Inpefa
sotagliflozin
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
“This includes a single-dose rat study, a battery of definitive repeat-dose general toxicity studies in rats (up to 26 weeks) and dogs (up to 39 weeks), a full battery of genetic toxicity studies, mouse and rat carcinogenicity studies”
Why that species
All species used are pharmacologically relevant
“Repeat-dose toxicity studies were performed in rats and dogs. Carcinogenicity evaluation was performed in mice and rats. Embryofetal development studies were performed in rats and rabbits. All species are pharmacologically relevant.”
Surrogate molecule
No surrogate; the clinical compound was tested
“the NOAEL in 39-week oral sotagliflozin for male and female beagle dogs was 20 mg/kg/day”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“This includes a single-dose rat study, a battery of definitive repeat-dose general toxicity studies in rats (up to 26 weeks) and dogs (up to 39 weeks), a full battery of genetic toxicity studies, mouse and rat carcinogenicity studies”
Pivotal GLP studies
26-week rat and 39-week dog oral studies (with 4-week recovery), plus 13-week rat and dog studies
“13-week repeat dose studies (with 4 weeks recovery) in the rat and the dog, 26-week repeat dose study (with 4 weeks recovery) in the rat, and 39-week repeat dose study (with 4 weeks recovery) in the dog.”
Route in tox
Oral
“Seven oral GLP toxicology studies have been completed”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosomal aberration and in vivo rat bone marrow micronucleus assays
“A standard battery of GLP genetic toxicology studies including an in vitro bacterial reverse mutation (Ames) assay, an in vitro chromosomal aberration test in CHO cells, and an in vivo rat bone marrow micronucleus assay were completed with sotagliflozin. Sotagliflozin was neither mutagenic nor clastogenic in the three valid assays.”
Carcinogenicity
rasH2 mouse and rat: no treatment-related, statistically significant neoplasms
“Sotagliflozin did not cause any treatment-related, statistically significant neoplasms in transgenic RasH2 (Tg.RasH2) mice or the rat in either sex.”
Reproductive & developmental
Not teratogenic in rats (100 mg/kg) or rabbits (200 mg/kg); maternal and fetal toxicity with malformations in rats at 350 mg/kg
“Sotagliflozin was not teratogenic in the rat at 100 mg/kg (40X MHRD) or in the rabbit at 200 mg/kg (9X MHRD). In rats, a higher dose (350 mg/kg; 161X MHRD) caused both maternal and fetal toxicity including significant reduction in maternal weight gain, embryo-lethality, reduced fetal weights, altered sex ratio, and cardiovascular and skeletal malformations.”
Safety pharmacology
hERG IC50 >23.5 µM; no QT/QTc effect in dog telemetry up to 500 mg/kg
“Sotagliflozin has an IC50 >23.5 µM in the human ether-a-go-go related gene (hERG) assay. A cardiac telemetry study in Beagle dogs showed that sotagliflozin had no significant effect on QT or QTc interval (corrected with the Fridericia method) at dose levels up to 500 mg/kg.”
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 Inpefa 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 NOAEL 30 mg/kg/day (females; males LOAEL 30); 39-week dog NOAEL 20 mg/kg/day (FDA integrated review, p. 260)
NOAEL / key findings
26-week rat NOAEL 30 mg/kg/day (females; males LOAEL 30); 39-week dog NOAEL 20 mg/kg/day
“the low-observed-adverse level (LOAEL) for male rats and No-observed adverse level (NOAEL) for female rats in 26-week oral sotagliflozin were 30 and 30 mg/kg/day, respectively; the NOAEL in 39-week oral sotagliflozin for male and female beagle dogs was 20 mg/kg/day”
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
No significant CNS accumulation; no selective association with melanin-containing tissues
“There was no significant accumulation of radioactivity in the central nervous system (CNS), and radioactivity was not selectively associated with the melanin-containing tissues or red blood cells.”
Modality-specific risk
Prostate inflammation in rats of unclear clinical relevance
“Clinical implication of prostate inflammation observed in rats is unclear and may become apparent with post-market experience.”