Exxua
gepirone
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.”
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.”
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.”