Identification

Summary

Ganaxolone is a neuroactive steroid GABA-A receptor modulator used for the treatment of seizures associated with CDKL5 deficiency disorder (CDD).

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 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

Type
Small Molecule
Groups
Approved, Investigational
Structure
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.5

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug events
Improve clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events & improve clinical decision support.
Learn more
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

TargetActionsOrganism
AGABA(A) Receptor
positive allosteric modulator
Humans
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
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.
Learn more
Improve decision support & research outcomes with our structured adverse effects data.
Learn more
Toxicity

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.
DrugInteraction
ApalutamideThe metabolism of Ganaxolone can be increased when combined with Apalutamide.
BexaroteneThe metabolism of Ganaxolone can be increased when combined with Bexarotene.
BosentanThe metabolism of Ganaxolone can be increased when combined with Bosentan.
CarbamazepineThe metabolism of Ganaxolone can be increased when combined with Carbamazepine.
DexamethasoneThe metabolism of Ganaxolone can be increased when combined with Dexamethasone.
Dexamethasone acetateThe metabolism of Ganaxolone can be increased when combined with Dexamethasone acetate.
EchinaceaThe metabolism of Ganaxolone can be increased when combined with Echinacea.
EfavirenzThe metabolism of Ganaxolone can be increased when combined with Efavirenz.
EnzalutamideThe metabolism of Ganaxolone can be increased when combined with Enzalutamide.
EtravirineThe metabolism of Ganaxolone can be increased when combined with Etravirine.
Identify potential medication risks
Easily compare up to 40 drugs with our drug interaction checker.
Get severity rating, description, and management advice.
Learn more
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.

Categories

Drug Categories
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
  1. Nohria V, Giller E: Ganaxolone. Neurotherapeutics. 2007 Jan;4(1):102-5. [Article]
  2. 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]
  3. 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]
  4. 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]
  5. FDA Approved Drug Products: Ztalmy (ganaxolone) suspension for oral use [Link]
  6. BioSpace: Marinus Pharmaceuticals Announces FDA Approval of ZTALMY® (ganaxolone) for CDKL5 Deficiency Disorder [Link]
PubChem Compound
6918305
PubChem Substance
175426940
ChemSpider
5293511
BindingDB
50369240
ChEMBL
CHEMBL1568698
ZINC
ZINC000003824281
Wikipedia
Ganaxolone

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentCDKL5 Deficiency Disorder (CDD)1
3CompletedTreatmentDrug Resistant Partial Onset Seizure1
3Not Yet RecruitingTreatmentCDKL5 Deficiency Disorder (CDD)1
3RecruitingTreatmentEpilepsies / Non Convulsive Status Epilepticus / Status Epilepticus (Convulsive)1
3TerminatedTreatmentDrug Resistant Partial Onset Seizure1
2Active Not RecruitingPreventionEpilepsies1
2Active Not RecruitingTreatmentPCDH19-Related Epilepsy1
2Active Not RecruitingTreatmentTuberous Sclerosis Complex (TSC)1
2CompletedTreatmentCatamenial Epilepsy / Epilepsy, Localization Related1
2CompletedTreatmentDepression / Depressive Disorder / Moods Disorders / Postpartum Blues / Postpartum Depression / Postpartum disorder / PPD / Pregnancy, Complications / Psychiatric Disorder NOS / Symptoms, Behavioral1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)190-198CNohria V, Giller E: Ganaxolone. Neurotherapeutics. 2007 Jan;4(1):102-5.
water solubilityLow aqueous solubilityhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215904s000lbl.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.000712 mg/mLALOGPS
logP4.37ALOGPS
logP4.27ChemAxon
logS-5.7ALOGPS
pKa (Strongest Acidic)19.1ChemAxon
pKa (Strongest Basic)-1ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area37.3 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity97.54 m3·mol-1ChemAxon
Polarizability40.68 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.984
Caco-2 permeable+0.8629
P-glycoprotein substrateSubstrate0.5627
P-glycoprotein inhibitor IInhibitor0.5153
P-glycoprotein inhibitor IINon-inhibitor0.6722
Renal organic cation transporterNon-inhibitor0.8105
CYP450 2C9 substrateNon-substrate0.7608
CYP450 2D6 substrateNon-substrate0.9117
CYP450 3A4 substrateSubstrate0.7529
CYP450 1A2 substrateNon-inhibitor0.5
CYP450 2C9 inhibitorNon-inhibitor0.6907
CYP450 2D6 inhibitorNon-inhibitor0.9731
CYP450 2C19 inhibitorNon-inhibitor0.8725
CYP450 3A4 inhibitorNon-inhibitor0.8587
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9634
Ames testNon AMES toxic0.9326
CarcinogenicityNon-carcinogens0.8955
BiodegradationNot ready biodegradable0.9827
Rat acute toxicity2.2244 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9399
hERG inhibition (predictor II)Non-inhibitor0.5786
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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

Targets

Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more

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
  1. 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
  1. 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
  1. 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
  1. 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
  1. FDA Approved Drug Products: Ztalmy (ganaxolone) suspension for oral use [Link]

Drug created at October 21, 2007 22:23 / Updated at April 01, 2022 19:23