Quviviq
daridorexant
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
“repeat dose general toxicology studies in the mouse for up to 28 days, rat for up to 26 weeks, and dog for up to 39 weeks”
Why that species
Orexin receptor binding with high potency, human-like metabolic pathways and partly similar plasma protein binding
“Species selection was based on pharmacologically relevant binding to Orexin receptors in humans and in these non-clinical species with high selectivity and potency, metabolically relevant pathways in these species are similar to those in humans, as well as close plasma protein binding properties for some species only.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In Beagle dogs were administered 10, 30, or 100mg/kg/day Daridorexant for 39 consecutive weeks”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“repeat dose general toxicology studies in the mouse for up to 28 days, rat for up to 26 weeks, and dog for up to 39 weeks”
Pivotal GLP studies
26-week rat and 39-week dog oral gavage studies, each with 8-week recovery
“Toxicity Study by the Oral (Gavage) Route in the Beagle Dog Followed by an 8-Week Treatment-Free Period (Study T-16.017)”
Route in tox
Oral (gavage)
“Toxicity Study by the Oral (Gavage) Route in the Beagle Dog Followed by an 8-Week Treatment-Free Period”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (human lymphocytes) and in vivo rat micronucleus assays
“Daridorexant was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or in the in vitro mammalian chromosome aberration assay in human lymphocytes and was not clastogenic in the in vivo rat micronucleus assay.”
Carcinogenicity
2-year rat and 26-week Tg.rasH2 mouse: no increase in tumors
“Daridorexant did not increase the incidence of tumors in rats treated for 2 years at oral doses of 15, 50, and 150 mg/kg/day. The high dose of 150 mg/kg/day is approximately 4 times the MRHD of 50 mg, based on AUC. Daridorexant did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks”
Reproductive & developmental
Rat and rabbit EFD: no effects on embryo-fetal survival and no malformations
“Embryo-fetal development toxicity studies were conducted in rats and rabbits. Treatment-related effects on embryo-foetal survival or foetal malformations were not reported in any species.”
Safety pharmacology
Weak hERG inhibition (IC50 25 µM); no adverse CNS, cardiovascular or respiratory effects at relevant levels
“In an in vitro hERG assay (Study T-14.012, GLP), daridorexant induced weak inhibition of the potassium current with an IC20 of 7.4µM (~3400 ng/mL) and IC50 of 25µM (~11500 ng/mL), respectively.”
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 Quviviq 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: 39-week dog NOAEL 10 mg/kg/day, based on cataplexy-like signs and increased liver enzymes (FDA integrated review, p. 179)
NOAEL / key findings
39-week dog NOAEL 10 mg/kg/day, based on cataplexy-like signs and increased liver enzymes
“Based on the cataplexy-like clinical signs and increased liver enzyme levels, the NOAEL is considered to be 10 mg/kg/day in both males and females in the 39-week dog study.”
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 QWBA: no accumulation in uveal tract, pigmented skin or meninges; no melanin binding
“There was no significant distribution/accumulation of radioactivity in the uveal tract/retina, pigmented skin, or meninges of the brain, suggesting that daridorexant does not bind to melanin.”
Modality-specific risk
Cataplexy-like signs in dogs from exaggerated orexin receptor antagonism
“The cataplexy-like effects at higher doses in the dog are due to the exaggerated pharmacology of orexin receptor antagonists.”