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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
Structure for Gepirone (DB12184)
- 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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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Major depressive disorder (mdd) •••••••••••• ••••• ••••••• •••••••• ••••••• - Contraindications & Blackbox Warnings
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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
Target Actions Organism A5-hydroxytryptamine receptor 1A partial agonistHumans - 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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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.
Drug Interaction Integrate drug-drug
interactions in your software1,2-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.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- 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 18.2 mg/1 Oral Fabre Kramer Pharmaceuticals, Inc. 2024-01-01 Not applicable US 
Exxua Tablet, extended release 72.6 mg/1 Oral Fabre Kramer Pharmaceuticals, Inc. 2024-01-01 Not applicable US Exxua Tablet, extended release 54.5 mg/1 Oral Fabre Kramer Pharmaceuticals, Inc. 2024-01-01 Not applicable US Exxua Tablet, extended release 36.3 mg/1 Oral Fabre Kramer Pharmaceuticals, Inc. 2024-01-01 Not applicable US
Categories
- ATC Codes
- N06AX19 — Gepirone
- 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 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
- 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]
- 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]
- 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]
- FDA Approved Drug Products: EXXUA (gepirone) extended-release tablets, for oral use [Link]
- Gepirone US Patent Application Publication [Link]
- 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
- 2672253
- ChEBI
- 135990
- ChEMBL
- CHEMBL284092
- ZINC
- ZINC000002021499
- Wikipedia
- Gepirone
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data2 Completed Treatment Cocaine Related Disorders 1 somestatus stop reason just information to hide
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 US
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 predictedDeepCCS 1.0 (2019) [M+H]+ 188.9149 predictedDeepCCS 1.0 (2019) [M+Na]+ 196.18336 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Partial agonist
- General Function
- G-protein coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:22957663, PubMed:3138543, PubMed:33762731, PubMed:37935376, PubMed:37935377, PubMed:8138923, PubMed:8393041). Also functions as a receptor for various drugs and psychoactive substances (PubMed:22957663, PubMed:3138543, PubMed:33762731, PubMed:38552625, PubMed:8138923, PubMed:8393041). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase (PubMed:22957663, PubMed:3138543, PubMed:33762731, PubMed:8138923, PubMed:8393041). HTR1A is coupled to G(i)/G(o) G alpha proteins and mediates inhibitory neurotransmission: signaling inhibits adenylate cyclase activity and activates a phosphatidylinositol-calcium second messenger system that regulates the release of Ca(2+) ions from intracellular stores (PubMed:33762731, PubMed:35610220). Beta-arrestin family members regulate signaling by mediating both receptor desensitization and resensitization processes (PubMed:18476671, PubMed:20363322, PubMed:20945968). Plays a role in the regulation of 5-hydroxytryptamine release and in the regulation of dopamine and 5-hydroxytryptamine metabolism (PubMed:18476671, PubMed:20363322, PubMed:20945968). Plays a role in the regulation of dopamine and 5-hydroxytryptamine levels in the brain, and thereby affects neural activity, mood and behavior (PubMed:18476671, PubMed:20363322, PubMed:20945968). Plays a role in the response to anxiogenic stimuli (PubMed:18476671, PubMed:20363322, PubMed:20945968)
- Specific Function
- G protein-coupled serotonin receptor activity
- Gene Name
- HTR1A
- Uniprot ID
- P08908
- Uniprot Name
- 5-hydroxytryptamine receptor 1A
- Molecular Weight
- 46106.335 Da
References
- 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
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- 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