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{{Short description|Chemical compound}}
{{Drugbox
{{Use dmy dates|date=November 2023}}
| verifiedrevid =
{{cs1 config |name-list-style=vanc |display-authors=6}}
⚫
| 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
{{Infobox drug
| image = Valbenazine.svg
| image = Valbenazine.svg
| chirality =
| width =
| alt =
| caption =


<!--Clinical data-->
<!-- Clinical data -->
| pronounce =
| tradename =Ingrezza
| tradename = Ingrezza
| Drugs.com = {{drugs.com|parent|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 =
| pregnancy_category =
| legal_status =
⚫
| legal_US = Rx-only
| routes_of_administration = [[Oral administration|By mouth]]
| routes_of_administration = [[Oral administration|By mouth]]
| class =
| ATCvet =
| ATC_prefix = N07
⚫
| ATC_suffix = XX13
| ATC_supplemental =


<!--Pharmacokinetic data-->
<!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
⚫
| bioavailability =
| legal_AU_comment =
⚫
| protein_bound = >99%
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
⚫
| metabolism = Activation by [[hydrolysis]], deactivation by [[CYP3A]], [[CYP2D6]]
| legal_BR_comment =
⚫
| metabolites = [+]-α-[[Dihydrotetrabenazine]] (active metabolite)
| onset =
| 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
| elimination_half-life = 15–22 hrs
| duration_of_action =
| duration_of_action =
| excretion = 60% urine, 30% faeces
| excretion = 60% urine, 30% faeces


<!--Identifiers-->
<!-- Identifiers -->
| index2_label = as salt
| index2_label = as salt
⚫
| IUPHAR_ligand =
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 1025504-45-3
| CAS_number = 1025504-45-3
| ATC_prefix = N07
| CAS_supplemental =
⚫
| ATC_suffix = XX13
| PubChem = 24795069
| PubChem = 24795069
⚫
| IUPHAR_ligand =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB11915
| DrugBank = DB11915
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 28536134
| ChemSpiderID = 28536134
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 54K37P50KH
| UNII = 54K37P50KH
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D10675
| KEGG = D10675
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D10999
| KEGG2 = D10999
| ChEBI =
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 2364639
| ChEMBL = 2364639
| NIAID_ChemDB =
| PDB_ligand =
| synonyms = NBI-98854
| synonyms = NBI-98854


<!--Chemical data-->
<!-- 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
| 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
| 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_Ref = {{stdinchicite|correct|chemspider}}
| 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 = 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_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = GEJDGVNQKABXKG-CFKGEZKQSA-N
| 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 trade name '''Ingrezza''', is a medication used to treat [[tardive dyskinesia]].<ref name=USlabel2017>{{cite web|title=Valbenazine label|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209241lbl.pdf|publisher=FDA|access-date=16 July 2017|date=April 2017}} For label updates see [https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=209241 FDA index page for NDA 209241]</ref> It acts as a [[vesicular monoamine transporter 2]] (VMAT2) [[enzyme inhibitor|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>
'''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) [[enzyme inhibitor|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==
==Medical use==
Valbenazine is used to treat [[tardive dyskinesia]] in adults.<ref name=USlabel2017/> 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|language=en|date=1 June 2017|url-status=live|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 [[FDA]] approval of valbenazine were 6 weeks in duration.<ref name=USlabel2017/> 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 | name-list-style = vanc |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}}</ref>
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|url-status=live|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 ==
== Contraindications ==
There are no contraindications for the use of valbenazine according to the prescribing information.<ref name=USlabel2017 />
There are no contraindications for the use of valbenazine according to the prescribing information.<ref name="Ingrezza FDA label" />

⚫
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?source=preview&search=valbenazine&anchor=F49948929#F49948929|title=Valbenazine: Drug Information|website=www.uptodate.com|language=en|access-date=2017-07-14}}</ref>


== Adverse effects ==
== Adverse effects ==
Side effects may include [[somnolence|sleepiness]] or [[Drug-induced QT prolongation|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" />
Side effects may include [[somnolence|sleepiness]] or [[Drug-induced QT prolongation|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 ==
== Pharmacology ==
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{{See also|Monoamine-depleting agent}}
{{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 [[Vesicular monoamine transporter 1|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|url-status=dead}}</ref> Although the exact cause of tardive dyskinesia is unknown, it is hypothesized that it may result from [[Antipsychotic|neuroleptic]]-induced dopamine hypersensitivity.<ref>{{Cite web|url=http://www.priory.com/tardive-dyskinesia.htm|title=tardive-dyskinesia|website=www.priory.com|access-date=2016-11-13}}</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}}</ref>
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 [[Vesicular monoamine transporter 1|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|url-status=dead}}</ref> Although the exact cause of tardive dyskinesia is unknown, it is hypothesized that it may result from [[Antipsychotic|neuroleptic]]-induced dopamine [[upregulation|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 transporter]]s 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 (bioprocess)|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 ===
=== Pharmacokinetics ===
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== Society and culture ==
== Society and culture ==
=== Commercial aspects ===
=== Legal status ===
Valbenazine is produced by [[Neurocrine Biosciences]], a company based in San Diego. Valbenazine was the first drug approved by the FDA for the treatment of [[tardive dyskinesia]], on 11 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|language=en}}</ref>
Valbenazine is produced by [[Neurocrine Biosciences]]. Valbenazine is 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 |url-status=live }}</ref>


=== Intellectual property ===
=== Economics ===
While Neurocrine Biosciences does not currently 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 | }}</ref>
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 ===
=== 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}}</ref>{{rp|114}}
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==
==Research==
Valbenazine is being studied for the treatment of [[Tourette syndrome|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}}</ref><ref name=":2">{{ClinicalTrialsGov|NCT02581865|Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome}}</ref>
Valbenazine is being studied for the treatment of [[Tourette syndrome|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/|url-status= dead}}</ref><ref name=":2">{{ClinicalTrialsGov|NCT02581865|Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome}}</ref>


== References ==
== References ==
{{Reflist}}
{{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 = | pages = 2045125319847882 | date = 2019 | pmid = 31205680 | pmc = 6535739 | doi = 10.1177/2045125319847882 }}


{{Antipsychotics}}
{{Antipsychotics}}
{{Other nervous system drugs}}
{{Other nervous system drugs}}
{{Monoamine reuptake inhibitors}}
{{Monoamine reuptake inhibitors}}
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[[Category:Antidyskinetic agents]]
[[Category:Monoamine-depleting agents]]
[[Category:Monoamine-depleting agents]]
[[Category:Prodrugs]]
[[Category:Prodrugs]]

Latest revision as of 10:25, 26 November 2024

Valbenazine
Clinical data
Trade namesIngrezza
Other namesNBI-98854
AHFS/Drugs.comMonograph
MedlinePlusa617023
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding>99%
MetabolismActivation by hydrolysis, deactivation by CYP3A, CYP2D6
Metabolites[+]-α-Dihydrotetrabenazine (active metabolite)
Elimination half-life15–22 hrs
Excretion60% urine, 30% faeces
Identifiers
  • (2R,3R,11bR)-3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl L-valinate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.236.234 Edit this at Wikidata
Chemical and physical data
FormulaC24H38N2O4
Molar mass418.578 g·mol−1
3D model (JSmol)
  • CC(C)C[C@@H]1CN2CCc3cc(c(cc3[C@H]2C[C@H]1OC(=O)[C@H](C(C)C)N)OC)OC
  • InChI=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
  • Key:GEJDGVNQKABXKG-CFKGEZKQSA-N

Valbenazine, sold under the brand name Ingrezza, is a medication used to treat tardive dyskinesia.[1] It acts as a vesicular monoamine transporter 2 (VMAT2) inhibitor.[2]

Medical use

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Valbenazine is used to treat tardive dyskinesia in adults.[1] Tardive dyskinesia is a drug-induced neurological injury characterized by involuntary movements.[3] The clinical trials that led to the approval of valbenazine by the US Food and Drug Administration (FDA) were six weeks in duration.[1] 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.[4]

Contraindications

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There are no contraindications for the use of valbenazine according to the prescribing information.[1]

Adverse effects

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Side effects may include sleepiness or QT prolongation.[5] 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.[5]

Valbenazine has not been effectively studied in pregnancy, and it is recommended that women who are pregnant or breastfeeding avoid use of valbenazine.[5]

Pharmacology

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Mechanism of action

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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.[6] 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.[7] By selectively reducing the ability of VMAT2 to load dopamine into synaptic vesicles,[8] 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.[9]

Pharmacokinetics

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Valbenazine is a prodrug which is an ester of [+]-α-dihydrotetrabenazine (DTBZ) with the amino acid L-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%).[10]

Society and culture

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Valbenazine is produced by Neurocrine Biosciences. Valbenazine is the first medication approved by the FDA for the treatment of tardive dyskinesia, in April 2017.[11]

Economics

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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)-1H,2H,3H,4H,6H,7H,11bH-pyrido-[2,1-a]isoquinolin-2-yl]methanol and related compounds, which includes valbenazine.[12]

Names

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The International Nonproprietary Name (INN) is valbenazine.[13]: 114 

Research

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Valbenazine is being studied for the treatment of Tourette's syndrome.[14][15]

References

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  1. ^ a b c d e "Ingrezza- valbenazine capsule; Ingrezza- valbenazine kit". DailyMed. 18 August 2023. Retrieved 17 November 2023.
  2. ^ O'Brien CF, Jimenez R, Hauser RA, Factor SA, Burke J, Mandri D, et al. (October 2015). "NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double-blind, placebo-controlled study". Movement Disorders. 30 (12): 1681–7. doi:10.1002/mds.26330. PMC 5049616. PMID 26346941.
  3. ^ "Tardive dyskinesia". rarediseases.info.nih.gov. 1 June 2017. Archived from the original on 18 June 2017. Retrieved 21 February 2018.
  4. ^ Janeczko L. "Long-term Valbenazine Appears Safe for Patients With Tardive Dyskinesia". www.medscape.com. Reuters Health Information. Retrieved 21 February 2018.[permanent dead link‍]
  5. ^ a b c "Valbenazine: Drug Information". UpToDate. Retrieved 14 July 2017.
  6. ^ "NBI-98854 – VMAT2 Inhibitor | Tics in Children Treatment | Neurocrine Biosciences". www.neurocrine.com. Archived from the original on 30 January 2015. Retrieved 13 November 2016.
  7. ^ "tardive-dyskinesia". www.priory.com. Archived from the original on 18 January 2008. Retrieved 13 November 2016.
  8. ^ Purves D, et al. (2018). Neuroscience (Sixth ed.). Sinauer Associates. ISBN 978-1-60535-380-7.
  9. ^ "NBIX: NDA for Valbenazine in Tardive Dyskinesia to be Filed in 2016…". Archived from the original on 14 November 2016. Retrieved 13 November 2016.
  10. ^ Valbenazine Professional Drug Facts.
  11. ^ Office of the Commissioner. "Press Announcements - FDA approves first drug to treat tardive dyskinesia". www.fda.gov. Archived from the original on 12 April 2017. Retrieved 12 April 2017.
  12. ^ US 20160289226, Ashweek N, Harriott N, "[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", published 6 October 2016, assigned to Neurocrine Biosciences, Inc. [permanent dead link‍]
  13. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 71" (PDF). World Health Organization. Archived (PDF) from the original on 18 May 2016. Retrieved 18 November 2016.
  14. ^ "Tourette Syndrome Clinical Trials". Neurocrine Biosciences. Archived from the original on 14 November 2016. Retrieved 13 November 2016.
  15. ^ Clinical trial number NCT02581865 for "Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome" at ClinicalTrials.gov

Further reading

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