Valbenazine

Identification

Name

Valbenazine

Accession Number

DB11915

Description

Valbenazine (development name NBI-98854) has been used in trials studying the treatment and basic science of Tourette Syndrome and Tardive Dyskinesia. In April, 2017, valbenazine was approved by the FDA (as Ingrezza) as the first and only approved treatment for adults with Tardive Dyskinesia (TD).

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Valbenazine (DB11915)

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Weight

Average: 418.578
Monoisotopic: 418.283157712

Chemical Formula

C₂₄H₃₈N₂O₄

Synonyms

• Valbenazine

External IDs

• MT-5199
• NBI-98854

Pharmacology

Indication

For the treatment of tardive dyskinesia in adults ^Label.

Associated Conditions

• Tardive Dyskinesia (TD)

Contraindications & Blackbox Warnings

Learn about our commercial Contraindications & Blackbox Warnings data.

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Pharmacodynamics

Valbenazine decreases the availability of monoamine neurotransmitters by preventing their storage in synaptic vesicles ². This is believed to be the reason behind its therapeutic effect in tardive dyskinesia although the exact mechanism is unknown.

Mechanism of action

Valbenazine and its active meabolites bind to and inhibit vesicular monoamine transporter 2 (VMAT2)with high selectivity (valbenazine Ki = 150nM, [+]-α-HTBZ Ki = 1.98nM, NBI136110 Ki = 160nM) with no significant binding to VMAT1 (Ki <10microM for each) ². This prevents the reuptake and storage of monoamine neurotransmitters noradrenaline, dopamine, and serotonin in synaptic vesicles making them vulnerable to metabolism by cytosolic enzymes. The presynaptic release of monoamine neurotransmitters is decreased due to the lack of vesicles with packaged neurotransmitter ready for release into the synapse. Neither valbenazine nor its active metabolite exhibit significant off target binding at dopamine, serotonin, or adrenaline receptors or uptake transporters at 10microM concentrations.

Target	Actions	Organism
Avesicular monoamine transporter 2 (VMAT2)	antagonist	Humans

Absorption

Oral bioavailability of 49% ^Label. Tmax of 0.5-1h.

Volume of distribution

92 Liters ^Label.

Protein binding

Valbenazine is >99% bound to plasma proteins ^Label. Its active metabolite [+]-α-HTBZ is 64% bound to plasma proteins.

Metabolism

Valbenzine is extensively metabolized to one active metabolite [+]-α-dihydrotetrabenazine ([+]-α-HTBZ) through hydrolysis of the valine ester reaching Cmax within 4-8 hours ^Label. It is also metabolized via oxidation by CYP3A4/5 to a mono-oxidzed metabolite NBI-136110 which also appears to pharmacologically active. [+]-α-HTBZ is metabolized by CYP2D6.

Hover over products below to view reaction partners

• Valbenazine
  • NBI-136110
  • [+]-α-HTBZ

Route of elimination

Roughly 60% is excreted in urine and 30% in feces ^Label. Less than 2% if the parent compound or active metabolite was excreted unchanged.

Half-life

Both valbenazine and its active metabolite [+]-α-HTBZ have a half life of 15-22 hours ^Label.

Clearance

7.2 Liters/hour ^Label.

Adverse Effects

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Toxicity

No carcinogenicity, mutagenicity, or impairment of fertility has been observed ^Label. QT prolongation may occur with strong CYP2D6 or CYP3A4 inhibitors, or in people who are poor CYP2D6 metabolizers. No overdose information is currently available.

Affected organisms

• Humans and other mammals

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abacavir	Abacavir may decrease the excretion rate of Valbenazine which could result in a higher serum level.
Abametapir	The serum concentration of Valbenazine can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Valbenazine can be increased when combined with Abatacept.
Abiraterone	The metabolism of Valbenazine can be decreased when combined with Abiraterone.
Acalabrutinib	The metabolism of Valbenazine can be decreased when combined with Acalabrutinib.
Acarbose	Acarbose may decrease the excretion rate of Valbenazine which could result in a higher serum level.
Acebutolol	The metabolism of Valbenazine can be decreased when combined with Acebutolol.
Aceclofenac	Aceclofenac may decrease the excretion rate of Valbenazine which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Valbenazine which could result in a higher serum level.
Acetaminophen	Acetaminophen may decrease the excretion rate of Valbenazine which could result in a higher serum level.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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Severity
Severity
A severity rating for each drug interaction, from minor to major.
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Evidence Level
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
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Action
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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Food Interactions

• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of valbenazine.
• Take with or without food.

Products

Product Ingredients

Ingredient	UNII	CAS	InChI Key
Valbenazine tosylate	5SML1T733B	1639208-54-0	BXGKAGLZHGYAMW-TZYFFPFWSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
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Ingrezza	Capsule	80 mg/1	Oral	Neurocrine Biosciences, Inc.	2017-10-04	Not applicable
Ingrezza	Capsule	40 mg/1	Oral	Neurocrine Biosciences, Inc.	2017-04-20	2021-02-25
Ingrezza	Capsule	40 mg/1	Oral	Neurocrine Biosciences, Inc.	2018-12-14	Not applicable

Additional Data Available

Application Number
Application Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Ingrezza	Valbenazine (40 mg/1) + Valbenazine (80 mg/1)	Kit	Oral	Neurocrine Biosciences, Inc.	2018-08-14	2020-03-07
Ingrezza	Valbenazine (40 mg/1) + Valbenazine (80 mg/1)	Kit	Oral	Neurocrine Biosciences, Inc.	2018-12-14	Not applicable
Ingrezza	Valbenazine (40 mg/1) + Valbenazine (80 mg/1)	Kit	Oral	Neurocrine Biosciences, Inc.	2018-08-14	2020-03-07
Ingrezza	Valbenazine (40 mg/1) + Valbenazine (80 mg/1)	Kit	Oral	Neurocrine Biosciences, Inc.	2018-12-14	Not applicable

Categories

ATC Codes

N07XX13 — Valbenazine

• N07XX — Other nervous system drugs
• N07X — OTHER NERVOUS SYSTEM DRUGS
• N07 — OTHER NERVOUS SYSTEM DRUGS
• N — NERVOUS SYSTEM

Drug Categories

• Amino Acids
• Amino Acids, Branched-Chain
• Amino Acids, Essential
• Amino Acids, Peptides, and Proteins
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A5 Substrates
• Cytochrome P-450 Substrates
• Drugs that are Mainly Renally Excreted
• Heterocyclic Compounds, Fused-Ring
• Nervous System
• Quinolizines
• Vesicular Monoamine Transporter 2 Inhibitor
• Vesicular Monoamine Transporter 2 Inhibitors

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as alpha amino acid esters. These are ester derivatives of alpha amino acids.

Kingdom

Organic compounds

Super Class

Organic acids and derivatives

Class

Carboxylic acids and derivatives

Sub Class

Amino acids, peptides, and analogues

Direct Parent

Alpha amino acid esters

Alternative Parents

Valine and derivatives / Tetrahydroisoquinolines / Anisoles / Fatty acid esters / Aralkylamines / Alkyl aryl ethers / Piperidines / Trialkylamines / Carboxylic acid esters / Monocarboxylic acids and derivatives / Azacyclic compounds / Organic oxides / Monoalkylamines / Hydrocarbon derivatives / Carbonyl compounds

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Substituents

Alkyl aryl ether / Alpha-amino acid ester / Amine / Anisole / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carbonyl group / Carboxylic acid ester / Ether / Fatty acid ester / Fatty acyl / Hydrocarbon derivative / Monocarboxylic acid or derivatives / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Phenol ether / Piperidine / Primary aliphatic amine / Primary amine / Tertiary aliphatic amine / Tertiary amine / Tetrahydroisoquinoline / Valine or derivatives

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Chemical Identifiers

UNII

54K37P50KH

CAS number

1025504-45-3

InChI Key

GEJDGVNQKABXKG-CFKGEZKQSA-N

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

IUPAC Name

(2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl (2S)-2-amino-3-methylbutanoate

SMILES

COC1=C(OC)C=C2[[email protected]]3C[[email protected]@H](OC(=O)[[email protected]@H](N)C(C)C)[[email protected]](CC(C)C)CN3CCC2=C1

References

General References

1. O'Brien CF, Jimenez R, Hauser RA, Factor SA, Burke J, Mandri D, Castro-Gayol JC: NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double-blind, placebo-controlled study. Mov Disord. 2015 Oct;30(12):1681-7. doi: 10.1002/mds.26330. Epub 2015 Sep 8. [PubMed:26346941]
2. Grigoriadis DE, Smith E, Hoare SRJ, Madan A, Bozigian H: Pharmacologic Characterization of Valbenazine (NBI-98854) and Its Metabolites. J Pharmacol Exp Ther. 2017 Jun;361(3):454-461. doi: 10.1124/jpet.116.239160. Epub 2017 Apr 12. [PubMed:28404690]
3. FDA Approved Drug Products: Ingrezza (valbenazine) oral capsules [Link]

External Links

PubChem Compound

24795069

PubChem Substance

347828246

ChemSpider

28536134

RxNav

1918219

ChEMBL

CHEMBL2364639

ZINC

ZINC000043195697

Wikipedia

Valbenazine

FDA label

Download (358 KB)

MSDS

Download (21.3 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Tardive Dyskinesia (TD)	1
4	Recruiting	Treatment	Tardive Dyskinesia (TD)	1
3	Completed	Treatment	Tardive Dyskinesia (TD)	3
3	Enrolling by Invitation	Treatment	Chorea, Huntington	1
3	Recruiting	Treatment	Chorea, Huntington	1
2	Completed	Treatment	Gilles de la Tourette's Syndrome	5
2	Completed	Treatment	Tardive Dyskinesia (TD)	4
2	Terminated	Treatment	Gilles de la Tourette's Syndrome	2
2, 3	Completed	Treatment	Tardive Dyskinesia (TD)	1
1	Completed	Basic Science	Effect of Ketoconazole on the PK of NBI-98854 in Healthy Subjects	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	40 mg/1
Capsule	Oral	80 mg/1
Kit	Oral

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
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US8039627	No	2011-10-18	2029-10-06
US8357697	No	2013-01-22	2027-11-08
US10065952	No	2018-09-04	2036-10-28

Additional Data Available

Filed On
Filed On
The date on which a patent was filed with the relevant government.
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Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0383 mg/mL	ALOGPS
logP	3.63	ALOGPS
logP	3.65	ChemAxon
logS	-4	ALOGPS
pKa (Strongest Basic)	8.41	ChemAxon
Physiological Charge	2	ChemAxon
Hydrogen Acceptor Count	5	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	74.02 Å2	ChemAxon
Rotatable Bond Count	8	ChemAxon
Refractivity	118.4 m3·mol-1	ChemAxon
Polarizability	48.97 Å3	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

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Drug created on October 20, 2016 15:00 / Updated on June 12, 2020 10:53