- Accession Number
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.
- Small Molecule
- Approved, Investigational
- Average: 318.4935
- Chemical Formula
- 3alpha-OH DHP
- External IDs
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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
- Contraindications & Blackbox Warnings
- Contraindications & Blackbox WarningsWith our commercial data, access important information on dangerous risks, contraindications, and adverse effects.Our Blackbox Warnings cover Risks, Contraindications, and Adverse Effects
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.
Target Actions Organism AGABA(A) Receptorpositive allosteric modulator Humans
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.
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.
The terminal half-life observed for brexanolone is approximately 9 hours Label.
The total plasma clearance determined for brexanolone is approximately 1 L/h/kg Label.
- Adverse Effects
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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
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
- 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 Acetazolamide The risk or severity of adverse effects can be increased when Acetazolamide is combined with Brexanolone. Acetophenazine The risk or severity of adverse effects can be increased when Acetophenazine is combined with Brexanolone. Aclidinium Brexanolone may increase the central nervous system depressant (CNS depressant) activities of Aclidinium. Agomelatine The risk or severity of adverse effects can be increased when Agomelatine is combined with Brexanolone. Alfentanil The risk or severity of adverse effects can be increased when Alfentanil is combined with Brexanolone. Alimemazine The risk or severity of adverse effects can be increased when Alimemazine is combined with Brexanolone. Almotriptan The risk or severity of adverse effects can be increased when Almotriptan is combined with Brexanolone. Alosetron The risk or severity of adverse effects can be increased when Alosetron is combined with Brexanolone. Alprazolam The risk or severity of adverse effects can be increased when Alprazolam is combined with Brexanolone. Alverine The risk or severity of adverse effects can be increased when Alverine is combined with Brexanolone.Improve patient outcomesBuild effective decision support tools with the industry’s most comprehensive drug-drug interaction checker.Learn more
- Food Interactions
- Avoid alcohol. Ingesting alcohol may increase the dizziness and drowsiness caused by brexanolone.
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- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Zulresso Injection, solution 5 mg/1mL Intravenous Sage Therapeutics, Inc. 2019-06-17 Not applicable
- Drug Categories
- Central Nervous System Agents
- Central Nervous System Depressants
- Compounds used in a research, industrial, or household setting
- Corpus Luteum Hormones
- Diet, Food, and Nutrition
- Dietary Carbohydrates
- Fused-Ring Compounds
- GABA Modulators
- Gonadal Hormones
- Gonadal Steroid Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Macromolecular Substances
- Pharmaceutical Preparations
- Physiological Phenomena
- Progesterone Congeners
- Chemical TaxonomyProvided by Classyfire
- 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.
- Organic compounds
- Super Class
- Lipids and lipid-like molecules
- 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
- 20-oxosteroid / 3-alpha-hydroxysteroid / 3-hydroxysteroid / Alcohol / Aliphatic homopolycyclic compound / Carbonyl group / Cyclic alcohol / Hydrocarbon derivative / Hydroxysteroid / Ketone
- Molecular Framework
- Aliphatic homopolycyclic compounds
- External Descriptors
- 3-hydroxy-5alpha-pregnan-20-one (CHEBI:50169) / C21 steroids (gluco/mineralocorticoids, progestogins) and derivatives (LMST02030156)
- CAS number
- InChI Key
- IUPAC Name
- General References
- 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]
- 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]
- 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]
- 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]
- 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]
- Sage Therapeutics Reports Top-Line Results from Phase 3 STATUS Trial of Brexanolone in Super-Refractory Status Epilepticus: Press Release [Link]
- NHS Evidence Briefing January 2019: Brexanolone for postpartum depression [File]
- FDA approves first treatment for post-partum depression: Press Release [File]
- FDA Briefing Document: New Drug Application 211371/New Drug Application, brexanolone for the Treatment of Postpartum Depression [File]
- Clonazepam Fact Sheet from http://cdn.neiglobal.com/content/pg/live/clonazepam.pdf [File]
- FDA label
- Download (553 KB)
- Download (189 KB)
- Clinical Trials
Phase Status Purpose Conditions Count 4 Withdrawn Other Postpartum Depression 1 3 Completed Treatment Postpartum Depression 3 3 Completed Treatment Super-Refractory Status Epilepticus 1 3 Recruiting Treatment Acute Respiratory Distress Syndrome (ARDS) / Coronavirus Disease 2019 (COVID‑19) 1 2 Completed Treatment Fragile X-Associated Tremor/Ataxia Syndrome 1 2 Completed Treatment Postpartum Depression 1 2 Completed Treatment Posttraumatic Epilepsy / Traumatic Brain Injury (TBI) 1 2 Completed Treatment Severe Postpartum Depression 1 2 Completed Treatment Tremor, Essential 1 2 Not Yet Recruiting Other Post Traumatic Stress Disorder (PTSD) 1
- Not Available
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Intravenous 5 mg/1mL
- Not Available
Patent Number Pediatric Extension Approved Expires (estimated) Region US7635773 No 2009-12-22 2029-03-13 US8410077 No 2013-04-02 2029-03-13 US9200088 No 2015-12-01 2029-03-13 US9750822 No 2017-09-05 2029-03-13 US10117951 No 2018-11-06 2029-03-13 US10251894 No 2019-04-09 2033-11-27 US10322139 No 2019-06-18 2033-01-23
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00136 mg/mL ALOGPS logP 4.28 ALOGPS logP 3.99 ChemAxon logS -5.4 ALOGPS pKa (Strongest Acidic) 18.3 ChemAxon pKa (Strongest Basic) -1.4 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 2 ChemAxon Hydrogen Donor Count 1 ChemAxon Polar Surface Area 37.3 Å2 ChemAxon Rotatable Bond Count 1 ChemAxon Refractivity 92.91 m3·mol-1 ChemAxon Polarizability 38.52 Å3 ChemAxon Number of Rings 4 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule Yes ChemAxon MDDR-like Rule No ChemAxon
- Predicted ADMET Features
- Not Available
- Mass Spec (NIST)
- Not Available
Spectrum Spectrum Type Splash Key GC-MS Spectrum - GC-MS (1 MEOX; 1 TMS) GC-MS splash10-0udi-6910000000-837b37f206729753b640 Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available GC-MS Spectrum - GC-MS GC-MS splash10-0udi-6910000000-837b37f206729753b640 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
- Protein group
- Pharmacological action
- 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...
- Pharmacological action
- 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
- Uniprot ID
- Uniprot Name
- Aldose reductase
- Molecular Weight
- 35853.125 Da
Drug created on October 20, 2016 20:54 / Updated on February 21, 2021 18:53