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 5HT1A 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 5HT1A 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
Weight
Average: 359.474
Monoisotopic: 359.232125194
Chemical Formula
C19H29N5O2
Synonyms
  • Gepirone

Pharmacology

Indication

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

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofMajor depressive disorder (mdd)•••••••••••••••••••••••• •••••••• •••••••
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 5HT1A receptors (Ki = 38 nM and 58 nM, respectively), where they act as agonists, while the 1-PP metabolite binds to α2 receptors (Ki = 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 5HT1a receptors.4 Particularly, gepirone

TargetActionsOrganism
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 (Cmax) after dosing is reached within 6 hours post-dose (Tmax).4

After a high-fat meal, Tmax is reached at 3 hours. A significant effect of food has been observed on the peak plasma concentration (Cmax) of gepirone and, to a lesser extent, on the total exposure (AUC0-tlast, AUC0-∞) 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 Cmax 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 Cmax 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

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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
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of CNS depression can be increased when Gepirone is combined with 1,2-Benzodiazepine.
AbametapirThe serum concentration of Gepirone can be increased when it is combined with Abametapir.
AcalabrutinibThe serum concentration of Gepirone can be increased when it is combined with Acalabrutinib.
AcebutololThe risk or severity of QTc prolongation can be increased when Gepirone is combined with Acebutolol.
AcenocoumarolThe 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.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Gepirone Hydrochloride80C9L8EP6V83928-66-9DGOCVISYYYQFEP-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ExxuaTablet, extended release72.6 mg/1OralFabre Kramer Pharmaceuticals, Inc.2024-01-01Not applicableUS flag
ExxuaTablet, extended release18.2 mg/1OralFabre Kramer Pharmaceuticals, Inc.2024-01-01Not applicableUS flag
ExxuaTablet, extended release54.5 mg/1OralFabre Kramer Pharmaceuticals, Inc.2024-01-01Not applicableUS flag
ExxuaTablet, extended release36.3 mg/1OralFabre Kramer Pharmaceuticals, Inc.2024-01-01Not applicableUS flag

Categories

ATC Codes
N06AX19 — Gepirone
Drug Categories
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
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
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]
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
PhaseStatusPurposeConditionsCount
2CompletedTreatmentCocaine Related Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, extended releaseOral18.2 mg/1
Tablet, extended releaseOral36.3 mg/1
Tablet, extended releaseOral54.5 mg/1
Tablet, extended releaseOral72.6 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7538116No2009-05-262025-09-02US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility1.09 mg/mLALOGPS
logP2.09ALOGPS
logP1.35Chemaxon
logS-2.5ALOGPS
pKa (Strongest Basic)7.62Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area69.64 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity101.49 m3·mol-1Chemaxon
Polarizability40.93 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-03xr-0039000000-5c4c70d92f0097810f84
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-0009000000-35404b10cdf1fb4cac2a
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-017i-0093000000-835d4315182b456865d5
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-0119000000-fc530299a0a3404940b4
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-014l-1690000000-2e1e72202d3b21c4aa52
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0w4i-6954000000-c187836cfc751410fc87
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[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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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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: EXXUA (gepirone) extended-release tablets, for oral use [Link]

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