NAV

Zuranolone

Identification

Summary

Zuranolone is a neuroactive steroid drug used to treat postpartum depression

Brand Names
Zurzuvae
Generic Name
Zuranolone
DrugBank Accession Number
DB15490
Background

Zuranolone is a neuroactive steroid that acts as a positive allosteric modulator of the GABAA receptors. Unlike other more common GABAA positive allosteric modulators on the market like benzodiazepines, zuranolone can modulate both synaptic and extrasynaptic GABAA conductance due to binding to a non-benzodiazepine site on the receptor.1,3 Zuranolone was designed with a pharmacological profile of a neuroactive steroid in mind while also possessing a pharmacokinetics profile of an oral, once-daily dosing formulation.4

Zuranolone was approved by the FDA on August 4th, 2023, and it is currently the only approved treatment for women with postpartum depression. This approval was based on favorable results from 2 phase 3 clinical trials.6

Type
Small Molecule
Groups
Approved, Experimental
Structure
3D
Similar Structures
Weight
Average: 409.574
Monoisotopic: 409.272927379
Chemical Formula
C25H35N3O2
Synonyms
  • Zuranolone
External IDs
  • SAGE 217
  • SAGE-217
  • SAGE217
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Pharmacology

Indication

Zuranolone is indicated for the treatment of postpartum depression (PPD) in adults.5

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofPostpartum depression••••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

At two times the maximum recommended dose, zuranolone does not cause clinically significant QTc interval prolongation. Co-administration of repeated 50 mg daily doses of zuranolone with alcohol or alprazolam led to impairment in psychomotor performance.5

Zuranolone exhibited an EC50 of 430 nM and 118 nM at the α1β2γ2 and α4β3δ GABAA receptors respectively, the two most abundant synaptic and extrasynaptic receptors in the brain.1 Therefore, zuranolone can potentiate both phasic and tonic postsynaptic currents associated with modulation of the synaptic and extrasynaptic GABAA receptors respectively.1,3 Since tonic current can produce a larger inhibitory effect compared to phasic current, the ability of zuranolone to modulate the tonic current provides a greater opportunity to enhance GABA conductance.1

Mechanism of action

The mechanism of action of zuranolone in the treatment of PPD is not fully understood but is thought to be related to its positive allosteric modulation of GABAA receptors.5

Unlike benzodiazepines, another class of GABAA positive modulators, zuranolone binds to the α/β subunit interface presented in all GABAA receptors instead of the α/γ subunit interface.1 Therefore, zuranolone can bind to both synaptic GABAA receptors, composed of 2α2βγ subunits, and extrasynaptic GABAA receptors, composed of 2α2βδ subunits.2

TargetActionsOrganism
AGABA(A) Receptor
positive allosteric modulator
Humans
Absorption

Following oral administration, peak zuranolone concentrations occur at 5 to 6 hours (Tmax). The absolute bioavailability of zuranolone was not evaluated.5

Zuranolone exposure (Cmax and AUC) increased approximately dose proportionally with doses ranging from 30 mg to 60 mg (1.2 times the recommended dosage of zuranolone) with a moderate-fat meal (700 calories; 30% fat). Once-daily administration of Zuranolone resulted in an accumulation of approximately 1.5-fold in systemic exposures and a steady state was achieved in 3 to 5 days.5

Following administration of 30 mg of zuranolone to healthy subjects, the Cmax increased by approximately 3.5-fold, and the AUClast increased by approximately 1.8-fold with a low-fat meal (400 to 500 calories, 25% fat) compared to fasted conditions. The Cmax increased by approximately 4.3-fold and the AUClast increased by approximately 2-fold with a high-fat meal (800 to 1,000 calories, 50% fat) compared to fasted conditions. The Tmax was not impacted by food.5

Volume of distribution

The volume of distribution of zuranolone following oral administration is greater than 500 L.5

Protein binding

The mean blood-to-plasma concentration ratio ranged from 0.54 to 0.58. Plasma protein binding is greater than 99.5%.5

Metabolism

Zuranolone undergoes extensive metabolism, with CYP3A4 identified as a primary enzyme involved. There were no circulating human metabolites greater than 10% of total drug-related materials and none are considered to contribute to the therapeutic effects of zuranolone.5

Route of elimination

Following oral administration of radiolabeled zuranolone, 45% of the dose was recovered in urine as metabolites with negligible unchanged zuranolone and 41% in feces as metabolites with less than 2% as unchanged zuranolone.5

Half-life

The terminal half-life of zuranolone is approximately 19.7 to 24.6 hours in the adult population.5

Clearance

The mean apparent clearance (CL/F) of zuranolone is 33 L/h.5

Adverse Effects
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Toxicity

Based on findings from animal studies, zuranolone may cause fetal harm. Advise pregnant women of the potential risk to a fetus. Available data on zuranolone use in pregnant women from the clinical development program are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.5

In animals, oral administration of zuranolone to pregnant rats during organogenesis resulted in developmental toxicity, including embryofetal death and fetal malformations, with a no adverse effect level (NOAEL) associated with maternal plasma exposures 7 times greater than in humans at the maximum recommended human dose (MRHD) of 50 mg. Oral administration of zuranolone to rats during pregnancy and lactation resulted in developmental toxicity in the offspring, including, perinatal mortality, at maternal exposures similar to that in humans at the MRHD. Developmental toxicity was observed at doses that were also maternally toxic. Neuronal death was observed in rats exposed to zuranolone during a period of brain development that begins during the third trimester of pregnancy in humans and continues up to a few years after birth.5

Zuranolone has abuse potential with associated risks of misuse, abuse, and substance use disorder including addiction. Abuse is the intentional non-therapeutic use of a drug, even once, for its desired psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Individuals with a history of drug abuse or substance use disorders may be at a greater risk of these outcomes with zuranolone.5

In a human abuse potential study, single oral doses of 30 mg, 60 mg, and 90 mg of zuranolone (0.6 times, 1.2 times, and 1.8 times the recommended daily dose, respectively) were compared to single oral doses of alprazolam (1.5 mg and 3 mg) and placebo in healthy, non-dependent individuals with a history of recreational CNS depressant use. The study demonstrated that zuranolone has dose-dependent abuse potential comparable to alprazolam and greater abuse potential than placebo on positive subjective measures of “drug liking,” “overall drug liking,” “take drug again,” “high,” and “good drug effects.” In the human abuse potential study, dose-dependent, abuse-related adverse reactions, including euphoric mood, feeling drunk, and somnolence, were reported with zuranolone use.5

Zuranolone may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.5

Adverse reactions reported upon discontinuation of zuranolone in healthy subjects who received 50 mg of zuranolone for 5 to 7 days (on the 7th-day subjects received 50 mg or 100 mg ) included: insomnia, palpitations, decreased appetite, nightmare, nausea, hyperhidrosis, and paranoia. These adverse reactions indicate a potential for physical dependence on zuranolone. These adverse reactions were mild-to-moderate in severity.5

The risk of developing physical dependence and a subsequent withdrawal syndrome upon abrupt zuranolone discontinuation for individuals who take a higher-than-recommended dosage and/or use zuranolone for a longer duration than recommended has not been evaluated in clinical studies. However, convulsions were observed in a dog upon abrupt zuranolone discontinuation after dogs were administered zuranolone for 14 days at doses that produced exposures higher than the maximum recommended human dose.5

There was a case of intentional overdose with zuranolone reported during premarketing clinical trials. The patient took 330 mg (6.5 times the maximum recommended dose) of zuranolone and was reported to be in an altered state of consciousness. The event resolved the next day, following treatment with intravenous fluids.5

Overdosage with zuranolone may result in excessive CNS depressant effects such as somnolence and disturbance in consciousness. There is no specific antidote for zuranolone overdosage.5

Consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.5

Oral administration of zuranolone in a 26-week carcinogenicity study in transgenic mice (0, 10, 30, or 100 mg/kg/day), and in a 104-week carcinogenicity study in rats (0, 2, 6, or 20 mg/kg/day in males and 0, 0.2, 0.6, or 1.5 mg/kg/day in females) was not associated with increases in tumors in either species. Plasma exposures (AUC) in rats at the highest dose tested were approximately 4 times that in humans at the maximum recommended human dose (MRHD) of 50 mg.5

Zuranolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay, an in vitro chromosome aberration assay in Chinese hamster ovary cells, and an in vivo bone marrow micronucleus assay in rats.5

Pathways
Not Available
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Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
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
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1,2-BenzodiazepineThe risk or severity of CNS depression can be increased when Zuranolone is combined with 1,2-Benzodiazepine.
AbametapirThe serum concentration of Zuranolone can be increased when it is combined with Abametapir.
AcenocoumarolThe risk or severity of adverse effects can be increased when Zuranolone is combined with Acenocoumarol.
AcetaminophenThe serum concentration of Zuranolone can be decreased when it is combined with Acetaminophen.
AcetazolamideThe risk or severity of CNS depression can be increased when Zuranolone is combined with Acetazolamide.
Food Interactions
  • Take with a high fat meal. Cmax and AUClast increased by approximately 4.3 and 2 fold respectively with a high fat meal.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZurzuvaeCapsule25 mg/1OralBiogen MA Inc.2023-10-31Not applicableUS flag
ZurzuvaeCapsule30 mg/1OralBiogen MA Inc.2023-10-31Not applicableUS flag
ZurzuvaeCapsule20 mg/1OralBiogen MA Inc.2023-10-31Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
7ZW49N180B
CAS number
1632051-40-1
InChI Key
HARRKNSQXBRBGZ-GVKWWOCJSA-N
InChI
InChI=1S/C25H35N3O2/c1-24(30)9-7-18-17(11-24)3-4-20-19(18)8-10-25(2)21(20)5-6-22(25)23(29)15-28-14-16(12-26)13-27-28/h13-14,17-22,30H,3-11,15H2,1-2H3/t17-,18+,19-,20-,21+,22-,24-,25+/m1/s1
IUPAC Name
1-{2-[(1S,3aS,3bR,5aR,7R,9aS,9bR,11aS)-7-hydroxy-7,11a-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]-2-oxoethyl}-1H-pyrazole-4-carbonitrile
SMILES
[H][C@@]1(CC[C@@]2([H])[C@]3([H])CC[C@]4([H])C[C@](C)(O)CC[C@]4([H])[C@@]3([H])CC[C@]12C)C(=O)CN1C=C(C=N1)C#N

References

General References
  1. Althaus AL, Ackley MA, Belfort GM, Gee SM, Dai J, Nguyen DP, Kazdoba TM, Modgil A, Davies PA, Moss SJ, Salituro FG, Hoffmann E, Hammond RS, Robichaud AJ, Quirk MC, Doherty JJ: Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABA(A) receptor positive allosteric modulator. Neuropharmacology. 2020 Dec 15;181:108333. doi: 10.1016/j.neuropharm.2020.108333. Epub 2020 Sep 22. [Article]
  2. Reddy DS: Role of anticonvulsant and antiepileptogenic neurosteroids in the pathophysiology and treatment of epilepsy. Front Endocrinol (Lausanne). 2011 Oct 5;2:38. doi: 10.3389/fendo.2011.00038. eCollection 2011. [Article]
  3. Clayton AH, Lasser R, Nandy I, Sankoh AJ, Jonas J, Kanes SJ: Zuranolone in Major Depressive Disorder: Results From MOUNTAIN-A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial. J Clin Psychiatry. 2023 Feb 20;84(2):22m14445. doi: 10.4088/JCP.22m14445. [Article]
  4. Martinez Botella G, Salituro FG, Harrison BL, Beresis RT, Bai Z, Blanco MJ, Belfort GM, Dai J, Loya CM, Ackley MA, Althaus AL, Grossman SJ, Hoffmann E, Doherty JJ, Robichaud AJ: Neuroactive Steroids. 2. 3alpha-Hydroxy-3beta-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5beta-pregnan-20-one (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (gamma-Aminobutyric Acid)(A) Receptor. J Med Chem. 2017 Sep 28;60(18):7810-7819. doi: 10.1021/acs.jmedchem.7b00846. Epub 2017 Aug 17. [Article]
  5. FDA Approved Drug Products: ZURZUVAETM (zuranolone) capsules, for oral use, [Link]
  6. FDA Approves ZURZUVAE™ (zuranolone), the First and Only Oral Treatment Approved for Women with Postpartum Depression, and Issues a Complete Response Letter for Major Depressive Disorder [Link]
ChemSpider
71117610
BindingDB
50258216
RxNav
2669905
ChEMBL
CHEMBL4105630
Wikipedia
Zuranolone

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
3CompletedTreatmentMajor Depressive Disorder (MDD)4
3CompletedTreatmentPostpartum Depression2
3TerminatedTreatmentInsomnia / Major Depressive Disorder (MDD)1
3TerminatedTreatmentMajor Depressive Disorder (MDD)1
2CompletedTreatmentBipolar 1 Disorder / Bipolar Disorder, Type II / Major Depressive Episode1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral20 mg/1
CapsuleOral25 mg/1
CapsuleOral30 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10342810No2014-04-172034-04-17US flag
US10172871No2014-04-172034-04-17US flag
US9512165No2014-04-172034-04-17US flag
US11236121No2017-08-232037-08-23US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0159 mg/mLALOGPS
logP4.03ALOGPS
logP3.93Chemaxon
logS-4.4ALOGPS
pKa (Strongest Acidic)17.85Chemaxon
pKa (Strongest Basic)1.36Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area78.91 Å2Chemaxon
Rotatable Bond Count3Chemaxon
Refractivity127.19 m3·mol-1Chemaxon
Polarizability47.55 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
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/MSsplash10-0006-0009000000-6ff94fa7332c96d25c95
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-01ox-0849400000-e5b3fccf5f3f59cd5aaa
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-0000900000-10031b460f461478e9b4
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a59-2009600000-4ea45cbcdbf4f4ec11f1
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00ai-1964100000-cae1298fc75bb249060a
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0ir0-3009100000-8f89ea66ee04a1b42190
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Enzymes

Details1. Cytochrome P450 3A4
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: ZURZUVAETM (zuranolone) capsules, for oral use, [Link]

Drug created at September 05, 2019 15:08 / Updated at January 10, 2024 06:22