Qelbree
viloxazine
Species
RatDog
Longest study
78 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“There are substantial species differences in the metabolism of viloxazine between the nonclinical species (rats and dogs) and humans.”
Why that species
Parent drug and major human metabolite exposures adequately represented in rat despite metabolic differences
“It should be noted that despite the differences in the metabolic profiles, the exposure level to both the parent drug and its major human metabolite (glucuronidated-5-hydroxy-viloxazine) are adequately represented and characterized in rat”
Surrogate molecule
No surrogate; the clinical compound was tested
“Viloxazine did not increase the incidence of tumors in rats treated for 2 years at oral doses of 30/22, 87/65/43, and 217/130/87 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
78 (18-month rat)
“Study title: An 18-Month Chronic Oral Toxicity in Rats”
Pivotal GLP studies
13-week and 18-month rat repeat-dose studies
“drug-induced hepatocellular hypertrophy and/or vacuolation were observed at comparable doses in previous 13-week and 18-month repeat-dose studies in rats of both sexes.”
Route in tox
Oral (gavage and dietary administration)
“It should be noted that viloxazine was administered via dietary intake in this study; therefore, the exposure profile is expected to be different from oral gavage studies”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and rat bone marrow micronucleus assays
“It was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro mammalian chromosomal aberration assay (human peripheral blood) or the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
2-year rat and 26-week Tg.rasH2 mouse: no increase in tumors
“Viloxazine did not increase the incidence of tumors in rats treated for 2 years at oral doses of 22, 43, and 87 mg/kg/day. The high dose of 87 mg/kg/day is approximately equal to the MRHD of 600 mg in adults, based on mg/m 2 . Viloxazine did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks at oral doses of 4.3, 13, and 43 mg/kg/day.”
Reproductive & developmental
Rat EFD: resorptions, delayed development and low-incidence malformations at 82 mg/kg/day
“However, at a dose of 82 mg/kg/day, viloxazine increased early and late resorptions, delayed fetal development, and caused low incidences of fetal malformations or anomalies (craniorachischisis, missing cervical vertebrae, and morphological changes associated with hydranencephaly).”
Safety pharmacology
No ECG (including QTcF) or blood pressure changes in telemetered dogs up to 50 mg/kg
“In telemetry-instrumented male conscious dogs (Study 809V-Tox2007-031, GLP), after a single oral dose (capsule) of viloxazine at 0 (control, empty capsule), 5, 25, and 50 mg/kg (n=4, Latin square design) there were no drug-related changes in ECG (PR, QRS, QT, or QTcF) or blood pressure”
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 Qelbree 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: Dose-dependent hepatocellular hypertrophy and/or vacuolation in rat, mouse and dog (FDA integrated review, p. 68)
NOAEL / key findings
Dose-dependent hepatocellular hypertrophy and/or vacuolation in rat, mouse and dog
“In all three species (rat, mouse, and dog), repeat administration of viloxazine caused dose-dependent hepatocellular hypertrophy and/or vacuolation in the liver.”
Risksopen answer page →
Immune & cytokine safety
Decreased thymus weight, considered secondary to stress and poor condition; reversible
“thymus with correlative decreased thymus weight in both sexes and arterial inflammation or degeneration in males. These findings were most likely secondary to the stress and poor condition of the animals, rather than a direct drug effect, and were reversible after recovery.”
Biodistribution & persistence
No skin accumulation; reversible melanin binding in the uveal tract with rapid elimination
“These data suggest that viloxazine or its metabolites do not preferentially distribute to or accumulate in the skin; viloxazine and its metabolites reversibly bind to melanin in the uveal tract but are rapidly dissociated or eliminated.”
Modality-specific risk
Seizures/convulsions in multiple species at therapeutically relevant doses
“Viloxazine caused seizures/convulsions in multiple animal species (rat, dog, and mouse) at therapeutically relevant doses, suggesting a potential risk for seizures with chronic use of viloxazine.”