Exxua
gepirone
Sources:FDA pharmacology/toxicology review ↗FDA multi-discipline review ↗US prescribing information ↗
Species
RatDog
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Repeated-dose toxicology studies of adequate duration and at MTDs were performed in rats and dogs.”
Why that species
Both major human metabolites (1-PP, 3'-OH-gepirone) are present at substantial levels in rat and dog plasma
“In humans, 2 major metabolites of gepirone have been identified: 1-PP (which is also a metabolite of buspirone, currently approved and marketed as an anxiolytic) and 3’-OH-gepirone. Both of these metabolites have been identified and found to be present in substantial amounts (many times the levels of gepirone) in plasma of the 2 major species used in the preclinical studies, namely rats and dogs, following gepirone administration.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 1-year study in dogs (4, 8, and 16 mg/kg/day orally, in a capsule), decreases in body weights (and food consumption at the HD) limited doses.”
Species: general tox
Rat and dog
“Repeated-dose toxicology studies of adequate duration and at MTDs were performed in rats and dogs.”
Species: DART
Rat (EFD, pre/postnatal) and rabbit (EFD)
“traditional Segment II studies, in rats and rabbits, with oral gavage dosing of pregnant females during the period of organogenesis; and 3) a traditional Segment III study in rats, with oral gavage dosing of pregnant females from late pregnancy through lactation”
Species: carcinogenicity
Rat and mouse (2-year bioassays)
“More importantly, there was no evidence of carcinogenic potential in the completed two-year mouse and rat bioassays.”
Surrogate used in
No surrogate used; rat and dog form the major human metabolites
“Both of these metabolites have been identified and found to be present in substantial amounts (many times the levels of gepirone) in plasma of the 2 major species used in the preclinical studies, namely rats and dogs, following gepirone administration.”
Study lengthopen answer page →
Longest pivotal study
52 (12-month dog)
“A chronic (12 month) oral [capsule] toxicity study of MJ 13805-1 in Beagle dogs.”
Pivotal GLP studies
12-month rat and 1-year dog repeat-dose studies (plus 3- and 6-month rat studies)
“Below I have presented the results from the 3-month study in rats and the 1-year study in dogs. Only exposure verification, not kinetic analysis, was performed on longer studies in rats (see summary of 6-mo study results, below, and reviews of 12-mo general toxicity study and 2-yr carcinogenicity study, in their respective sections below).”
Route in tox
Oral (capsule in dogs)
“Route, form: oral, 1 capsule per day, ~30 min after feeding.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, CHO/HGPRT, hepatocyte DNA repair, rat micronucleus and 5-hour CHO chromosome aberration assays
“Gepirone HCl tested negative in 4 genotoxicity assays (Ames, in vivo rat micronucleus, hepatocyte DNA repair, and CHO/HGPRT mammalian gene mutation assays) and in a chromosome aberrations assay conducted in CHO cells with 5 hours treatment.”
Carcinogenicity
Rat and mouse carcinogenicity studies: no drug-related tumors up to MTD
“This reviewer agreed with the Sponsor that there were no gepirone-related tumors evident in either rats or mice up to maximum tolerated doses (MTD); concurrence by the Executive-CAC was given on January 8, 2002.”
Reproductive & developmental
Rat and rabbit EFD: decreased fetal weight and length with skeletal variations at mid and high doses
“In embryo/fetal development studies, oral administration of gepirone to pregnant rats (75, 150, and 300 mg/kg/day) or pregnant rabbits (50, 100, and 200 mg/kg/day) during the period of organogenesis resulted in decreased embryo/fetal body weights and lengths, with accompanying skeletal variations, at the mid and high doses.”
Safety pharmacology
Reversible decreases in heart rate, blood pressure and contractility without ECG changes; lowered seizure thresholds in rats
“Convulsions were occasionally noted in some general toxicology studies, and gepirone lowered seizure thresholds for strychinine and picrotoxin in rats. Acute cardiac effects were reversible and included decreased heart rate, mean arterial pressure, and contractility, with no apparent alterations in EKG parameters.”
Genotox: Ames
Negative
“It was no mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test of rat bone marrow cells, but was not adequately tested in an in vitro chromosomal aberration test.”
Genotox: in vitro mammalian
CHO/HGPRT gene mutation and CHO chromosome aberration (5-hour treatment): negative
“Gepirone HCl tested negative in 4 genotoxicity assays (Ames, in vivo rat micronucleus, hepatocyte DNA repair, and CHO/HGPRT mammalian gene mutation assays) and in a chromosome aberrations assay conducted in CHO cells with 5 hours treatment.”
Genotox: in vivo
Rat bone marrow micronucleus/chromosomal aberration: negative
“It was no mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test of rat bone marrow cells, but was not adequately tested in an in vitro chromosomal aberration test.”
Carcinogenicity model
2-year rat and mouse bioassays: no carcinogenic potential
“More importantly, there was no evidence of carcinogenic potential in the completed two-year mouse and rat bioassays.”
Carcinogenicity timing
2-year mouse and rat bioassays completed before the marketing application; no carcinogenic potential
“More importantly, there was no evidence of carcinogenic potential in the completed two-year mouse and rat bioassays.”
hERG / QT
In vivo: reversible decreases in heart rate, MAP and contractility; no EKG changes
“Acute cardiac effects were reversible and included decreased heart rate, mean arterial pressure, and contractility, with no apparent alterations in EKG parameters.”
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 Exxua 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: pulmonary histiocytosis, distended bladders, prostate/ovary/uterus weight changes; dose-limiting body weight loss (FDA pharmacology/toxicology review, p. 132)
NOAEL / key findings
Rat: pulmonary histiocytosis, distended bladders, prostate/ovary/uterus weight changes; dose-limiting body weight loss
“Toxicities were limited to slightly increased incidence of histiocytosis in lungs at the high dose, distended bladders seen at necropsy in high dose males, and some changes in organ weights (increased weights of prostate and ovaries, decreased weights of uteruses) that might indicate “endocrine effects,” a not unexpected effect of serotonergic compounds in rats.”
Risksopen answer page →
Immune & cytokine safety
Increased mesenteric lymph node plasmablasts at end of dosing (highest at 70 mg/kg), reversible after recovery
“At the end of the dosing period (Day 42) a greater number of plasmablasts were observed in the mesenteric lymph nodes of dose group animals relative to controls with the highest numbers observed in the 70 mg/kg group. Following the recovery period (Day 56) there was no difference in lymph node plasmablasts between controls and dose group animals.”
Biodistribution & persistence
Gepirone and/or metabolites cross the placenta; fetal radioactivity similar to maternal plasma
“The amount of radiolabel (gepirone-equivalents per gm) was essentially identical in maternal plasma and total fetus, at all time-points, and very similar for maternal and fetal hearts, whereas maternal liver levels were much (5-24-fold) greater than those in fetal liver. Geprione and/or metabolites crossed the placental barrier from mother to fetus.”
Modality-specific risk
Embryo-fetal and postnatal developmental toxicity
“Based on animal reproduction studies, gepirone has been shown to have adverse effects on embryo/fetal and postnatal development.”
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
Boxed warning: Boxed warning
- Suicidal Thoughts and Behaviors in Adolescents and Young Adults
- QT Prolongation
- Serotonin Syndrome
- Activation of Mania or Hypomania
PsychiatricCardiovascularNeurotoxicity
US prescribing information, Boxed Warning and 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 Exxua 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: pulmonary histiocytosis, distended bladders, prostate/ovary/uterus weight changes; dose-limiting body weight loss (FDA pharmacology/toxicology review, p. 132)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
12-month oral beagle dog study with 3-month drug-free recovery (the year-long dietary rat study had no recovery groups)
“5/sex/group were dosed for 12 months, with 3/sex/group necropsied after 12 months of dosing and the remaining 2/sex/group given a 3-month, drug-free recovery period before necropsy.”
Pivotal GLP studies
12-month rat and 1-year dog repeat-dose studies (plus 3- and 6-month rat studies)
“Below I have presented the results from the 3-month study in rats and the 1-year study in dogs. Only exposure verification, not kinetic analysis, was performed on longer studies in rats (see summary of 6-mo study results, below, and reviews of 12-mo general toxicity study and 2-yr carcinogenicity study, in their respective sections below).”
DART package
Species: DART
Rat (EFD, pre/postnatal) and rabbit (EFD)
“traditional Segment II studies, in rats and rabbits, with oral gavage dosing of pregnant females during the period of organogenesis; and 3) a traditional Segment III study in rats, with oral gavage dosing of pregnant females from late pregnancy through lactation”
Reproductive & developmental
Rat and rabbit EFD: decreased fetal weight and length with skeletal variations at mid and high doses
“In embryo/fetal development studies, oral administration of gepirone to pregnant rats (75, 150, and 300 mg/kg/day) or pregnant rabbits (50, 100, and 200 mg/kg/day) during the period of organogenesis resulted in decreased embryo/fetal body weights and lengths, with accompanying skeletal variations, at the mid and high doses.”
PPND / ePPND: when
Segment III (PPND) study in rat completed and reviewed with the marketing application
“A Segment III reproductive toxicology study with orally administered BMY 13805-1 in rats.”
Carcinogenicity
Species: carcinogenicity
Rat and mouse (2-year bioassays)
“More importantly, there was no evidence of carcinogenic potential in the completed two-year mouse and rat bioassays.”
Carcinogenicity model
2-year rat and mouse bioassays: no carcinogenic potential
“More importantly, there was no evidence of carcinogenic potential in the completed two-year mouse and rat bioassays.”
Carcinogenicity timing
2-year mouse and rat bioassays completed before the marketing application; no carcinogenic potential
“More importantly, there was no evidence of carcinogenic potential in the completed two-year mouse and rat bioassays.”
Safety marginopen answer page →
Safety margin at NOAEL
Developmental NOAEL (EFD) 9x (rat) and 12x (rabbit) MRHD on mg/m2 basis; no repeat-dose margin stated
“The developmental NOAEL was 9 and 12 times the MRHD on a mg/m 2 basis in rats and rabbits, respectively.”
NOAEL / key findings
Rat: pulmonary histiocytosis, distended bladders, prostate/ovary/uterus weight changes; dose-limiting body weight loss
“Toxicities were limited to slightly increased incidence of histiocytosis in lungs at the high dose, distended bladders seen at necropsy in high dose males, and some changes in organ weights (increased weights of prostate and ovaries, decreased weights of uteruses) that might indicate “endocrine effects,” a not unexpected effect of serotonergic compounds in rats.”
Efficacy evidenceopen answer page →
Efficacy evidence
Active in animal models predictive of antidepressant and anxiolytic activity
“Neurological effects: Gepirone was active in animal models that are predictive of antidepressant and anxiolytic activity in humans.”
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: centrally acting drug, active in animal models predictive of antidepressant and anxiolytic activity
“Gepirone is a centrally acting drug and was active in animal models that are predictive of antidepressant and anxiolytic activities in humans.”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityAcceptedBeyond the letter
In vitro chromosome aberration assay inadequate: 5-hour treatment only, no ~24-hour continuous treatment without activation
Why: Weight of evidence suggests gepirone is neither genotoxic nor carcinogenic · Weight of evidence
“The in vitro chromosomal aberration assay was inadequate because although gepirone was negative for 5-hour treatment, with and without metabolic activation, this negative finding (without activation) should have been followed up with a study using continuous treatment with gepirone (without activation) for ~ 24 hours (1.5 cell doubling times) in accordance with current guidelines.”
“Since the weight of evidence suggests that gepirone is neither genotoxic nor carcinogenic, we are not requiring that this study be repeated; however, it will have to be repeated if it is to be included in product labeling.”
Safety marginAcceptedBeyond the letter
Exposure multiples expressed on body surface area (mg/m2) rather than AUC ratios
Why: Pharmacokinetic and drug metabolism data support body-surface-area comparison · Pharmacology or kinetics
“It is also noted that although the current practice is to express exposure multiples in the labeling based on AUC ratios, the pharmacokinetics and drug metabolism data provide a strong rationale for expressing exposure multiples in the toxicity studies on the basis of body surface area (Mg/M2”
DARTVerdict not stated
Pre- and postnatal development study did not establish a no-effect dose for offspring effects
“Increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at all doses. The no-effect dose for fetal effects was not determined in this study.”
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