Vivjoa
oteseconazole
Sources:FDA integrated review ↗
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
“In rats and dogs, oteseconazole exposure was less dose proportional and the drug accumulated up to 126-fold in dogs with repeated dosing over 39 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
“Dogs were dosed with oteseconazole for 39 weeks at 0.75, 1.5, 5.5 and 17 mg/kg, equivalent to between 1 and 26 times the MRHD based on AUC comparisons”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“Study # 2130-001. A 39-Week Oral Toxicity Study of VT-1161 in Dogs With a 33-Week Recovery”
Pivotal GLP studies
26-week rat and 39-week dog repeat-dose studies
“In contrast, there was no drug-related increase in hemorrhage in the 39-week dog study and the 26-week rat study.”
Route in tox
Oral gavage
“Dose and frequency of dosing: 0, 0.15, 0.5, 1.5 and 5 mg/kg. Daily Route of administration: Oral gavage”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and rat micronucleus assays
“Oteseconazole was negative in the bacterial reverse mutation assay, in vitro chromosomal aberration assay, and in vivo micronucleus assay in rats.”
Carcinogenicity
Rat: Leydig cell adenomas and thyroid follicular tumors at ≥1.5 mg/kg/day
“In a 2-year oral carcinogenicity study of oteseconazole, male Sprague Dawley rats showed increased incidence of Leydig cell adenomas of the testes and thyroid follicular cell adenomas/carcinomas combined at ≥1.5 mg/kg/day.”
Reproductive & developmental
Rat PPND: offspring lens opacities, buphthalmos, retinal and optic nerve atrophy at 7.5 mg/kg/day
“In pre- and postnatal studies, oteseconazole administration to pregnant and lactating rats at 7.5 mg/kg/day resulted in lens opacities, swollen eyes, hemorrhage, hyphema, buphthalmos, corneal ulceration, retinal and optic nerve atrophy, as well as lens degeneration.”
Safety pharmacology
No CNS or respiratory effects in rats up to 1000 mg/kg; no CV effects in dogs up to 300 mg/kg
“Oteseconazole administered as a single oral dose (up to 1000 mg/kg) had no significant effect on neurobehavioral or respiratory function in rats. Similarly, a single oral dose (up to 300 mg/kg) had no significant effect on cardiovascular function 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 Vivjoa 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: 26-week rat: liver, adrenal, thyroid, kidney and ovary changes; no significant effects at 0.15 mg/kg/day (FDA integrated review, p. 132)
NOAEL / key findings
26-week rat: liver, adrenal, thyroid, kidney and ovary changes; no significant effects at 0.15 mg/kg/day
“Oteseconazole dosing for 26 weeks in rats resulted in changes in the liver, adrenals, thyroid, kidneys, and ovaries with no significant effects at 0.15 mg/kg”
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
Highest levels in small intestine and Harderian gland (rat); half-life 30 days in dogs, 8.5 days in rats
“The half-life was 30 days in dogs and 8.5 days in rats. In a tissue distribution study in rats, the highest levels of oteseconazole were observed in the small intestines and in the Harderian gland.”
Modality-specific risk
Embryofetal/developmental toxicity: ocular abnormalities in rat offspring after gestational exposure
“Ocular abnormalities were observed in rat pups born to dams dosed with oteseconazole while pregnant in four separate pre- and postnatal toxicity studies.”