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.”
Species: general tox
Rat only (28-day IV study)
“In the 28-day toxicity study in rats, amisulpride was administered IV to Charles River Wistar (Crl:WI(Han)) rats at doses of 0, 2, 5 and 10 mg/kg/day.”
Species: DART
Rat and rabbit (embryo-fetal development)
“Embryo fetal development studies were conducted in pregnant rat and rabbits.”
Species: carcinogenicity
Not conducted; not required for 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.”
Surrogate used in
No surrogate used; amisulpride itself tested in rats
“In the 28-day toxicity study in rats, 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.”
Genotox: Ames
Negative
“Amisulpride had no mutagenic potential in the Bacterial Reverse Mutation Assay.”
Genotox: in vitro mammalian
Chromosome aberration in human peripheral blood lymphocytes: negative
“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.”
Genotox: in vivo
Rat micronucleus (oral): negative up to 300 mg/kg/day
“Amisulpride was negative in the in vivo micronucleus assay in rats at oral doses up to 300 mg/kg/day.”
Carcinogenicity model
Not conducted (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.”
Carcinogenicity timing
Not required: single-dose indication; not conducted
“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.”
hERG / QT
hERG IC50 ~100 µM; 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.”
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
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
28-day rat (IV slow bolus) with 14-day treatment-free recovery
“Amisulpride: Intravenous (Slow Bolus) 28-Day Toxicity Study in the Rat with a 14 Day Treatment Free Period (Study # BGX0002).”
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).”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“Embryo fetal development studies were conducted in pregnant rat and rabbits.”
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.”
PPND / ePPND: when
PPND in rat (oral) completed before the marketing application
“In a prenatal and postnatal development study in rats, amisulpride was administered daily by oral gavage (0, 60, 100 and 160 mg/kg/day) to pregnant rats from gestation day 6 to lactation day 20.”
Carcinogenicity
Species: carcinogenicity
Not conducted; not required for 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.”
Carcinogenicity model
Not conducted (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.”
Carcinogenicity timing
Not required: single-dose indication; not conducted
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat EFD study: no adverse embryo-fetal effects up to 160 mg/kg/day, 43x human AUC at 10 mg
“Reproduction studies of amisulpride were conducted in pregnant rats administered oral doses up to 160 mg/kg/day (43 times the exposure based on area under the curve (AUC) at the highest recommended dose of 10 mg) throughout the period of organogenesis. No adverse embryo-fetal developmental effects were observed at any dose level.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Ferret emesis models (apomorphine-, morphine- and cisplatin-induced)
“Studies conducted in ferrets have shown that amisulpride inhibits emesis caused by apomorphine, with an estimated ED 50 of less than 1 mcg/kg, subcutaneously; and inhibits cisplatin-induced emesis at 2 mg/kg and morphine-induced emesis at 3 to 6 mg/kg, when given intravenously.”
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: SC amisulpride fully inhibited apomorphine emesis in ferrets; IV dosing had no consistent effect on morphine-induced emesis
“In conclusion, apomorphine-induced emesis in ferrets was completely inhibited by subcutaneous administration of amisulpride at doses of 10 and 100 μg/kg. Intravenously administered amisulpride (3, 6 and 12 mg/kg) had no consistent anti-emetic effects on morphine-induced emesis in ferrets.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
Repeat-dose toxicity limited to a single 28-day IV study in one species (rat)
Why: Extensive clinical experience with amisulpride at higher doses outside the US; single-dose indication · Human data · Other reason
“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.”
CarcinogenicityAccepted
No carcinogenicity studies conducted
Why: Drug administered as a single dose · Within the guideline
“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.”
OtherVerdict not stated
No secondary pharmacology studies submitted; published literature on related receptor activity used instead
“No secondary pharmacology studies were submitted. Literature cited by the applicant that assessed activity at related receptors is reviewed in section 5.3.1, above.”
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