Barhemsys
amisulpride
Species
Rat
Longest study
4 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat
“amisulpride was administered IV to Charles River Wistar (Crl:WI(Han)) rats at doses of 0, 2, 5 and 10 mg/kg/day.”
Why that species
Single species accepted given extensive prior clinical experience at higher doses and single-dose use
“Based on extensive clinical experience with amisulpride, outside of the Unites States, at higher doses, the Division agreed that a 28-day repeat dose toxicity in a single species would be adequate for the proposed indication in which only a single dose will be administered.”
Surrogate molecule
No surrogate; the clinical compound was tested
“amisulpride was administered IV to Charles River Wistar (Crl:WI(Han)) rats at doses of 0, 2, 5 and 10 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
4 (28-day rat)
“In support of the safety of amisulpride, the applicant submitted the following nonclinical studies: pharmacodynamic studies, a 4-week repeat-dose IV toxicity study in rats, and a battery of genotoxicity and reproductive and developmental toxicity studies.”
Pivotal GLP studies
28-day IV (slow bolus) rat study with 14-day recovery
“Study title/number: Amisulpride: Intravenous (Slow Bolus) 28-Day Toxicity Study in the Rat with a 14 Day Treatment Free Period (Study # BGX0002).”
Route in tox
Intravenous
“amisulpride was administered IV to Charles River Wistar (Crl:WI(Han)) rats at doses of 0, 2, 5 and 10 mg/kg/day.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosome aberration and rat micronucleus assays
“Amisulpride was negative in the Ames test, the in vitro mammalian chromosome aberration assay in human peripheral blood lymphocytes and the in vivo micronucleus assay in rats by oral gavage.”
Carcinogenicity
Not conducted; not required for a single-dose indication
“Carcinogenicity studies of amisulpride were not conducted. Carcinogenicity studies are not required for this indication for which the drug will be administered as a single dose.”
Reproductive & developmental
Rat fertility: most females (90-95%) stayed in diestrus and failed to mate; effect reversed after treatment stopped
“Most female animals (90% to 95%) at each dose level remained in diestrus and failed to mate. However, this effect on mating reversed following cessation of treatment.”
Safety pharmacology
hERG IC50 ~100 µM, suggesting a low risk of clinical QT prolongation
“In an in vitro hERG assay, amisulpride showed hERG channel inhibitory effects with an IC50 of ~100μM, suggesting a low risk for clinical QT prolongation.”
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 Barhemsys 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: Rat: mammary feminization (males) and acinar proliferation/secretory activity (females) at all doses, reversed after 14-day recovery (FDA multi-discipline review, p. 66)
NOAEL / key findings
Rat: mammary feminization (males) and acinar proliferation/secretory activity (females) at all doses, reversed after 14-day recovery
“Microscopic examinations showed changes in the mammary area (feminization in surviving males and acinar proliferation/secretory activity in surviving females) in all dose groups. These findings were reversed following 14-day treatment free period.”
Risksopen answer page →
Immune & cytokine safety
High-dose males: 24% decrease in lymphocytes and 19% decrease in total white blood cells
“HD males: 24% decrease in lymphocytes and 19% decrease in total white blood cells”
Biodistribution & persistence
Radioactivity retained in meninges up to 336 h and uveal tract up to 840 h, suggesting melanin affinity
“The levels of radioactivity detected in the meninges up to 336 hours and uveal tract up to 840 hours post-dose suggest an affinity of amisulpride for the melanin pigmented tissues.”
Modality-specific risk
QT prolongation; possible additive QTc effect with ondansetron
“As both ondansetron and amisulpride prolong QT interval in a concentration-dependent manner, pharmacodynamic interaction in terms of QTc prolongation is possible with additive effect.”