Vivjoa
oteseconazole
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”
Species: general tox
Rat and dog (up to 39 weeks)
“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.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicology studies included fertility studies in male and female rats, embryo-fetal development studies in rats and rabbits, and four pre- and postnatal development studies in rats.”
Species: carcinogenicity
Tg.rasH2 mouse (6-month) and Sprague Dawley rat (up to 90 weeks)
“There was no increase in the incidence of tumors following daily oral administration of oteseconazole to Tg.rasH2 mice for 6 months at doses of 5 mg/kg/day (males) and 15 mg/kg/day (females), which are up to 3 and 10 times, respectively, the maximum human exposure for RVVC based on AUC comparisons. In an oral carcinogenicity study, Sprague Dawley rats were administered doses of 0.5, 1.5, or 5 mg/kg/day oteseconazole once daily for up to 90 weeks.”
Surrogate used in
No surrogate used; oteseconazole tested directly
“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.”
Genotox: Ames
Negative (bacterial reverse mutation)
“Oteseconazole was negative in the bacterial reverse mutation assay, in vitro chromosomal aberration assay, and in vivo micronucleus assay in rats.”
Genotox: in vitro mammalian
In vitro chromosomal aberration: negative
“Oteseconazole was negative in the bacterial reverse mutation assay, in vitro chromosomal aberration assay, and in vivo micronucleus assay in rats.”
Genotox: in vivo
Rat micronucleus: negative
“Oteseconazole was negative in the bacterial reverse mutation assay, in vitro chromosomal aberration assay, and in vivo micronucleus assay in rats.”
Carcinogenicity model
6-month Tg.rasH2 mouse; Sprague Dawley rat up to 90 weeks
“There was no increase in the incidence of tumors following daily oral administration of oteseconazole to Tg.rasH2 mice for 6 months at doses of 5 mg/kg/day (males) and 15 mg/kg/day (females), which are up to 3 and 10 times, respectively, the maximum human exposure for RVVC based on AUC comparisons. In an oral carcinogenicity study, Sprague Dawley rats were administered doses of 0.5, 1.5, or 5 mg/kg/day oteseconazole once daily for up to 90 weeks.”
Carcinogenicity timing
2-year rat and 6-month rasH2 mouse completed before the marketing application
“Studies One Two Year Oral Gavage Carcinogenicity Study in Rats and One Six-Month Oral Gavage Carcinogenicity Study in rasH2 Transgenic Mice.”
hERG / QT
hERG IC50 1.9 µM
“The IC50 for the inhibitory effect of VT-1161 on hERG potassium current was 1.9µM.”
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.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
- Embryo-Fetal Toxicity
Embryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
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.
Repeat-dose tox before first-in-human
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.
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog with 33-week recovery
“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.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicology studies included fertility studies in male and female rats, embryo-fetal development studies in rats and rabbits, and four pre- and postnatal development studies in rats.”
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.”
PPND / ePPND: when
Four rat PPND studies completed and reviewed in the NDA
“Reproductive and developmental toxicology studies included fertility studies in male and female rats, embryo-fetal development studies in rats and rabbits, and four pre- and postnatal development studies in rats.”
Carcinogenicity
Species: carcinogenicity
Tg.rasH2 mouse (6-month) and Sprague Dawley rat (up to 90 weeks)
“There was no increase in the incidence of tumors following daily oral administration of oteseconazole to Tg.rasH2 mice for 6 months at doses of 5 mg/kg/day (males) and 15 mg/kg/day (females), which are up to 3 and 10 times, respectively, the maximum human exposure for RVVC based on AUC comparisons. In an oral carcinogenicity study, Sprague Dawley rats were administered doses of 0.5, 1.5, or 5 mg/kg/day oteseconazole once daily for up to 90 weeks.”
Carcinogenicity model
6-month Tg.rasH2 mouse; Sprague Dawley rat up to 90 weeks
“There was no increase in the incidence of tumors following daily oral administration of oteseconazole to Tg.rasH2 mice for 6 months at doses of 5 mg/kg/day (males) and 15 mg/kg/day (females), which are up to 3 and 10 times, respectively, the maximum human exposure for RVVC based on AUC comparisons. In an oral carcinogenicity study, Sprague Dawley rats were administered doses of 0.5, 1.5, or 5 mg/kg/day oteseconazole once daily for up to 90 weeks.”
Carcinogenicity timing
2-year rat and 6-month rasH2 mouse completed before the marketing application
“Studies One Two Year Oral Gavage Carcinogenicity Study in Rats and One Six-Month Oral Gavage Carcinogenicity Study in rasH2 Transgenic Mice.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat 26-week NOAEL 0.5 mg/kg: ~0.2x human AUC at MRHD
“The no observed adverse effect level (NOAEL) was considered to be 0.5 mg/kg which was associated with a maximum plasma concentration (Cmax) of 741 ng/mL and an AUC of 14,295 ngꞏhr/mL (about 0.2 times the MRHD based on AUC comparisons).”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Estrogen-dependent murine model of vaginal candidiasis (C. albicans infection)
“The activity of oteseconazole was evaluated in two studies using an estrogen-dependent murine model of vaginal candidiasis.”
Why that model
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.
Reviewer's view of the efficacy data
FDA used the murine-model plasma threshold (≥1 µg/mL) to support clinical dose selection
“Based on these studies, a threshold oteseconazole plasma concentration of ≥1 µg/mL (which was associated with the 4 mg/kg dose) was used to inform dose selection in clinical efficacy trials.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
26-week rat NOAEL exposure about 0.2 times the MRHD by AUC
“The no observed adverse effect level (NOAEL) was considered to be 0.5 mg/kg which was associated with a maximum plasma concentration (Cmax) of 741 ng/mL and an AUC of 14,295 ngꞏhr/mL (about 0.2 times the MRHD based on AUC comparisons).”
Similar precedents
ArtesunateSmall molecules · artesunate · Plasmodium (antimalarial)Rodent + dog or minipig · 4 wkBlujepaSmall molecules · gepotidacin · Bacterial topoisomerases (gyrase/topo IV)Rodent + dog or minipig · 13 wkBrexafemmeSmall molecules · ibrexafungerp · Fungal glucan synthaseRodent + dog or minipig · 26 wkEgatenSmall molecules · triclabendazole · Fasciola (tubulin)Rodent + dog or minipig · 13 wkExblifepSmall molecules · cefepime and enmetazobactam · PBPs; beta-lactamase (enmetazobactam)Rodent + dog or minipig · 13 wkFexinidazoleSmall molecules · fexinidazole · Trypanosoma bruceiRodent + dog or minipig · 4 wk