Gepirone

Identification

Summary

Gepirone is a serotonin receptor agonist used to treat major depressive disorder in adults

Brand Names

Exxua

Generic Name

Gepirone

DrugBank Accession Number

DB12184

Background

Gepirone, an azapirone, is a pharmacologic analog of buspirone that acts selectively on the pre- and post-synaptic 5HT_1A receptors. Although earlier clinical trials showed promising results for gepirone, its formulation as an immediate-release tablet necessitates frequent administration due to the short half-lives. It was not until an extended-release formulation of gepirone was made available that gepirone became a potential candidate for a new antidepressant.^1,2,3

Gepirone was approved by the FDA on September 28, 2023, under the brand name EXXUA for the treatment of adults with major depressive disorder. It represents a novel class of antidepressants that selectively targets the 5HT_1A receptors, thus possessing a more favorable side effects profile with comparable incidence of sexual dysfunction side effects as that of the placebo.⁶

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Gepirone (DB12184)

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Weight

Average: 359.474
Monoisotopic: 359.232125194

Chemical Formula

C₁₉H₂₉N₅O₂

Synonyms

• Gepirone

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Pharmacology

Indication

Gepirone is indicated for the treatment of major depressive disorder (MDD) in adults.⁴

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Major depressive disorder (mdd)		••••••••••••	•••••		••••••• •••••••• •••••••

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Contraindications & Blackbox Warnings

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Pharmacodynamics

The pharmacological activity of gepirone is attributed to the parent drug and its major metabolites 3’-OH-gepirone and 1- PP. Gepirone and its 3’-OH metabolite bind to 5HT_1A receptors (K_i = 38 nM and 58 nM, respectively), where they act as agonists, while the 1-PP metabolite binds to α₂ receptors (K_i = 42 nM).⁴

In a thorough QT study, the largest mean increase in baseline- and placebo-corrected QTc interval with administration of 100 mg per day immediate-release formulation of gepirone was 18.4 msec (upper 90% confidence interval [CI] = 22.7 ms) on Day 1 and 16.1 msec (upper 90% CI = 20.7 ms) on Day 7. The exposure in this study was 2-fold the exposure of the maximum recommended dose.⁴

Mechanism of action

The mechanism of the antidepressant effect of gepirone is not fully understood but is thought to be related to its modulation of serotonergic activity in the CNS through selective agonist activity at 5HT_1a receptors.⁴ Particularly, gepirone

Target	Actions	Organism
A5-hydroxytryptamine receptor 1A	partial agonist	Humans

Absorption

The pharmacokinetics of gepirone are linear and dose-proportional from 18.2 mg to 72.6 mg. Steady-state plasma concentrations are typically achieved within two to four days of daily dosing.⁴

The absolute bioavailability is 14% to 17%. The maximal plasma gepirone concentration (C_max) after dosing is reached within 6 hours post-dose (T_max).⁴

After a high-fat meal, T_max is reached at 3 hours. A significant effect of food has been observed on the peak plasma concentration (C_max) of gepirone and, to a lesser extent, on the total exposure (AUC_0-tlast, AUC_0-∞) to gepirone. The magnitude of the food effect was dependent of the fat content of the meal. The systemic exposure of gepirone and major metabolites was consistently higher under fed conditions as compared to the fasted state. Gepirone C_max after intake of a low-fat (~ 200 calories) breakfast was 27% higher, after medium-fat (~500 calories) breakfast 55% higher, and after a high-fat (~ 850 calories) breakfast 62% higher as compared to the fasted state. The AUC after intake of a low-fat breakfast was about 14% higher, after a medium-fat breakfast 22% higher, and after a high-fat breakfast 32 to 37% higher as compared to the fasted state. The effect of varying amounts of fat on C_max and AUC of the major metabolites 3-OH-gepirone and 1PP were similar to that found for gepirone.⁴

Volume of distribution

The apparent volume of distribution of gepirone is approximately 94.5L.⁴

Protein binding

The in vitro plasma protein binding in humans is 72% and is not concentration-dependent. The in vitro plasma protein binding for metabolite 3’-OH gepirone is 59% and 42% for 1-PP.⁴

Metabolism

Gepirone is extensively metabolized and both major metabolites 1-PP and 3’-OH-gepirone are present in plasma in higher concentrations than the parent compound. CYP3A4 is the primary enzyme catalyzing the metabolism of EXXUA to its major pharmacologically active metabolites.⁴

Hover over products below to view reaction partners

• Gepirone
  • 3'-OH-gepirone
    • 3',5-di-OH-gepirone
  • 5-OH-gepirone
    • 5-OH 1-PP
    • 3',5-di-OH-gepirone
  • 4-OH-methyl-gepirone
  • 2-piperazinyl-OH-gepirone
  • 1-PP
    • 5-OH 1-PP

Route of elimination

Following a single oral dose of [¹⁴C]-labeled gepirone, approximately 81% and 13% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. 60% of the gepirone was eliminated in the urine within the first 24 hours. The presence of hepatic or renal impairment did affect the apparent clearance of gepirone.⁴

Half-life

The mean terminal half-life is approximately 5 hours.⁴

Clearance

After the administration of 80 mg of gepirone, the apparent clearance of gepirone and its 2 metabolites, 1-PP and 3’-OH-gepirone, was calculated to be 692 ± 804 L/h, 417 ± 249 L/h, and 146 ± 61.7 L/h respectively.⁵

Adverse Effects

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Toxicity

In embryo-fetal development studies, oral administration of gepirone to pregnant rats (75, 150, and 300 mg/kg) or pregnant rabbits (50, 100, and 200 mg/kg) during the period of organogenesis resulted in decreased embryofetal growth, body weights, and lengths, with accompanying skeletal variations at mid and high doses; the mid doses are 18 and 24 times the maximum recommended human dose (MRHD) on a mg/m² basis in rats and rabbits, respectively. No malformations were seen in these studies. The developmental no observed adverse effect level (NOAEL) was 9 and 12 times the MRHD on a mg/m2 basis in rats and rabbits, respectively.⁴

When pregnant rats were treated with gepirone (10, 20, and 40 mg/kg) from late gestation through weaning, decreased birth weights were seen at mid and high doses; the mid-dose is twice the MRHD. Increased offspring mortality during the first 4 days after birth and persistent reduction in body weight were observed at all doses; the lowest dose is approximately equal to the MRHD on a mg/m² basis. The no-effect dose for fetal effects was not determined in this study.⁴

When gepirone was administered orally to male and female rats prior to and throughout mating, gestation, and lactation at doses of 5, 27, 64, and 150 mg/kg/day, increased stillbirths were seen at ≥64 mg/kg. Early postnatal mortality was increased at 150 mg/kg (18 times the MRHD on a mg/m² basis). The NOAEL (27 mg/kg) for stillbirths was associated with a maternal dose 3 times the MRHD on a mg/m² basis. Fetal weights were decreased at 27 mg/kg (3 times the MRHD on a mg/m2 basis) and fetal lengths were decreased at 64 mg/kg (8 times the MRHD on a mg/m² basis) and above. Pup weights were decreased at birth, throughout lactation and weaning, and until at least 14 weeks of age, with delays of some developmental landmarks, at 64 mg/kg and above. The NOAEL for growth and development (5 mg/kg) was associated with a maternal dose below the MRHD on a mg/m2 basis.⁴

In the pediatric trial patients, there was a higher occurrence of vomiting in pediatric patients (13%) compared to adults (6.6%). Antidepressants, such as gepirone, increase the risk of suicidal thoughts and behaviors in pediatric patients.⁴

In clinical studies, cases of acute ingestions of up to 454 mg (6.25 times the maximum recommended dose) of gepirone alone or in combination with other drugs, were reported. Signs and symptoms reported with an overdose of gepirone at doses up to 454 mg included vomiting and transient incomplete bundle branch block; an unknown dose of gepirone produced an altered level of consciousness and a 60-second convulsion.⁴

No specific antidotes for gepirone are known. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.⁴

No evidence of carcinogenic potential was observed in lifetime carcinogenicity studies performed in rats and mice at doses up to 43.6 and 317.8 mg/kg/day, respectively. These doses are approximately 6 and 18 times the MRHD, respectively, on a mg/m² basis.⁴

Gepirone showed no mutagenicity in three different in vitro genotoxicity assays (bacterial gene mutation, mammalian gene mutation, or DNA repair). No clastogenicity was observed in a rat micronucleus assay.⁴

When gepirone was administered orally to male and female rats prior to and throughout mating at daily doses of 5, 27, 64, and 150 mg/kg, the latency to mating was increased at doses of 64 mg/kg (8 times the MRHD on a mg/m² basis) and above.⁴

Pathways

Not Available

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Not Available

Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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1,2-Benzodiazepine	The risk or severity of CNS depression can be increased when Gepirone is combined with 1,2-Benzodiazepine.
Abametapir	The serum concentration of Gepirone can be increased when it is combined with Abametapir.
Acalabrutinib	The serum concentration of Gepirone can be increased when it is combined with Acalabrutinib.
Acebutolol	The risk or severity of QTc prolongation can be increased when Gepirone is combined with Acebutolol.
Acenocoumarol	The risk or severity of adverse effects can be increased when Gepirone is combined with Acenocoumarol.

Food Interactions

• Take with food. Take gepirone 1 time each day with food at about the same time each day.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Gepirone Hydrochloride	80C9L8EP6V	83928-66-9	DGOCVISYYYQFEP-UHFFFAOYSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Exxua	Tablet, extended release	36.3 mg/1	Oral	Fabre Kramer Pharmaceuticals, Inc.	2024-01-01	Not applicable
Exxua	Tablet, extended release	72.6 mg/1	Oral	Fabre Kramer Pharmaceuticals, Inc.	2024-01-01	Not applicable
Exxua	Tablet, extended release	18.2 mg/1	Oral	Fabre Kramer Pharmaceuticals, Inc.	2024-01-01	Not applicable
Exxua	Tablet, extended release	54.5 mg/1	Oral	Fabre Kramer Pharmaceuticals, Inc.	2024-01-01	Not applicable

Categories

ATC Codes

N06AX19 — Gepirone

• N06AX — Other antidepressants
• N06A — ANTIDEPRESSANTS
• N06 — PSYCHOANALEPTICS
• N — NERVOUS SYSTEM

Drug Categories

• Anti-Anxiety Agents
• Antidepressive Agents
• Central Nervous System Agents
• Central Nervous System Depressants
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Nervous System
• Neurotransmitter Agents
• Psychoanaleptics
• Psychotropic Drugs
• Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
• Serotonin Agents
• Serotonin Receptor Agonists
• Tranquilizing Agents

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as n-arylpiperazines. These are organic compounds containing a piperazine ring where the nitrogen ring atom carries an aryl group.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Diazinanes

Sub Class

Piperazines

Direct Parent

N-arylpiperazines

Alternative Parents

Piperidinediones / Dialkylarylamines / N-alkylpiperazines / Delta lactams / Aminopyrimidines and derivatives / N-substituted carboxylic acid imides / Heteroaromatic compounds / Dicarboximides / Trialkylamines / Amino acids and derivatives / Azacyclic compounds / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds

show 5 more

Substituents

Amine / Amino acid or derivatives / Aminopyrimidine / Aromatic heteromonocyclic compound / Azacycle / Carbonyl group / Carboxylic acid derivative / Carboxylic acid imide / Carboxylic acid imide, n-substituted / Delta-lactam / Dialkylarylamine / Dicarboximide / Heteroaromatic compound / Hydrocarbon derivative / Lactam / N-alkylpiperazine / N-arylpiperazine / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Piperidine / Piperidinedione / Piperidinone / Pyrimidine / Tertiary aliphatic amine / Tertiary amine

show 19 more

Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

JW5Y7B8Z18

CAS number

83928-76-1

InChI Key

QOIGKGMMAGJZNZ-UHFFFAOYSA-N

InChI

InChI=1S/C19H29N5O2/c1-19(2)14-16(25)24(17(26)15-19)9-4-3-8-22-10-12-23(13-11-22)18-20-6-5-7-21-18/h5-7H,3-4,8-15H2,1-2H3

IUPAC Name

4,4-dimethyl-1-{4-[4-(pyrimidin-2-yl)piperazin-1-yl]butyl}piperidine-2,6-dione

SMILES

CC1(C)CC(=O)N(CCCCN2CCN(CC2)C2=NC=CC=N2)C(=O)C1

References

General References

1. Robinson DS, Sitsen JM, Gibertini M: A review of the efficacy and tolerability of immediate-release and extended-release formulations of gepirone. Clin Ther. 2003 Jun;25(6):1618-33. doi: 10.1016/s0149-2918(03)80159-5. [Article]
2. Jenkins SW, Robinson DS, Fabre LF Jr, Andary JJ, Messina ME, Reich LA: Gepirone in the treatment of major depression. J Clin Psychopharmacol. 1990 Jun;10(3 Suppl):77S-85S. doi: 10.1097/00004714-199006001-00014. [Article]
3. Yocca FD: Neurochemistry and neurophysiology of buspirone and gepirone: interactions at presynaptic and postsynaptic 5-HT1A receptors. J Clin Psychopharmacol. 1990 Jun;10(3 Suppl):6S-12S. [Article]
4. FDA Approved Drug Products: EXXUA (gepirone) extended-release tablets, for oral use [Link]
5. Gepirone US Patent Application Publication [Link]
6. Fabre-Kramer Pharmaceuticals Announces FDA Approval of EXXUA™, the First and Only Oral Selective 5HT1a Receptor Agonist for the Treatment of Major Depressive Disorder in Adults [Link]

External Links

Human Metabolome Database

HMDB0252698

PubChem Compound

55191

PubChem Substance

347828470

ChemSpider

49836

BindingDB

50005132

RxNav

2672253

ChEBI

135990

ChEMBL

CHEMBL284092

ZINC

ZINC000002021499

Wikipedia

Gepirone

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
2	Completed	Treatment	Cocaine Related Disorders	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, extended release	Oral	18.2 mg/1
Tablet, extended release	Oral	36.3 mg/1
Tablet, extended release	Oral	54.5 mg/1
Tablet, extended release	Oral	72.6 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US7538116	No	2009-05-26	2025-09-02

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	1.09 mg/mL	ALOGPS
logP	2.09	ALOGPS
logP	1.35	Chemaxon
logS	-2.5	ALOGPS
pKa (Strongest Basic)	7.62	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	6	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	69.64 Å2	Chemaxon
Rotatable Bond Count	6	Chemaxon
Refractivity	101.49 m3·mol-1	Chemaxon
Polarizability	40.93 Å3	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-03xr-0039000000-5c4c70d92f0097810f84
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0009000000-35404b10cdf1fb4cac2a
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-017i-0093000000-835d4315182b456865d5
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0119000000-fc530299a0a3404940b4
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-014l-1690000000-2e1e72202d3b21c4aa52
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0w4i-6954000000-c187836cfc751410fc87
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	186.46135	predicted	DeepCCS 1.0 (2019)
[M+H]+	188.9149	predicted	DeepCCS 1.0 (2019)
[M+Na]+	196.18336	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. 5-hydroxytryptamine receptor 1A

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Partial agonist

General Function

Serotonin receptor activity

Specific Function

G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers...

Gene Name

HTR1A

Uniprot ID

P08908

Uniprot Name

5-hydroxytryptamine receptor 1A

Molecular Weight

46106.335 Da

References

1. FDA Approved Drug Products: EXXUA (gepirone) extended-release tablets, for oral use [Link]

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Drug created at October 20, 2016 21:33 / Updated at January 09, 2024 06:15