Ganaxolone: Difference between revisions

{{Short description|Chemical compound}}

{{Refimprove science|date=May 2017}}

{{Use dmy dates|date=April 2017}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 444273990

| type = <!-- empty -->

| image = Ganaxolone.svg

| width = 235

| alt =

| caption =

<!-- Clinical data -->

| pronounce =

| tradename = Ztalmy

| Drugs.com =

| MedlinePlus =

| licence_EU = <!-- EMA uses INN (or special INN_EMA) -->

| DailyMedID = Ganaxolone

| licence_US = <!-- FDA may use generic or brand name (generic name preferred) -->

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_AU_comment =

| pregnancy_category=

| routes_of_administration = [[Oral administration|By mouth]]

| class = [[Neurosteroid]]

| ATC_prefix = N03

| ATC_suffix = AX27

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = Schedule V

| legal_US_comment = <ref name="Ztalmy FDA label">{{cite web | title=Ztalmy- ganaxolone suspension | website=DailyMed | date=15 November 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d91612c4-b03a-4be4-a1ee-6a13e3b83d4e | access-date=21 January 2023 | archive-date=21 January 2023 | archive-url=https://web.archive.org/web/20230121053425/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d91612c4-b03a-4be4-a1ee-6a13e3b83d4e | url-status=live }}</ref>

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Ztalmy EPAR">{{cite web | title=Ztalmy EPAR | website=European Medicines Agency | date=31 July 2023 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/ztalmy | access-date=25 August 2023 | archive-date=25 August 2023 | archive-url=https://web.archive.org/web/20230825213211/https://www.ema.europa.eu/en/medicines/human/EPAR/ztalmy | url-status=live }}</ref>

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->

| bioavailability =

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<!-- Identifiers -->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 38398-32-2

| CAS_supplemental =

| PubChem = 6918305

| IUPHAR_ligand =

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB05087

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 5293511

| =

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 161915

| NIAID_ChemDB =

| =

| synonyms = GNX; CCD-1042; 3β-Methyl-5α-pregnan-3α-ol-20-one; 3α-Hydroxy-3β-methyl-5α-pregnan-20-one

<!-- Chemical and physical data -->

| IUPAC_name = 1-[(3''R'',5''S'',8''R'',9''S'',10''S'',13''S'',14''S'',17''S'')-3-Hydroxy-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[''a'']phenanthren-17-yl]ethanone

| C=22 | H=36 | O=2

| SMILES = CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CC[C@@H]4[C@@]3(CC[C@@](C4)(C)O)C)C

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 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

| StdInChI_comment =

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = PGTVWKLGGCQMBR-FLBATMFCSA-N

| =

| density_notes =

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'''Ganaxolone''' '''''' is a [[]] [[]] [[ ><> |Carter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, White HS, Wolf HH, Mirsadeghi S, Tahir SH, Bolger MB, Lan NC, Gee KW Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; -hydroxy--methyl--pregnan-20-one), a selective, high-affinity, steroid modulator of the -aminobutyric acidA receptor Journal of Pharmacology and Experimental Therapeutics 280 <ref> - .<ref />

The most common side effects of treatment with ganaxolone include [[somnolence]] (sleepiness), fever, excessive saliva or drooling, and seasonal allergy.<ref name="Ztalmy FDA snapshot" />

Ganaxolone was approved for medical use in the United States in March 2022,<ref name="Ztalmy FDA label" /><ref name="Ztalmy FDA snapshot" /><ref name="Lamb_2022">{{cite journal | vauthors = Lamb YN | title = Ganaxolone: First Approval | journal = Drugs | volume = 82 | issue = 8 | pages = 933–940 | date = June 2022 | pmid = 35596878 | doi = 10.1007/s40265-022-01724-0 }}</ref> and in the European Union in July 2023.<ref name="Ztalmy EPAR" /> The US [[Food and Drug Administration]] (FDA) considers it to be a [[first-in-class medication]].<ref name="New Drug Therapy Approvals 2022">{{cite web | title=Advancing Health Through Innovation: New Drug Therapy Approvals 2022 | website=U.S. [[Food and Drug Administration]] (FDA) | date=10 January 2023 | url=https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2022 | access-date=22 January 2023 | archive-date=21 January 2023 | archive-url=https://web.archive.org/web/20230121035714/https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2022 | url-status=live }} {{PD-notice}}</ref><ref>{{cite report | title=New Drug Therapy Approvals 2022 | website=U.S. [[Food and Drug Administration]] (FDA) | date=January 2024 | url=https://www.fda.gov/media/164429/download | format=PDF | access-date=14 January 2024 | archive-url=https://web.archive.org/web/20240114065648/https://www.fda.gov/media/164429/download | archive-date=14 January 2024 | url-status=live }} {{PD-notice}}</ref>

====

Ganaxolone is indicated for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder.<ref name="Ztalmy FDA label" /><ref name="Ztalmy EPAR" /><ref name="Gould_2024">{{cite journal | vauthors = Gould A, Amin S | title = An overview of ganaxolone as a treatment for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder | journal = Expert Review of Neurotherapeutics | volume = | issue = | pages = 1–7 | date = July 2024 | pmid = 39082513 | doi = 10.1080/14737175.2024.2385937 }}</ref><ref name="Khan_2024">{{cite journal | vauthors = Khan P, Saini S, Hussain S, Majid H, Gupta S, Agarwal N | title = A systematic review and meta-analysis on efficacy and safety of Ganaxolone in epilepsy | journal = Expert Opinion on Pharmacotherapy | volume = 25 | issue = 5 | pages = 621–632 | date = April 2024 | pmid = 38606458 | doi = 10.1080/14656566.2024.2342413 }}</ref>

==Pharmacology==

===Mechanism of action===

The exact mechanism of action for ganaxolone is unknown; however, results from animal studies suggest that it acts by blocking seizure propagation and elevating seizure thresholds.<ref name="Kaminski_2004" /><ref name="Reddy_2010"/>

Ganaxolone is thought to modulate both [[synapse|synaptic]] and extrasynaptic [[GABAA receptor|GABA_A receptors]] to normalize over-excited [[neuron]]s.<ref name="Carter_1997" /> Ganaxolone's activation of the extrasynaptic receptor is an additional mechanism that provides stabilizing effects that potentially differentiates it from other drugs that increase [[GABA]] signaling.<ref name="Carter_1997" />

Ganaxolone binds to [[allosteric]] sites of the GABA_A receptor to modulate and open the [[Chloride channel|chloride ion channel]], resulting in a [[Hyperpolarization (biology)|hyperpolarization]] of the neuron.<ref name="Carter_1997" /> This causes an inhibitory effect on [[neurotransmission]], reducing the chance of a successful [[action potential]] ([[depolarization]]) from occurring.<ref name="Carter_1997" /><ref name="Kaminski_2004">{{cite journal | vauthors = Kaminski RM, Livingood MR, Rogawski MA | title = Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice | journal = Epilepsia | volume = 45 | issue = 7 | pages = 864–867 | date = July 2004 | pmid = 15230714 | doi = 10.1111/j.0013-9580.2004.04504.x | s2cid = 21974013 }}</ref><ref name="Reddy_2010">{{cite journal | vauthors = Reddy DS, Rogawski MA | title = Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model | journal = Epilepsy Research | volume = 89 | issue = 2–3 | pages = 254–260 | date = May 2010 | pmid = 20172694 | pmc = 2854307 | doi = 10.1016/j.eplepsyres.2010.01.009 }}</ref>

It is unknown whether ganaxolone possesses significant hormonal activity [[in vivo]], with a 2020 study finding evidence of [[in vitro]] binding to the membrane [[progesterone receptor]].<ref>{{cite journal | vauthors = Thomas P, Pang Y | title = Anti-apoptotic Actions of Allopregnanolone and Ganaxolone Mediated Through Membrane Progesterone Receptors (PAQRs) in Neuronal Cells | journal = Frontiers in Endocrinology | volume = 11 | issue = 417 | pages = 417 | date = Jun 24, 2020 | pmid = 32670200 | pmc = 7331777 | doi = 10.3389/fendo.2020.00417 | doi-access = free }}</ref>

==Chemistry==

{{Unreferenced section|date=March 2022}}

Ganaxolone is an [[structural analog|analog]] of the [[neurosteroid]] [[allopregnanolone]] that possesses no known hormonal activity and, instead, is thought to primarily function by binding to GABA_A receptors as a [[positive allosteric modulator]].<ref>{{cite web |title=Ganaxolone |url=https://pubchem.ncbi.nlm.nih.gov/compound/6918305 | work = PubChem |publisher= U.S. National Center for Biotechnology Information (NCBI), National Library of Medicine (NLM) |access-date=6 August 2022 |archive-date=10 December 2022 |archive-url=https://web.archive.org/web/20221210192506/https://pubchem.ncbi.nlm.nih.gov/compound/6918305 |url-status=live }}</ref>

Other pregnane neurosteroids include [[alfadolone]], [[alfaxolone]], [[hydroxydione]], [[minaxolone]], [[pregnanolone]] (eltanolone), and [[renanolone]], among others.<ref>{{Cite patent| country = US | number = 20190160078A1 |title=Ganaxolone for use in treating genetic epileptic disorders|gdate=2019-05-30| inventor = Masuoka LK, Lappalainen J | assign = Marinus Pharmaceuticals Inc. |url=https://patents.google.com/patent/US20190160078A1/en}}</ref>

== History ==

The FDA approved ganaxolone based on evidence from a single, double-blind, randomized, placebo-controlled study (Study 1, NCT03572933) of 101 participants with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder who were two years of age and older.<ref name="Ztalmy FDA snapshot" /> The trial was conducted at 36 sites in 8 countries including Australia, France, Israel, Italy, Poland, Russian Federation, the United Kingdom, and the United States.<ref name="Ztalmy FDA snapshot" /> Forty-four (40.7%) of the participants were from US sites.<ref name="Ztalmy FDA snapshot">{{cite web | title=Drug Trials Snapshots: Ztalmy | website=U.S. Food and Drug Administration | date=18 March 2022 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-ztalmy | access-date=9 October 2023}} {{PD-notice}}</ref> Safety was assessed from a pool of two clinical studies.<ref name="Ztalmy FDA snapshot" /> These include the study of participants with cyclin-dependent kinase-like 5 deficiency disorder and a clinical study that included seven additional participants from a trial of ganaxolone in children and young adults.<ref name="Ztalmy FDA snapshot" />

== References ==

{{Reflist}}

== External links ==

* {{ClinicalTrialsGov|NCT03572933|Study of Adjunctive Ganaxolone Treatment in Children and Young Adults With CDKL5 Deficiency Disorder (Marigold)}}

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