Zulresso
brexanolone
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
“General toxicology studies with up to 28-days of continuous IV administration in two species (rat and dog) were conducted to support acute use of brexanolone.”
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
“Sedative anesthesia was observed rapidly after single bolus IV doses of brexanolone in rats and dogs at 0.75- and 2-times, respectively, the MRHD based on body surface area, which were the lowest doses tested.”
Study lengthopen answer page →
Longest pivotal study
4 weeks
“General toxicology studies with up to 28-days of continuous IV administration in two species (rat and dog) were conducted to support acute use of brexanolone.”
Pivotal GLP studies
28-day continuous IV infusion studies in rat and dog
“General toxicology studies with up to 28-days of continuous IV administration in two species (rat and dog) were conducted to support acute use of brexanolone.”
Route in tox
Continuous intravenous infusion
“General toxicology studies with up to 28-days of continuous IV administration in two species (rat and dog) were conducted to support acute use of brexanolone.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte micronucleus and in vivo rat bone marrow micronucleus assays
“Brexanolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes, and an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (acute treatment of PPD)
“Brexanolone was not assessed for carcinogenicity because the treatment of PPD with brexanolone infusion is considered acute.”
Reproductive & developmental
Rat and rabbit EFD: no malformations up to 5-6x MRHD; developmental toxicity at 5x (rat) and >=3x (rabbit)
“In animal reproduction studies, malformations were not seen in rats or rabbits at plasma levels up to 5 and 6 times the maximum recommended human dose (MRHD), respectively. Developmental toxicities were seen in the fetuses of rats and rabbits at 5 and ≥3 times the plasma levels at the MRHD, respectively.”
Safety pharmacology
CNS (rat FOB) and cardiovascular/respiratory (dog) endpoints embedded in 14-day toxicology studies
“CNS safety pharmacology was evaluated as part of the 14-day rat toxicology study using a Functional Observation Battery (FOB). Cardiovascular and respiratory safety pharmacology was evaluated as part of the 14-day dog toxicology study”
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 Zulresso 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: Rat IV infusion NOAEL 60 mg/kg/day (5x human exposure at MRHD) (FDA multi-discipline review, p. 46)
NOAEL / key findings
Rat IV infusion NOAEL 60 mg/kg/day (5x human exposure at MRHD)
“NOAEL is 60 mg/kg/day based on the absence of adverse effects at this dose, which is 5- times the human exposure”
Risksopen answer page →
Immune & cytokine safety
No dermal irritation, skin sensitization or hemolytic potential
“In addition, brexanolone showed no sign of dermal irritation, skin sensitization, or hemolytic potential.”
Biodistribution & persistence
CNS tissue radioactivity above blood levels; low levels in testis
“Radioactivity concentrations were observed in CNS tissues at higher than blood concentrations and in testis at low levels.”
Modality-specific risk
Post-infusion convulsions in dogs, possibly from abrupt discontinuation of GABA-A modulation
“It is possible that the convulsions could be due to the rapid discontinuation of brexanolone, which is consistent with modulation of the GABAA receptor”