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.”
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.”
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.”