Identification

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Name
Brexanolone
Accession Number
DB11859
Type
Small Molecule
Groups
Approved, Investigational
Description

As of March 2019, brexanolone - developed and made available commercially by Sage Therapeutics Inc. as the brand name product Zulresso - is the first drug to have ever been approved by the US FDA specifically for the treatment of postpartum depression (PPD) in adult females 8. Since PPD, like various other types of depression, is characterized by feelings of sadness, worthlessness or guilt, cognitive impairment, and/or possibly suicidal ideation, it is considered a life-threatening condition 9. Studies have consequently found that PPD can genuinely have profound negative effects on the maternal-infant bond and later infant development 9,1,2. The development and availability of brexanolone for the treatment of PPD in adult females subsequently provides a new and promising therapy where few existed before 8.

In particular, the use of brexanolone in treating PPD is surrounded with promise because it acts in part as a synthetic supplement for possible deficiencies in endogenous brexanolone (allopregnanolone) in postpartum women susceptible to PPD whereas many commonly used anti-depressive medications elicit actions that may modulate the presence and activity of substances like serotonin, norepinephrine, and/or monoamine oxidase but do not mediate activities directly associated with PPD like natural fluctuations in the levels of endogenous neuroactive steroids like allopregnanolone 7.

And finally, although brexanolone may also be undergoing clinical trials to investigate its abilities to treat super-refractory status epilepticus, it appears that some such studies have failed to meet primary endpoints that compare success in the weaning of third-line agents and resolution of potentially life-threatening status epilepticus with brexanolone vs. placebo when added to standard-of-care 6.

Structure
Thumb
Synonyms
  • 3alpha-OH DHP
  • allopregnan-3α-ol-20-one
  • Allopregnanolone
  • Brexanolone
External IDs
SAGE-547 / SGE-102
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ZulressoInjection, solution5 mg/1mLIntravenousSage Therapeutics, Inc.2019-06-17Not applicableUs
Additional Data Available
  • Application Number
    Application Number

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  • Product Code
    Product Code

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Categories
UNII
S39XZ5QV8Y
CAS number
516-54-1
Weight
Average: 318.4935
Monoisotopic: 318.255880332
Chemical Formula
C21H34O2
InChI Key
AURFZBICLPNKBZ-SYBPFIFISA-N
InChI
InChI=1S/C21H34O2/c1-13(22)17-6-7-18-16-5-4-14-12-15(23)8-10-20(14,2)19(16)9-11-21(17,18)3/h14-19,23H,4-12H2,1-3H3/t14-,15+,16-,17+,18-,19-,20-,21+/m0/s1
IUPAC Name
1-[(1S,3aS,3bR,5aS,7R,9aS,9bS,11aS)-7-hydroxy-9a,11a-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]ethan-1-one
SMILES
[H][C@@]1(CC[C@@]2([H])[C@]3([H])CC[C@@]4([H])C[C@H](O)CC[C@]4(C)[C@@]3([H])CC[C@]12C)C(C)=O

Pharmacology

Indication

Brexanolone is a synthetic neuroactive steroid gamma-aminobutyric acid A (GABA(a)) receptor positive modulator indicated for the treatment of postpartum depression (PPD) in adult women Label1,2,7,8,9.

Associated Conditions
Pharmacodynamics

Brexanolone potentiated GABA-mediated currents from recombinant human GABA(a) receptors in mammalian cells expressing α1β2γ2 receptor subunits, α4β3δ receptor subunits, and α6β3δ receptor subunits Label7,9.

Moreover, it was determined during a Phase 1 randomized, placebo and positive-controlled, double-blind, three-period crossover thorough QT study in 30 healthy adult subjects that brexanolone use did not prolong the QT interval to any clinically relevant extent when administered at 1.9-times the exposure occurring at the highest recommended infusion rate (90 mcg/kg/hour) Label7,9.

Mechanism of action

Brexanolone is a neuroactive steroid that occurs naturally (referred to as natural allopregnanolone) in the body when the female sex hormone progesterone is metabolized 7. This steroid compound is also believed to exhibit activity as a barbiturate-like, positive allosteric modulator of both synaptic and extrasynaptic GABA(a) receptors Label7,9. In doing so, brexanolone can enhance the activity of GABA at such receptors by having GABA(a) receptor calcium channels open more often and for longer periods of time. Furthermore, it is believed that brexanolone elicits such action on GABA(a) receptors at a binding site that is distinct from those associated with benzodiazepines 9.

Concurrently, GABA is considered the principal inhibitory neurotransmitter in the human body 3,4,5. When GABA binds to GABA(a) receptors found in neuron synapses, chloride ions are conducted across neuron cell membranes via an ion channel in the receptors 3,4,5,10. With enough chloride ions conducted, the local, associated neuron membrane potentials are hyperpolarized - making it more difficult or less likely for action potentials to fire, ultimately resulting in less excitation of the neurons, like those involved in neuronal pathways that may be in part responsible for eliciting certain traits of PPD like stress, anxiety, etc 3,4,5,10.

Postpartum depression (PPD) is a mood disorder that can affect women after childbirth Label1,2,7,8,9. Women with PPD experience feelings of extreme sadness, anxiety, and exhaustion that can make it difficult or even dangerous for them to perform various daily activities or care for themselves or for others, including newborn Label1,2,7,8,9. Although the exact pathophysiology of PPD remains unknown, it is believed that altered profiles and rapid, unpredictable fluctuations in the blood concentrations of neuroactive steroids like endogenous brexanolone (among others), GABA, and GABA receptors occur in women who are at risk of PPD after childbirth Label1,2,7,9.

In particular, within the context of PPD, it is proposed that endogenous brexanolone levels can quickly drop or fluctuate variedly after childbirth and that GABA(a) receptor levels and expression are decreased and down-regulated throughout pregnancy 7. Such fluctuations and decreases may consequently leave women susceptible to the possibility of PPD. As a medication, synthetic brexanolone can subsequently facilitate a return of positive allosteric modulator GABA(a) modulation while GABA(a) receptor levels and expression gradually return to normal in the time following postpartum 7. As such, studies suggest the potential for the development of brexanolone as a new mechanism for treatment of PPD that is directly related to the underlying pathophysiology as opposed to many other antidepressant medications whose pharmacological actions are usually entirely unrelated.

TargetActionsOrganism
AGABA-A receptor (anion channel)
positive allosteric modulator
Humans
Additional Data Available
Adverse Effects

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Absorption

It has been determined that brexanolone has a low oral bioavailability of approximately <5% in adults, which suggests infant exposure would also be expected to be low Label.

Volume of distribution

The volume of distribution documented for brexanolone is approximately 3 L/kg, a value which suggests relatively extensive distribution into tissues Label.

Protein binding

The plasma protein binding recorded for brexanolone is greater than 99% and was determined to be independent of plasma concentrations Label.

Metabolism

Brexanolone is extensively metabolized by non-cytochrome (CYP) based pathways by way of three main routes - keto-reduction (via aldo-keto reductases), glucuronidation (via UDP-glucuronosyltransferases), and sulfation (via sulfotransferases) Label. Three predominant circulating metabolites result from such metabolic pathways and they are all pharmacologically inactive and ultimately do not contribute to the overall efficacy of the medication Label.

Route of elimination

Following the administration of radiolabeled brexanolone, it was observed that 47% of the administrated dose was recovered largely as metabolites in the feces and 42% in urine, where less than 1% as recovered as unchanged brexanolone Label.

Half life

The terminal half-life observed for brexanolone is approximately 9 hours Label.

Clearance

The total plasma clearance determined for brexanolone is approximately 1 L/h/kg Label.

Toxicity

There is limited clinical trial experience regarding human overdosage with brexanolone Label. In premarketing clinical studies, two cases of accidental overdosage due to infusion pump malfunction resulted in transient loss of consciousness Label. Both patients regained consciousness approximately 15 minutes after discontinuation of the infusion without supportive measures Label. After full resolution of symptoms, both patients subsequently resumed and completed treatment Label. Overdosage may result in excessive sedation, including loss of consciousness, and the potential for accompanying respiratory changes Label.

There is no available data on brexanolone use in pregnant women to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes Label. However, based on findings from animal studies of other drugs that enhance GABAergic inhibition, brexanolone may cause fetal harm Label.

Available data from a lactation study in 12 women indicate that brexanolone is transferred to breastmilk in nursing mothers Label. However, the relative infant dose (RID) is low, 1% to 2% of the maternal weight-adjusted dosage Label. Also, as brexanolone has low oral bioavailability in adults, infant exposure is expected to be low Label. There were no reports of effects of brexanolone on milk production Label. There are no data on the effects of brexanolone on a breastfed infant Label. Available data on the use of brexanolone during lactation does not suggest a significant risk of adverse reactions to breastfed infants from exposure to brexanolone Label. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for brexanolone and any potential adverse effects on the breastfed child from brexanolone or from the underlying maternal condition Label.

Brexanolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes, and an in vivo rat bone marrow micronucleus assay Label.

Treatment of female and male rats with brexanolone at doses equal to and greater than 30 mg/kg/day, which is associated with 2 times the plasma levels at the maximum recommended human dose (MRHD) of 90 mcg/kg/hour, caused impairment of female and male fertility and reproduction Label. In female rats, brexanolone was associated with decreased mating and fertility indices, an increase in number of days to mating, prolonged/irregular estrous cycles, an increase in the number of early resorptions, and post implantation loss Label. Reversal of effects in females was observed following a 28-day recovery period Label. In male rats, brexanolone was associated with decreased mating and fertility indices, decreased conception rate, lower prostate, seminal vesicle, and epididymis weight, as well as decreased sperm numbers. Impaired female and male fertility and reproduction were not observed at 0.8 times the MRHD Label.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Brexanolone is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineBrexanolone may increase the excretion rate of 3-isobutyl-1-methyl-7H-xanthine which could result in a lower serum level and potentially a reduction in efficacy.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Brexanolone.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Brexanolone.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Brexanolone is combined with 5-methoxy-N,N-dimethyltryptamine.
6-O-benzylguanineBrexanolone may increase the excretion rate of 6-O-benzylguanine which could result in a lower serum level and potentially a reduction in efficacy.
7-DeazaguanineBrexanolone may increase the excretion rate of 7-Deazaguanine which could result in a lower serum level and potentially a reduction in efficacy.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Brexanolone.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of adverse effects can be increased when 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline is combined with Brexanolone.
7,9-DimethylguanineBrexanolone may increase the excretion rate of 7,9-Dimethylguanine which could result in a lower serum level and potentially a reduction in efficacy.
Additional Data Available
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Food Interactions
Not Available

References

General References
  1. Melon L, Hammond R, Lewis M, Maguire J: A Novel, Synthetic, Neuroactive Steroid Is Effective at Decreasing Depression-Like Behaviors and Improving Maternal Care in Preclinical Models of Postpartum Depression. Front Endocrinol (Lausanne). 2018 Nov 23;9:703. doi: 10.3389/fendo.2018.00703. eCollection 2018. [PubMed:30532739]
  2. Kanes SJ, Colquhoun H, Doherty J, Raines S, Hoffmann E, Rubinow DR, Meltzer-Brody S: Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression. Hum Psychopharmacol. 2017 Mar;32(2). doi: 10.1002/hup.2576. [PubMed:28370307]
  3. DeVane CL, Ware MR, Lydiard RB: Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines: alprazolam, adinazolam, and clonazepam. Psychopharmacol Bull. 1991;27(4):463-73. [PubMed:1687613]
  4. Nardi AE, Machado S, Almada LF, Paes F, Silva AC, Marques RJ, Amrein R, Freire RC, Martin-Santos R, Cosci F, Hallak JE, Crippa JA, Arias-Carrion O: Clonazepam for the treatment of panic disorder. Curr Drug Targets. 2013 Mar;14(3):353-64. [PubMed:23256724]
  5. Jenner P, Pratt JA, Marsden CD: Mechanism of action of clonazepam in myoclonus in relation to effects on GABA and 5-HT. Adv Neurol. 1986;43:629-43. [PubMed:2418652]
  6. Sage Therapeutics Reports Top-Line Results from Phase 3 STATUS Trial of Brexanolone in Super-Refractory Status Epilepticus: Press Release [Link]
  7. NHS Evidence Briefing January 2019: Brexanolone for postpartum depression [File]
  8. FDA approves first treatment for post-partum depression: Press Release [File]
  9. FDA Briefing Document: New Drug Application 211371/New Drug Application, brexanolone for the Treatment of Postpartum Depression [File]
  10. Clonazepam Fact Sheet from http://cdn.neiglobal.com/content/pg/live/clonazepam.pdf [File]
External Links
Human Metabolome Database
HMDB0001449
KEGG Compound
C13712
PubChem Compound
92786
PubChem Substance
347828198
ChemSpider
83760
BindingDB
50191342
ChEBI
50169
ChEMBL
CHEMBL207538
Wikipedia
Allopregnanolone
FDA label
Download (553 KB)
MSDS
Download (189 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAlzheimer's Disease (AD) / Mild Cognitive Impairment (MCI)1
1Not Yet RecruitingTreatmentAlzheimer Dementia (AD)1
1, 2CompletedTreatmentSuper-Refractory Status Epilepticus1
2CompletedTreatmentFragile X-Associated Tremor/Ataxia Syndrome1
2CompletedTreatmentPostpartum Depression1
2CompletedTreatmentPosttraumatic Epilepsy / Traumatic Brain Injury (TBI)1
2CompletedTreatmentSevere Postpartum Depression1
2CompletedTreatmentTremor, Essential1
2Not Yet RecruitingTreatmentTraumatic Brain Injury (TBI)1
3CompletedTreatmentSuper-Refractory Status Epilepticus1
3RecruitingTreatmentPost Partum Depression1
Not AvailableApproved for MarketingNot AvailablePostpartum Depression1
Not AvailableNo Longer AvailableNot AvailableSuper-Refractory Status Epilepticus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous5 mg/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00136 mg/mLALOGPS
logP4.28ALOGPS
logP3.99ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)18.3ChemAxon
pKa (Strongest Basic)-1.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area37.3 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity92.91 m3·mol-1ChemAxon
Polarizability38.52 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
GC-MS Spectrum - GC-MS (1 MEOX; 1 TMS)GC-MSsplash10-0udi-6910000000-837b37f206729753b640
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - GC-MSGC-MSsplash10-0udi-6910000000-837b37f206729753b640
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as gluco/mineralocorticoids, progestogins and derivatives. These are steroids with a structure based on a hydroxylated prostane moiety.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Pregnane steroids
Direct Parent
Gluco/mineralocorticoids, progestogins and derivatives
Alternative Parents
20-oxosteroids / 3-alpha-hydroxysteroids / Secondary alcohols / Ketones / Cyclic alcohols and derivatives / Organic oxides / Hydrocarbon derivatives
Substituents
Progestogin-skeleton / 20-oxosteroid / 3-hydroxysteroid / Hydroxysteroid / 3-alpha-hydroxysteroid / Oxosteroid / Cyclic alcohol / Ketone / Secondary alcohol / Organooxygen compound
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
3-hydroxy-5alpha-pregnan-20-one (CHEBI:50169) / C21 steroids (gluco/mineralocorticoids, progestogins) and derivatives (LMST02030156)

Targets

Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Positive allosteric modulator
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...

Components:
References
  1. Brexanolone FDA Label [File]
  2. NHS Evidence Briefing January 2019: Brexanolone for postpartum depression [File]
  3. FDA Briefing Document: New Drug Application 211371/New Drug Application, brexanolone for the Treatment of Postpartum Depression [File]

Enzymes

1. Sulfotransferase
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Sulfotransferases EC 2.8.2.- are transferase enzymes that catalyze the transfer of a sulfo group from a donor molecule to an acceptor alcohol or amine.
References
  1. Brexanolone FDA Label [File]
2. Glucuronosyltransferase
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Uridine 5'-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT) is a cytosolic glycosyltransferase (EC 2.4.1.17) that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule.
References
  1. Brexanolone FDA Label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Glyceraldehyde oxidoreductase activity
Specific Function
Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies.
Gene Name
AKR1B1
Uniprot ID
P15121
Uniprot Name
Aldose reductase
Molecular Weight
35853.125 Da
References
  1. Pfam Aldo/Keto Reductase Family Profile [Link]
  2. Brexanolone FDA Label [File]

Drug created on October 20, 2016 14:54 / Updated on June 04, 2019 07:28