{{Short description|Chemical compound}} {{Use dmy dates|date=November 2023}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | image = Valbenazine.svg | image_class = skin-invert-image | width = | alt = | caption =
<!-- Clinical data --> | pronounce = | tradename = Ingrezza | Drugs.com = {{drugs.com|monograph|valbenazine}} | MedlinePlus = a617023 | DailyMedID = Valbenazine | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth | class = | ATCvet = | ATC_prefix = N07 | ATC_suffix = XX13 | 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 = Rx-only | legal_US_comment = <ref name="Ingrezza FDA label" /> | legal_EU = | legal_EU_comment = | 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 = >99% | metabolism = Activation by hydrolysis, deactivation by CYP3A, CYP2D6 | metabolites = [+]-α-Dihydrotetrabenazine (active metabolite) | onset = | elimination_half-life = 15–22 hrs | duration_of_action = | excretion = 60% urine, 30% faeces
<!-- Identifiers --> | index2_label = as salt | CAS_number = 1025504-45-3 | CAS_supplemental = | PubChem = 24795069 | IUPHAR_ligand = | DrugBank = DB11915 | ChemSpiderID = 28536134 | UNII = 54K37P50KH | KEGG = D10675 | KEGG2 = D10999 | ChEBI = | ChEMBL = 2364639 | NIAID_ChemDB = | PDB_ligand = | synonyms = NBI-98854
<!-- Chemical and physical data --> | IUPAC_name = (2''R'',3''R'',11b''R'')-3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2''H''-pyrido[2,1-''a'']isoquinolin-2-yl <small>L</small>-valinate | C=24|H=38|N=2|O=4 | SMILES = CC(C)C[C@@H]1CN2CCc3cc(c(cc3[C@H]2C[C@H]1OC(=O)[C@H](C(C)C)N)OC)OC | StdInChI = InChI=1S/C24H38N2O4/c1-14(2)9-17-13-26-8-7-16-10-21(28-5)22(29-6)11-18(16)19(26)12-20(17)30-24(27)23(25)15(3)4/h10-11,14-15,17,19-20,23H,7-9,12-13,25H2,1-6H3/t17-,19-,20-,23+/m1/s1 | StdInChI_comment = | StdInChIKey = GEJDGVNQKABXKG-CFKGEZKQSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}
'''Valbenazine''', sold under the brand name '''Ingrezza''', is a medication used to treat tardive dyskinesia.<ref name="Ingrezza FDA label">{{cite web | title=Ingrezza- valbenazine capsule; Ingrezza- valbenazine kit | website=DailyMed | date=18 August 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c970164-cafb-421f-9eb5-c226ef0a3417 | access-date=17 November 2023}}</ref> It acts as a vesicular monoamine transporter 2 (VMAT2) inhibitor.<ref>{{cite journal | vauthors = O'Brien CF, Jimenez R, Hauser RA, Factor SA, Burke J, Mandri D, Castro-Gayol JC | title = NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double-blind, placebo-controlled study | journal = Movement Disorders | volume = 30 | issue = 12 | pages = 1681–7 | date = October 2015 | pmid = 26346941 | pmc = 5049616 | doi = 10.1002/mds.26330 }}</ref>
==Medical use== Valbenazine is used to treat tardive dyskinesia in adults.<ref name="Ingrezza FDA label" /> Tardive dyskinesia is a drug-induced neurological injury characterized by involuntary movements.<ref name=GARD2017>{{cite web|title=Tardive dyskinesia|url=https://rarediseases.info.nih.gov/diseases/7732/tardive-dyskinesia|website=rarediseases.info.nih.gov|access-date=21 February 2018|date=1 June 2017|archive-url=https://web.archive.org/web/20170618062648/https://rarediseases.info.nih.gov/diseases/7732/tardive-dyskinesia|archive-date=18 June 2017}}</ref> The clinical trials that led to the approval of valbenazine by the US Food and Drug Administration (FDA) were six weeks in duration.<ref name="Ingrezza FDA label" /> An industry-sponsored study has studied the use of valbenazine for up to 48 weeks, in which it was found to be safe and effective for maintaining short-term (6 week) improvements in tardive dyskinesia.<ref name="MedscLongTermValben">{{cite web|last1=Janeczko|first1=Lorraine|title=Long-term Valbenazine Appears Safe for Patients With Tardive Dyskinesia|url=https://www.medscape.com/viewarticle/889460|website=www.medscape.com|publisher=Reuters Health Information|access-date=21 February 2018}}{{Dead link|date=March 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>
== Contraindications == There are no contraindications for the use of valbenazine according to the prescribing information.<ref name="Ingrezza FDA label" />
== Adverse effects == Side effects may include sleepiness or QT prolongation.<ref name=":0" /> Significant prolongation has not yet been observed at recommended dosage levels; however, those taking inhibitors of the liver enzymes CYP2D6 or CYP3A4 – or who are poor CYP2D6 metabolizers – may be at risk for significant prolongation.<ref name=":0" />
Valbenazine has not been effectively studied in pregnancy, and it is recommended that women who are pregnant or breastfeeding avoid use of valbenazine.<ref name=":0">{{cite web|url=https://www.uptodate.com/contents/valbenazine-drug-information|title=Valbenazine: Drug Information|website=UpToDate|access-date=2017-07-14}}</ref>
== Pharmacology == === Mechanism of action === {{See also|Monoamine-depleting agent}}
Valbenazine is known to cause reversible reduction of dopamine release by selectively inhibiting pre-synaptic human vesicular monoamine transporter type 2 (VMAT2). ''In vitro'', valbenazine shows great selectivity for VMAT2 and little to no affinity for VMAT1 or other monoamine receptors.<ref>{{cite web|url=http://www.neurocrine.com/pipeline/nbi-98854-vmat2-inhibitor/|title=NBI-98854 – VMAT2 Inhibitor {{!}} Tics in Children Treatment {{!}} Neurocrine Biosciences|website=www.neurocrine.com|access-date=2016-11-13|archive-url=https://web.archive.org/web/20150130124821/http://www.neurocrine.com/pipeline/nbi-98854-vmat2-inhibitor/|archive-date=2015-01-30}}</ref> Although the exact cause of tardive dyskinesia is unknown, it is hypothesized that it may result from neuroleptic-induced dopamine hypersensitivity because it is exclusively associated with the use of neuroleptic drugs.<ref>{{cite web|url=http://www.priory.com/tardive-dyskinesia.htm|title=tardive-dyskinesia|website=www.priory.com|access-date=2016-11-13|archive-date=18 January 2008|archive-url=https://web.archive.org/web/20080118011913/http://www.priory.com/tardive-dyskinesia.htm|url-status=live}}</ref> By selectively reducing the ability of VMAT2 to load dopamine into synaptic vesicles,<ref>{{cite book | vauthors = Purves D, etal |title=Neuroscience |date=2018 |publisher=Sinauer Associates |isbn=978-1-60535-380-7 |edition=Sixth}}</ref> the drug reduces overall levels of available dopamine in the synaptic cleft, ideally alleviating the symptoms associated with dopamine hypersensitivity. The importance of valbenazine selectivity inhibiting VMAT2 over other monoamine transporters is that VMAT2 is mainly involved with the transport of dopamine, and to a much lesser extent other monoamines such as norepinephrine, serotonin, and histamine. This selectivity is likely to reduce the likelihood of "off-target" adverse effects which may result from the upstream inhibition of these other monoamines.<ref>{{cite news|url=https://finance.yahoo.com/news/nbix-nda-valbenazine-tardive-dyskinesia-193000126.html|title=NBIX: NDA for Valbenazine in Tardive Dyskinesia to be Filed in 2016…|access-date=2016-11-13|archive-date=14 November 2016|archive-url=https://web.archive.org/web/20161114165211/http://finance.yahoo.com/news/nbix-nda-valbenazine-tardive-dyskinesia-193000126.html|url-status=live}}</ref>
=== Pharmacokinetics === Valbenazine is a prodrug which is an ester of [+]-α-dihydrotetrabenazine (DTBZ) with the amino acid <small>L</small>-valine. It is extensively hydrolyzed to the active metabolite DTBZ. Plasma protein binding of valbenazine is over 99%, and that of DTBZ is about 64%. The biological half-life of both valbenazine and DTBZ is 15 to 22 hours. Liver enzymes involved in inactivation are CYP3A4, CYP3A5 and CYP2D6. The drug is excreted, mostly in form of inactive metabolites, via the urine (60%) and the feces (30%).<ref>Valbenazine {{Drugs.com|ppa|valbenazine}}.</ref>
== Society and culture == === Legal status === Valbenazine is produced by Neurocrine Biosciences. Valbenazine was the first medication approved by the FDA for the treatment of tardive dyskinesia, in April 2017.<ref name="FDAApprove">{{cite web |author=Office of the Commissioner |title=Press Announcements - FDA approves first drug to treat tardive dyskinesia |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm552418.htm |website=www.fda.gov |access-date=12 April 2017 |archive-date=12 April 2017 |archive-url=https://web.archive.org/web/20170412150022/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm552418.htm }}</ref>
=== Economics === While Neurocrine Biosciences does not hold a final patent for valbenazine or elagolix, they do hold a patent for the VMAT2 inhibitor [9,10-dimethoxy-3-(2-methylpropyl)-1''H'',2''H'',3''H'',4''H'',6''H'',7''H'',11b''H''-pyrido-[2,1-a]isoquinolin-2-yl]methanol and related compounds, which includes valbenazine.<ref>{{cite patent | country = US | number = 20160289226 | inventor = Ashweek N, Harriott N | assign1 = Neurocrine Biosciences, Inc. | pubdate = 6 October 2016 | url = http://www.freshpatents.com/-dt20161006ptan20160289226.php | title = [9,10-dimethoxy-3-(2-methylpropyl)-1h,2h,3h,4h,6h,7h,11bh-pyrido-[2,1-a]isoquinolin-2-yl]methanol And Compounds, Compositions And Methods Relating Thereto | 8 = }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>
=== Names === The International Nonproprietary Name (INN) is ''valbenazine''.<ref name="INN">{{cite web | title = International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 71 | url = https://www.who.int/medicines/publications/druginformation/innlists/RL71.pdf | publisher = World Health Organization | access-date = 18 November 2016 | archive-date = 18 May 2016 | archive-url = https://web.archive.org/web/20160518204601/http://www.who.int/medicines/publications/druginformation/innlists/RL71.pdf | url-status = live }}</ref>{{rp|114}}
==Research== Valbenazine is being studied for the treatment of Tourette's syndrome.<ref name=":1">{{cite web|url= http://www.neurocrine.com/pipeline/nbi-98854-vmat2-inhibitor/tourette-syndrome/clinical-trials/|title= Tourette Syndrome Clinical Trials|work= Neurocrine Biosciences|access-date= 2016-11-13|archive-date= 2016-11-14|archive-url= https://web.archive.org/web/20161114232430/http://www.neurocrine.com/pipeline/nbi-98854-vmat2-inhibitor/tourette-syndrome/clinical-trials/}}</ref><ref name=":2">{{ClinicalTrialsGov|NCT02581865|Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome}}</ref>
==See also== * List of investigational Tourette's syndrome drugs
== References == {{Reflist}}
== Further reading == * {{cite journal | vauthors = Patel RS, Mansuri Z, Motiwala F, Saeed H, Jannareddy N, Patel H, Zafar MK | title = A systematic review on treatment of tardive dyskinesia with valbenazine and deutetrabenazine | journal = Therapeutic Advances in Psychopharmacology | volume = 9 | issue = | article-number = 2045125319847882 | date = 2019 | pmid = 31205680 | pmc = 6535739 | doi = 10.1177/2045125319847882 }}
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Category:Antidyskinetic agents Category:Monoamine-depleting agents Category:Prodrugs Category:Tardive dyskinesia Category:VMAT inhibitors