{{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 | image_class = skin-invert-image | 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 = 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 = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = | excretion =
<!-- 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 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 98WI44OHIQ | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D04300 | ChEBI = | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 161915 | NIAID_ChemDB = | PDB_ligand = | 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 = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}
'''Ganaxolone''', sold under the brand name '''Ztalmy''', is a medication used to treat seizures in people with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder.<ref name="Ztalmy FDA label" /><ref name="Carter_1997">{{cite journal | vauthors = 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 | title = Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 280 | issue = 3 | pages = 1284–1295 | date = March 1997 | pmid = 9067315 }}</ref> Ganaxolone is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator.<ref name="Ztalmy FDA label" />
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=dead }} {{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>
== Medical uses == 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 synaptic and extrasynaptic GABA<sub>A</sub> receptors to normalize over-excited neurons.<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<sub>A</sub> receptor to modulate and open the chloride ion channel, resulting in a 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 analog of the neurosteroid allopregnanolone that possesses no known hormonal activity and, instead, is thought to primarily function by binding to GABA<sub>A</sub> 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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