kg/day (FDA integrated review, p. 257)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week intravenous zidebactam study in beagle dogs with 4-week recovery
“13-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of Zidebactam (WCK 5107) with a 4-Week Recovery Period in Beagle Dogs.”
Pivotal GLP studies
1-month rat, 1-month dog combination (with cefepime) and 13-week dog studies of zidebactam
“The nonclinical safety profile of intravenous zidebactam was extensively explored in single- and repeated-dose toxicology studies (a 1-month toxicology study in rats, a 1-month combination toxicology study in dogs and a 13-week toxicology study in dogs)”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD), zidebactam
“reproductive and developmental toxicity studies including fertility studies in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre-postnatal developmental toxicity study in rats”
Reproductive & developmental
Zidebactam rabbit EFD: late resorptions and fetal loss at 600 mg/kg/day; distended fetal bladder at ≥300 mg/kg/day (about 3 times RHD)
“In pregnant rabbits, intravenous administration of zidebactam during organogenesis was associated with increased late fetal resorptions and total fetal loss in two litters at a dose of 600 mg/kg/day (approximately 5 times the RHD) and distended bladder, a fetal anomaly, at zidebactam doses greater than or equal to 300 mg/kg/day (approximately 3 times the RHD).”
PPND / ePPND: when
Rat PPND (zidebactam, IV) completed and reviewed with the marketing application
“The study report for a WCK 5107 (zidebactam) pre-postnatal study in rats is reviewed below.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Long-term carcinogenicity studies have not been performed with cefepime or zidebactam.”
Carcinogenicity model
Not conducted for cefepime or zidebactam
“Long-term carcinogenicity studies have not been performed with cefepime or zidebactam.”
Carcinogenicity timing
Not conducted for cefepime or zidebactam; no reason given
“Long-term carcinogenicity studies have not been performed with cefepime or zidebactam.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog 13-week renal NOAEL (250 mg/kg/day zidebactam): 1.1-1.3x human AUC
“NOAEL =250 Male 607 1.3 Female 484 1.1”
NOAEL / key findings
Minimal kidney proximal tubule necrosis/regeneration in dogs at 500 and 1000 mg/kg/day
“Minimal necrosis and/or regeneration in kidney proximal tubule cells was observed in mid- and high-dose males and female dogs receiving 500 and 1000 mg/kg/day WCK 5107 (zidebactam).”
Efficacy evidenceopen answer page →
Efficacy evidence
Neutropenic mouse lung, thigh and cUTI infection models with human-simulated regimens
“The activity of cefepime/zidebactam was evaluated using three models: neutropenic lung, neutropenic thigh, and cUTI mouse models.”
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: no consistent bacterial reduction for isolates with MIC ≥32 µg/mL; activity may be inconsistent against them
“For isolates with MIC ≥32 µg/mL, there was no consistent significant change from baseline, as some of the isolates did not show any change from baseline, suggesting that cefepime/zidebactam may not have consistent activity against isolates with an MIC of ≥32 µg/mL”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityCriticised but acceptedBeyond the letter
Bacterial reverse mutation assay of a (redacted) test article limited to low concentrations because of antibacterial cytotoxicity
Why: Antibacterial activity and cytotoxicity in bacterial lawns made the deficiency unavoidable · Pharmacology or kinetics
“exhibited antibacterial activity and produced cytotoxicity in bacterial lawns in concentrations of ≥ mcg/plate. As a consequence, only low concentrations of could be tested in this assay, and the mutagenicity potential of higher concentrations were not assessed.”
“An unavoidable deficiency in this study is that high concentrations of up to a limit of mcg/plate, were not assessed.”
DARTVerdict not stated
Rat pre-/postnatal study learning and memory test indeterminate: atypical M-maze not validated with a positive control
“However, the M-maze employed in the assessment was of an atypical design, and the methods were not validated with a positive control compound. Consequently, the test results were considered to be indeterminate due to limitations in the study design.”
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