Nuzolvence
zoliflodacin
Species
RatDog
Longest study
4 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
“toxicology studies (repeat-dose studies in rats [up to 4 weeks] and dogs [up to 4 weeks])”
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
“Treatment with AZ13420914 was associated with increased heart rate (all groups), but not QTc prolongation.”
Species: general tox
Rat and dog
“toxicology studies (repeat-dose studies in rats [up to 4 weeks] and dogs [up to 4 weeks])”
Species: DART
Rat (male fertility, female fertility/EFD, pre/postnatal) and mouse (EFD)
“Reproductive toxicology studies with zoliflodacin included a male rat fertility study, a female rat fertility and embryo-fetal development (FEFD) study, a mouse embryo-fetal development (EFD) study, and a rat pre- and postnatal development study.”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies have not been conducted with zoliflodacin.”
Surrogate used in
No surrogate used; zoliflodacin itself tested in rats and dogs
“Nonclinical safety studies submitted to support the safety evaluation of zoliflodacin included pharmacology studies (primary, secondary, and safety pharmacology), pharmacokinetics studies”
Study lengthopen answer page →
Longest pivotal study
4 (4-week rat and dog)
“toxicology studies (repeat-dose studies in rats [up to 4 weeks] and dogs [up to 4 weeks])”
Pivotal GLP studies
Up to 4-week repeat-dose studies in rats and dogs
“toxicology studies (repeat-dose studies in rats [up to 4 weeks] and dogs [up to 4 weeks])”
Route in tox
Oral gavage
“Study 523980/AZ13420914: One Month Oral (Gavage) Toxicity Study With a Three Month Assessment of Recovery in the Rats (Good Laboratory Practice)”
Skipped studiesopen answer page →
Genotoxicity
Negative in mouse lymphoma and rat micronucleus assays; Ames positive in TA102, consistent with mechanism
“Zoliflodacin was not genotoxic in the mouse lymphoma assay (MLA) and rat in vivo micronucleus assay. In the Ames bacterial reverse mutation assay, zoliflodacin was mutagenic in the TA102 strain, consistent with its pharmacologic action as a bacterial topoisomerase II inhibitor.”
Carcinogenicity
Not conducted
“Carcinogenicity studies have not been conducted with zoliflodacin.”
Reproductive & developmental
Mouse EFD: exencephaly (neural tube malformation) at 500 and 1000 mg/kg/day
“In the mouse EFD study, exencephaly, a neural tube malformation, was present in litters in the 500 and 1000 mg/kg/day groups at levels above current and historical control rates.”
Safety pharmacology
Decreased blood pressure, increased heart rate and contractility in dogs/guinea pigs; no arrhythmias or adverse QTc prolongation
“In a safety pharmacology study in dogs, an oral 4-week repeat dose toxicity study in dogs, and an intravenous (IV) study in anesthetized guinea pigs, other reported cardiac effects included decreased blood pressure, increased heart rate, increase in cardiac contractility, and decreased cardiac relaxation. No arrhythmias or adverse QTc prolongation were detected in the IV-infusion safety pharmacology study in dogs.”
Genotox: Ames
Positive in TA102 (with/without S9), consistent with bacterial topoisomerase II inhibition; negative in other strains
“AZ13420914 was mutagenic in S. typhimurium strain TA102 ± rat S9 under the conditions of this assay. Mutagenicity was not observed in TA98, TA100, TA1535 or TA1537.”
Genotox: in vitro mammalian
Mouse lymphoma assay: negative
“Under the conditions of this assay, AZD0914 was not mutagenic or clastogenic to mouse lymphoma L5178Y cells regardless of metabolic activation with rat S9.”
Genotox: in vivo
Rat bone marrow micronucleus: negative up to 500 mg/kg/day
“AZD0914 did not induce micronuclei in immature erythrocytes in the bone marrow of male Wistar Han rats after 2 daily consecutive oral doses up to 500 mg/kg/day and is therefore not clastogenic in vivo.”
Carcinogenicity model
Not conducted
“Carcinogenicity studies have not been conducted with zoliflodacin.”
Carcinogenicity timing
No carcinogenicity studies conducted
“Carcinogenicity studies have not been conducted with zoliflodacin.”
hERG / QT
hERG IC50 449 µM, about 8-fold clinical Cmax; no adverse QTc prolongation in dogs
“In an in vitro human ether-a-go-go related gene (hERG) study, zoliflodacin inhibited hERG currents in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 449µM, which is about 8-fold higher than the Cmax calculated from clinical 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 Nuzolvence 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 NOAEL 100 mg/kg/day; reduced RBC parameters, increased bilirubin and testicular degeneration at 200 mg/kg/day (FDA integrated review, p. 131)
NOAEL / key findings
Dog NOAEL 100 mg/kg/day; reduced RBC parameters, increased bilirubin and testicular degeneration at 200 mg/kg/day
“The NOAEL in this study was the low dose of 100 mg/kg/day, based on the reduced RBC parameters, increased bilirubin, and testicular degeneration seen in the mid dose group (200 mg/kg/day).”
Risksopen answer page →
Immune & cytokine safety
One male dog at 500 mg/kg/day euthanized with marked necrosis and inflammation of ileum and gut-associated lymphoid tissue
“One male dog administered 500 mg/kg/day AZ13420914 was euthanized early for low feed consumption and body weight loss. The cause of morbidity in this animal appeared to be due to marked necrosis and inflammation of the ileum and gut-associated lymphoid tissue.”
Biodistribution & persistence
Highest in kidney and liver in rats; no preferential distribution to pigmented tissues
“In an IV dosed tissue distribution study with radiolabeled zoliflodacin in rats, the highest levels were detected in kidneys and liver, and the zoliflodacin concentration was not higher in pigmented tissues.”
Modality-specific risk
Male reproductive toxicity: complete infertility in male rats at 1000 mg/kg/day (8-fold the MRHD exposure)
“In male rats, once daily oral administration of zoliflodacin for 4 weeks resulted in dose-related effects on fertility. At 1000 mg/kg/day (exposures 8-fold the MRHD based on AUC), males were completely infertile.”
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
- Embryo-Fetal Toxicity: Potential Risk for Pregnant Females
- Embryo-Fetal Toxicity: Potential Risk Related to Males with Female Partners of Reproductive Potential
- Testicular Toxicity and Risks to Male Fertility
- Hypersensitivity Reactions
- Clostridioides difficile Infection
- Development of Drug-Resistant Bacteria
Embryo-fetal toxicityHypersensitivity & infusion reactionsInfections
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 Nuzolvence 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 NOAEL 100 mg/kg/day; reduced RBC parameters, increased bilirubin and testicular degeneration at 200 mg/kg/day (FDA integrated review, p. 131)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week rat and 4-week dog (oral), each with 3-month recovery
“histopathology assessments in a 4-week repeat dose rat study with a 3-month recovery period, histopathology assessments in a 4-week repeat dose dog study with a 3-month recovery period”
Pivotal GLP studies
Up to 4-week repeat-dose studies in rats and dogs
“toxicology studies (repeat-dose studies in rats [up to 4 weeks] and dogs [up to 4 weeks])”
DART package
Species: DART
Rat (male fertility, female fertility/EFD, pre/postnatal) and mouse (EFD)
“Reproductive toxicology studies with zoliflodacin included a male rat fertility study, a female rat fertility and embryo-fetal development (FEFD) study, a mouse embryo-fetal development (EFD) study, and a rat pre- and postnatal development study.”
Reproductive & developmental
Mouse EFD: exencephaly (neural tube malformation) at 500 and 1000 mg/kg/day
“In the mouse EFD study, exencephaly, a neural tube malformation, was present in litters in the 500 and 1000 mg/kg/day groups at levels above current and historical control rates.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In a pre- and postnatal development study, gravid female rats were administered 0, 50, 100, or 200 mg/kg/day zoliflodacin by oral gavage from GD 6 until weaning on lactation day 20.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies have not been conducted with zoliflodacin.”
Carcinogenicity model
Not conducted
“Carcinogenicity studies have not been conducted with zoliflodacin.”
Carcinogenicity timing
No carcinogenicity studies conducted
“Carcinogenicity studies have not been conducted with zoliflodacin.”
Safety marginopen answer page →
Safety margin at NOAEL
4-week oral rat NOAEL 200 mg/kg/day ~3x MRHD AUC
“4-week oral rat 200 1075 [3]”
NOAEL / key findings
Dog NOAEL 100 mg/kg/day; reduced RBC parameters, increased bilirubin and testicular degeneration at 200 mg/kg/day
“The NOAEL in this study was the low dose of 100 mg/kg/day, based on the reduced RBC parameters, increased bilirubin, and testicular degeneration seen in the mid dose group (200 mg/kg/day).”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro hollow fiber infection model (HFIM) with N. gonorrhoeae strains WHO-F and WHO-X; no animal infection studies
“Dose ranging and dose fractionation studies in HFIM showed that single doses ranging from 2 g to 8 g successfully eradicated N. gonorrhoeae reference strains WHO-F and WHO-X.”
Why that model
N. gonorrhoeae is a human-specific pathogen; animal infection models are unreliable
“Neisseria gonorrhoeae is a human specific pathogen that grows poorly in nonhumans. As such, animal models (mouse, rabbit, guinea pig, hamster, chimpanzees etc.) are unreliable models of N. gonorrhoeae infection.”
Reviewer's view of the efficacy data
FDA considered dosage supported by phase 2 data and by PTA analyses based on the nonclinical (HFIM) PK-PD target
“Additionally, the proposed dosage was supported by the safety and efficacy data from the phase 2 trial (DMID 14-0014) as well as the PTA analyses based on the nonclinical PK-PD target.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted with a conditionBeyond the letter
No sperm count or viability analyses in animals despite testicular toxicity and incomplete reversibility of epididymal findings
Why: Postmarketing human sperm study recommended to evaluate sperm count and viability
“While the fertility in the rats recovered after a 4-week recovery period, there was incomplete reversibility of the histopathology in the epididymides in rats and dogs. Analyses of sperm count and viability have not been conducted in animals or humans.”
“The review team has also recommended a postmarketing sperm study in humans to evaluate sperm count and viability following treatment with zoliflodacin.”
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