Gepirone

Clinical data
Trade names	Exxua
Other names	BMY-13805; MJ-13805; ORG-13011
Routes of administration	By mouth[1]
ATC code	N06AX19 (WHO)
Legal status
Legal status	US: ℞-only[1]
Pharmacokinetic data
Bioavailability	14–17%[1]
Protein binding	72%[1]
Metabolism	CYP3A4[1]
Metabolites	3'-OH-gepirone; 1-(2-Pyrimidinyl)piperazine[1]
Eliminationhalf-life	IRTooltip Instant release: 2–3 hours ERTooltip Modified-release dosage: 5 hours[1]
Excretion	Urine: 81%[1] Feces: 13%[1]
Identifiers
IUPAC name 4,4-Dimethyl-1-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]piperidine-2,6-dione
CAS Number	83928-76-1 Y 83928-66-9
PubChemCID	55191
DrugBank	DB12184 DBSALT002148
ChemSpider	49836 Y 49835
UNII	JW5Y7B8Z18 80C9L8EP6V
KEGG	D04314
ChEBI	CHEBI:135990
ChEMBL	ChEMBL284092 Y ChEMBL1204187
CompTox Dashboard(EPA)	DTXSID90232813
Chemical and physical data
Formula	C19H29N5O2
Molar mass	359.474 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C1N(C(=O)CC(C)(C)C1)CCCCN3CCN(c2ncccn2)CC3
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 Y Key:QOIGKGMMAGJZNZ-UHFFFAOYSA-N Y
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Gepirone, sold under the brand nameExxua, is amedication used for the treatment ofmajor depressive disorder.^[1] It is takenorally.^[1]

Side effects of gepirone includedizziness,nausea,insomnia,abdominal pain, anddyspepsia (indigestion).^[1] Gepirone acts as apartial agonist of theserotonin5-HT_1A receptor.^[1][2] Anactive metabolite of gepirone,1-(2-pyrimidinyl)piperazine, is anα₂-adrenergic receptorantagonist.^[1][3] Gepirone is a member of theazapirone group of compounds.^[2]

Gepirone was synthesized byBristol-Myers Squibb in 1986 and was developed and marketed byFabre-Kramer Pharmaceuticals.^[4] It was approved for the treatment of major depressive disorder in the United States in September 2023.^[4] This came after the drug had been rejected by theFood and Drug Administration (FDA) three times over two decades due to insufficient evidence of effectiveness.^[5]

Gepirone isindicated for the treatment ofmajor depressive disorder (MDD) in adults.^[1] Of 15 clinical trials of gepirone for major depressive disorder submitted to the U.S.Food and Drug Administration (FDA), three were excluded formethodological reasons, three were deemed "failed" and "uninformative", seven were deemed negative and did not demonstrate effectiveness, and two were deemed positive and did show effectiveness.^[6] Two positive trials are needed for FDA drug approval, with this being the case regardless of the number of negative trials.^[7] In the two positive trials of gepirone for depression, the drugsignificantly outperformedplacebo in terms of depressive symptom reduction and showedeffect sizes similar to those of other approved antidepressants.^[1][8] In both trials, gepirone reduced depressive symptoms by about 2.5 points more than placebo on the 52-pointHamilton Depression Rating Scale (17-item version or HAMD-17).^[1] The baseline depression scores in the trials ranged from 22.7 to 24.2 in the different patient groups.^[1]

Gepirone comes in the form ofextended-releasetablets of thehydrochloridesalt, gepirone hydrochloride, in the strengths 18.2 mg, 36.3 mg, 54.5 mg, and 72.6 mg.^[1]

It is not known if gepirone is safe in women who are breastfeeding. Medications with more data in this setting may be preferred.^[9]

Gepirone iscontraindicated in people that have experienced an allergic reaction to gepirone, a correctedQT interval > 450 msec, a history of congenitallong QT syndrome, use medications that strongly inhibit CYP3A4 (an enzyme involved in gepirone's metabolism), severe liver problems, or have used amonoamine oxidase inhibitor (MAOI) medication within 14 days.^[1]

Seriousside effects of gepirone includeQT prolongation (increases the risk of a potentially life-threatening cardiac arrhythmia calledtorsade de pointes),serotonin syndrome (especially in the presence of other serotonergic drugs), and activation ofmania orhypomania in people withbipolar disorder. Common side effects includedizziness,nausea,insomnia,abdominal pain, anddyspepsia (indigestion).^[1]

TheCYP3A4inhibitorsketoconazole andverapamil strongly increase exposure to gepirone, whereaslithium,paroxetine, andwarfarin have no effect on exposure to gepirone.^[1] The CYP3A4inducerrifampin profoundly decreases exposure to gepirone.^[1]

Gepirone acts as aselectivepartial agonist of the5-HT_1A receptor.^[2] Unlike its relativebuspirone, however, gepirone has greaterefficacy in activating the 5-HT_1A and has negligibleaffinity for theD₂ receptor (30- to 50-fold lower in comparison tobuspirone).^[10] However, similarly to buspirone, gepironemetabolizes into1-(2-pyrimidinyl)piperazine (1-PP), which is known to act as apotentantagonist of theα₂-adrenergic receptor.^[3]

Theabsolute bioavailability of gepirone is 14 to 17%.^[1] Thetime to peak concentrations of gepirone with the extended-release formulation is 6 hours.^[1] When taken with a high-fat meal, the time to peak levels decreases to 3 hours.^[1] A high-fat meal increases exposure to gepirone, with the effect increasing dependent on the amount of fat in the meal.^[1]Peak concentrations were increased by 27% with a low-fat meal, 55% with a medium-fat meal, and 62% with a high-fat meal, whilearea-under-the-curve levels of gepirone were increased by 14% with a low-fat meal, 22% with a medium-fat meal, and 32 to 37% with a high-fat meal.^[1] The effect was similar for themetabolites of gepirone, 1-PP and 3'-hydroxygepirone (3'-OH-gepirone).^[1]

The apparentvolume of distribution of gepirone is approximately 94.5 L.^[1] Theplasma protein binding of gepironein vitro is 72% and is independent of concentration.^[1] The plasma protein binding of 3'-OH-gepirone is 59% and of 1-PP is 42%.^[1]

Gepirone ismetabolized primarily byCYP3A4.^[1] Its major metabolites are 1-PP and 3'-OH-gepirone, both of which arepharmacologically active.^[1] These metabolites are present in the circulation at higher concentrations than gepirone.^[1]

With a single oral dose ofradiolabeled gepirone, 81% is recovered inurine and 13% is recovered infeces asmetabolites.^[1] About 60% of the gepirone is eliminated in urine within 24 hours.^[1]

Theterminal half-life of gepirone as the extended-release form is approximately 5 hours.^[1]

Gepirone is a member of theazapirone group of compounds and isstructurally related tobuspirone,tandospirone, and other azapirones.^[11]

Gepirone wasdeveloped by Bristol-Myers Squibb in 1986,^[5] but was out-licensed toFabre-Kramer in 1993. The FDA rejected approval for gepirone in 2002 and 2004.^[5] It was submitted for the preregistration (NDA) phase again in May 2007 after adding additional information from clinical trials as the FDA required in 2009. However, in 2012 it once again failed to convince the FDA of its qualities for treating anxiety and depression.^[5] In December 2015, the FDA once again gave gepirone a negative review for depression due to concerns of efficacy.^[12] However, in March 2016, the FDA reversed its decision and gave gepirone ER a positive review.^[13] Gepirone ER was finally approved for the treatment of major depressive disorder in the United States in September 2023.^[5]

The brand name of gepirone is Exxua.^[1] Former tentative brand names which were never used included Ariza, Variza, and Travivo.^[4]

Gepirone is under development for the treatment ofdecreased libido andgeneralized anxiety disorder (GAD).^[4][14][15] As of October 2023, it is inphase IIIclinical trials for these indications.^[4] Thepro-sexual effects of gepirone appear to be independent of its antidepressant and anxiolytic effects.^[14][15]

• 5-HT1A agonists
• Alpha-2 blockers
• Aminopyrimidines
• Antidepressants
• Anxiolytics
• Azapirones
• Glutarimides
• 1-(2-Pyrimidinyl)piperazines

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