Zurzuvae
zuranolone
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The toxicologic and toxicokinetic (TK) profile of orally administered zuranolone was assessed in a series of single and repeat dose studies in rats and dogs for up to 6 and 9 months, respectively.”
Why that species
Metabolite coverage: all human metabolites above 1% also detected in rat or dog plasma
“All human metabolites detected at greater than 1% of drug, were also detected in rat or dog plasma.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the pivotal 9-month study in dogs (0, 0.6, 1.2 and 2.5 mg/kg), sedation, sedation-related clinical signs (impaired equilibrium, hypoactivity, ataxia, tremors, and being prostrate) and increased heart rate and mortality were observed.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“In the pivotal 9-month study in dogs (0, 0.6, 1.2 and 2.5 mg/kg), sedation, sedation-related clinical signs (impaired equilibrium, hypoactivity, ataxia, tremors, and being prostrate) and increased heart rate and mortality were observed.”
Pivotal GLP studies
6-month rat and 9-month dog oral studies
“Dose selection for the 6- and 9-month toxicology studies in rat and dog was based on the results of shorter-duration studies that identified clear dose-limiting toxicity, including premature death and adverse clinical signs (e.g., sedation, convulsions).”
Route in tox
Oral gavage
“The toxicological assessment is based on in single and repeated dose oral (gavage) toxicity studies in rats and dogs, in vitro and in vivo genotoxicity tests, reproduction and developmental toxicity studies in rabbits and/or rats, juvenile toxicity studies using rats, carcinogenicity studies in rats and transgenic mice, and studies to assess abuse liability and dependence potential.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and rat bone marrow micronucleus assays
“Zuranolone was negative in Ames, in vitro chromosomal aberration, and rat bone marrow micronucleus assays.”
Carcinogenicity
6-month Tg.rasH2 mouse and 2-year rat: negative for drug-induced tumors
“The carcinogenic potential of zuranolone was tested in a 6-month Tg.rasH2 transgenic mouse assay and in a 2-year rat carcinogenicity study. Both studies were adequately conducted and, according to the Food and Drug Administration (FDA) statistical analyses, negative for drug-induced tumors.”
Reproductive & developmental
Rat EFD: malformations (exencephaly, tail, eye lens, vertebral/rib) at the high dose
“Malformations were observed in 10 HD pups (5 litters): exencephaly (1 fetus), absent tail (2 littermates), short thread-like tail and/or malformation of the sacral and caudal vertebrae (2 littermates), umbilical hernia and depressed eye bulges (1 fetus), absent or small lens of the eye (2 littermates) and vertebral/rib malformations (2 littermates).”
Safety pharmacology
Full CNS, cardiovascular, respiratory and ion-channel battery; hERG IC20 2.43 µM, ~10x human Cmax
“A complete battery of safety pharmacology studies (CNS, cardiovascular, respiratory, hERG channel, and cardiac ion channel assays) was conducted. In the in vitro hERG assay, the IC20 for inhibition by zuranolone was 2.43µM, which is approximately 10 times the human steady-state maximum plasma concentration (Cmax).”
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 Zurzuvae 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: Deaths and sedation; rat NOAEL 10 (M)/1.5 (F) mg/kg, 3x and 2x MRHD exposure (FDA integrated review, p. 158)
NOAEL / key findings
Deaths and sedation; rat NOAEL 10 (M)/1.5 (F) mg/kg, 3x and 2x MRHD exposure
“The safety margin at the NOAEL in males (10 mg/kg) and females (1.5 mg/kg) based on deaths and sedation was 3 and 2 times, respectively, relative to the exposure at the maximum recommended human dose (MRHD) of 50 mg.”
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
High brain penetration; brain:plasma ratio 2.23 (mouse) and 3.22 (rat)
“The brain to plasma ratio of zuranolone was 2.23 after IP injection (1 mg/kg) (SSN-868) in male mice and 3.22 (Study No. SSN-01237) after oral administration in male rats.”
Modality-specific risk
CNS: convulsions and deaths in dogs, including after dosing stopped
“Deaths, convulsions, and increased severity of clinical signs occurred in some dogs prior to a scheduled daily dose or some period after the previous dose (e.g., during a dosing holiday or recovery period after the end of dosing).”