Identification
- Summary
Ganaxolone is a neuroactive steroid GABA-A receptor modulator used for the treatment of seizures associated with CDKL5 deficiency disorder (CDD).
- Brand Names
- Ztalmy
- Generic Name
- Ganaxolone
- DrugBank Accession Number
- DB05087
- Background
Ganaxolone is the 3β-methylated synthetic analog of allopregnanolone,5 a metabolite of progesterone.1 Ganaxolone belongs to a class of compounds referred to as neurosteroids.1 Endogenous neurosteroids, which comprise certain metabolites of progesterone and deoxycorticosterone, bind potently and specifically to GABAA receptors to enhance their inhibitory effects, and are thus known to have anxiolytic, analgesic, anticonvulsant, sedative, hypnotic, and anesthetic properties.4
Ganaxolone, similar to its endogenous counterparts, is a positive allosteric modulator of GABAA receptors.5 It was approved under the brand name ZTALMY by the US FDA in March 2022 for the treatment of seizures associated with CDKL5 deficiency disorder (CDD), becoming the first FDA-approved treatment indicated specifically for CDD.6 In July 2023, ganaxolone was also approved under the same brand name and for the same indication by the EMA.8
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Ganaxolone (DB05087)
- Weight
- Average: 332.528
Monoisotopic: 332.271530399 - Chemical Formula
- C22H36O2
- Synonyms
- Ganaxolone
- External IDs
- CCD 1042
- CCD-1042
Pharmacology
- Indication
Ganaxolone is indicated for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients ≥2 years old by the FDA.5 It is also approved as an adjuvant treatment for the same condition in patients aged 2 to 17, although it may be continued in patients 18 years old or older, by the EMA.7
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Adjunct therapy in treatment of Epileptic seizure •••••••••••• •••••••••• Treatment of Seizures •••••••••••• •••••••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Ganaxolone - like other neurosteroids - lacks classical hormonal activity, and instead appears to exert its effects directly via modulation of GABAA receptors.1 Similar to other antiepileptic drugs, ganaxolone has been associated with significant somnolence and sedation - patients should be instructed to use caution when operating heavy machinery (e.g. driving).5 In addition, antiepileptic drugs may increase the risk of suicidal behaviour and ideation, although this risk has not been documented directly in patients taking ganaxolone.5 When considering ganaxolone therapy, clinicians should balance the risk of suicidal thoughts or behaviours with the risk of untreated illness.
Ganaxolone drug scheduling is currently under review by the US Drug Enforcement Administration (DEA), but it appears to carry some potential for abuse.5 Clinicians should consider assessing for a history of drug abuse when deciding to initiate therapy with ganaxolone.
- Mechanism of action
Ganaxolone belongs to a novel class of neuroactive steroids sometimes referred to as "epalons", which are potent and specific positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors in the central nervous system (CNS).3 It binds GABAA at one of several potential binding sites, all of which are distinct from the benzodiazepine binding site.1 By enhancing the inhibitory effects of GABAA receptors, endogenous and exogenous neurosteroids have been associated with anxiolytic, sedative, and anticonvulsant effects, amongst others.4
While the precise mechanism of action of ganaxolone in the treatment of seizures associated with CDD is unknown, its anticonvulsant effects are likely due to positive allosteric GABAA modulation5
Target Actions Organism AGABA(A) Receptor positive allosteric modulatorHumans - Absorption
Following oral administration, maximum plasma concentrations are reached within 2 to 3 hours.5
- Volume of distribution
Both ganaxolone and its metabolites are widely distributed into tissues following oral administration, with a typical tissue-to-plasma ratio >5:1.1
- Protein binding
Ganaxolone is approximately 99% protein-bound in serum.5
- Metabolism
Ganaxolone is extensively metabolized, primarily by CYP3A4/5 and, to a lesser extent, CYP2B6, CYP2C19, and CYP2D6.5 While data regarding ganaxolone metabolism are lacking, a 16-OH metabolite generated via CYP3A4 metabolism has been identified as one of its major metabolites.1
Hover over products below to view reaction partners
- Route of elimination
Following a single oral dose of radiolabeled ganaxolone in healthy male subjects, 55% of the administered radioactivity was recovered in the feces (2% as unchanged parent drug) and 18% was recovered in the urine (none of which comprised unchanged parent drug).5
- Half-life
The terminal half-life of ganaxolone is 34 hours.5
- Clearance
Not Available
- Adverse Effects
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Experience with ganaxolone overdose is limited to a single report of an unintentional overdose in a pediatric patient, in which the patient received ten-fold the prescribed dose. The patient was hospitalized for evaluation and recovered.5 No specific information is available regarding treatment of ganaxolone overdose - patients suspected of overdosage should be closely monitored and receive standard supportive care.5
- 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 sedation, somnolence, and CNS depression can be increased when 1,2-Benzodiazepine is combined with Ganaxolone. Acetazolamide The risk or severity of sedation, somnolence, and CNS depression can be increased when Acetazolamide is combined with Ganaxolone. Acetophenazine The risk or severity of sedation, somnolence, and CNS depression can be increased when Acetophenazine is combined with Ganaxolone. Agomelatine The risk or severity of sedation, somnolence, and CNS depression can be increased when Agomelatine is combined with Ganaxolone. Alfentanil The risk or severity of sedation, somnolence, and CNS depression can be increased when Alfentanil is combined with Ganaxolone. - Food Interactions
- Take with food. Co-administration with food increases ganaxalone Cmax and AUC by 3- and 2-fold, respectively. In clinical trials to establish efficacy, ganaxolone was administered with food.
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.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ztalmy Suspension 50 mg/ml Oral Marinus Pharmaceuticals Emerald Limited 2023-08-04 Not applicable EU 
Ztalmy Suspension 50 mg/1mL Oral Marinus Pharmaceuticals, Inc. 2022-06-06 Not applicable US 
Ztalmy Suspension 50 mg/ml Oral Marinus Pharmaceuticals Emerald Limited 2023-08-04 Not applicable EU
Categories
- ATC Codes
- N03AX27 — Ganaxolone
- Drug Categories
- Anticonvulsants
- Central Nervous System Depressants
- Cytochrome P-450 CYP2B6 Substrates
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Substrates
- Fused-Ring Compounds
- GABA Agents
- GABA Modulators
- Nervous System
- Neuroactive Steroid Gamma-Aminobutyric Acid A Receptor Positive Modulator
- Neurotransmitter Agents
- Pregnanes
- Steroids
- Chemical TaxonomyProvided by Classyfire
- 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 / Tertiary alcohols / Ketones / Cyclic alcohols and derivatives / Organic oxides / Hydrocarbon derivatives
- Substituents
- 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
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 98WI44OHIQ
- CAS number
- 38398-32-2
- InChI Key
- PGTVWKLGGCQMBR-FLBATMFCSA-N
- InChI
- InChI=1S/C22H36O2/c1-14(23)17-7-8-18-16-6-5-15-13-20(2,24)11-12-21(15,3)19(16)9-10-22(17,18)4/h15-19,24H,5-13H2,1-4H3/t15-,16-,17+,18-,19-,20+,21-,22+/m0/s1
- IUPAC Name
- 1-[(1S,2S,5R,7S,10R,11S,14S,15S)-5-hydroxy-2,5,15-trimethyltetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadecan-14-yl]ethan-1-one
- SMILES
- [H][C@@]12CC[C@H](C(C)=O)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CC[C@@]2([H])C[C@](C)(O)CC[C@]12C
References
- Synthesis Reference
Shaw, K., & Hutchison, A. (2011). METHOD FOR MAKING 3α-HYDROXY, 3β- METHYL-5α-PREGNAN-20-ONE (GANAXOLONE) (WO2011019821A2). World Intellectual Property Organization.
- General References
- Nohria V, Giller E: Ganaxolone. Neurotherapeutics. 2007 Jan;4(1):102-5. [Article]
- Pieribone VA, Tsai J, Soufflet C, Rey E, Shaw K, Giller E, Dulac O: Clinical evaluation of ganaxolone in pediatric and adolescent patients with refractory epilepsy. Epilepsia. 2007 Oct;48(10):1870-4. Epub 2007 Jul 18. [Article]
- Monaghan EP, Navalta LA, Shum L, Ashbrook DW, Lee DA: Initial human experience with ganaxolone, a neuroactive steroid with antiepileptic activity. Epilepsia. 1997 Sep;38(9):1026-31. doi: 10.1111/j.1528-1157.1997.tb01486.x. [Article]
- Belelli D, Lambert JJ: Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci. 2005 Jul;6(7):565-75. doi: 10.1038/nrn1703. [Article]
- FDA Approved Drug Products: Ztalmy (ganaxolone) suspension for oral use [Link]
- BioSpace: Marinus Pharmaceuticals Announces FDA Approval of ZTALMY® (ganaxolone) for CDKL5 Deficiency Disorder [Link]
- EMA Approved Drug Products: Ztalmy (ganaxolone) suspension for oral use [Link]
- Marinus Pharmaceuticals Announces European Commission Approval of ZTALMY® (ganaxolone) for the Adjunctive Treatment of Epileptic Seizures Associated with CDKL5 Deficiency Disorder [Link]
- External Links
- PubChem Compound
- 6918305
- PubChem Substance
- 175426940
- ChemSpider
- 5293511
- BindingDB
- 50369240
- 2604689
- ChEBI
- 177658
- ChEMBL
- CHEMBL1568698
- ZINC
- ZINC000003824281
- PharmGKB
- PA166278301
- Wikipedia
- Ganaxolone
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment CDKL5 Deficiency Disorder (CDD) 1 3 Completed Treatment Drug Resistant Partial Onset Seizure 1 3 Enrolling by Invitation Treatment Tuberous Sclerosis Complex (TSC) 1 3 Not Yet Recruiting Treatment CDKL5 Deficiency Disorder (CDD) 1 3 Not Yet Recruiting Treatment Refractory Status Epilepticus 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Suspension Oral 50 mg/mL Suspension Oral 50 mg/1mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8618087 No 2013-12-31 2026-11-28 US US10603308 No 2020-03-31 2037-08-10 US US9056116 No 2015-06-16 2026-11-28 US US8367651 No 2013-02-05 2026-11-28 US US9029355 No 2015-05-12 2026-11-28 US US8022054 No 2011-09-20 2026-11-28 US US7858609 No 2010-12-28 2026-11-28 US US8318714 No 2012-11-27 2026-11-28 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 190-198C Nohria V, Giller E: Ganaxolone. Neurotherapeutics. 2007 Jan;4(1):102-5. water solubility Low aqueous solubility https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215904s000lbl.pdf - Predicted Properties
Property Value Source Water Solubility 0.000712 mg/mL ALOGPS logP 4.37 ALOGPS logP 4.27 Chemaxon logS -5.7 ALOGPS pKa (Strongest Acidic) 19.1 Chemaxon pKa (Strongest Basic) -1 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 97.54 m3·mol-1 Chemaxon Polarizability 40.68 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
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.984 Caco-2 permeable + 0.8629 P-glycoprotein substrate Substrate 0.5627 P-glycoprotein inhibitor I Inhibitor 0.5153 P-glycoprotein inhibitor II Non-inhibitor 0.6722 Renal organic cation transporter Non-inhibitor 0.8105 CYP450 2C9 substrate Non-substrate 0.7608 CYP450 2D6 substrate Non-substrate 0.9117 CYP450 3A4 substrate Substrate 0.7529 CYP450 1A2 substrate Non-inhibitor 0.5 CYP450 2C9 inhibitor Non-inhibitor 0.6907 CYP450 2D6 inhibitor Non-inhibitor 0.9731 CYP450 2C19 inhibitor Non-inhibitor 0.8725 CYP450 3A4 inhibitor Non-inhibitor 0.8587 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9634 Ames test Non AMES toxic 0.9326 Carcinogenicity Non-carcinogens 0.8955 Biodegradation Not ready biodegradable 0.9827 Rat acute toxicity 2.2244 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9399 hERG inhibition (predictor II) Non-inhibitor 0.5786
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-00kb-0095000000-0e87b5344b06c525e27b Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-0009000000-8011e04e327003bbbd22 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-01ba-0294000000-fc315c262060709ccad9 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-01q9-0009000000-e1d816ef17550a892c9c Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0ue9-0009000000-e9215cd2fb14b8088259 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-066u-3940000000-2c9273040c906b14391b 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]- 192.857983 predictedDarkChem Lite v0.1.0 [M-H]- 183.70189 predictedDeepCCS 1.0 (2019) [M+H]+ 192.765383 predictedDarkChem Lite v0.1.0 [M+H]+ 185.59729 predictedDeepCCS 1.0 (2019) [M+Na]+ 192.685583 predictedDarkChem Lite v0.1.0 [M+Na]+ 191.3448 predictedDeepCCS 1.0 (2019)
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
- FDA Approved Drug Products: Ztalmy (ganaxolone) suspension for oral use [Link]
Enzymes
- 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
- FDA Approved Drug Products: Ztalmy (ganaxolone) suspension for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Oxygen binding
- 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 oxidizes a variety of structurally un...
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- FDA Approved Drug Products: Ztalmy (ganaxolone) suspension for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid 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 oxidizes a variety of structurally un...
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- FDA Approved Drug Products: Ztalmy (ganaxolone) suspension for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55930.545 Da
References
- FDA Approved Drug Products: Ztalmy (ganaxolone) suspension for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- FDA Approved Drug Products: Ztalmy (ganaxolone) suspension for oral use [Link]
Drug created at October 21, 2007 22:23 / Updated at August 29, 2023 11:14