Valbenazine

Identification

Summary

Valbenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia.

Brand Names
Ingrezza
Generic Name
Valbenazine
DrugBank Accession Number
DB11915
Background

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
Thumb
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.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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.

TargetActionsOrganism
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.

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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
Medicalerrors
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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.

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.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Valbenazine which could result in a higher serum level.
AbametapirThe serum concentration of Valbenazine can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Valbenazine can be increased when combined with Abatacept.
AbirateroneThe metabolism of Valbenazine can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Valbenazine can be decreased when combined with Acalabrutinib.
AcebutololThe metabolism of Valbenazine can be decreased when combined with Acebutolol.
AceclofenacAceclofenac may decrease the excretion rate of Valbenazine which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Valbenazine which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Valbenazine which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Valbenazine which could result in a lower serum level and potentially a reduction in efficacy.
Interactions
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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

Products
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Product Ingredients
IngredientUNIICASInChI Key
Valbenazine tosylate5SML1T733B1639208-54-0BXGKAGLZHGYAMW-TZYFFPFWSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
IngrezzaCapsule80 mg/1OralNeurocrine Biosciences, Inc.2017-10-04Not applicableUS flag
IngrezzaCapsule60 mg/1OralNeurocrine Biosciences, Inc.2021-04-23Not applicableUS flag
IngrezzaCapsule40 mg/1OralNeurocrine Biosciences, Inc.2017-04-202021-02-25US flag
IngrezzaCapsule40 mg/1OralNeurocrine Biosciences, Inc.2018-12-14Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
IngrezzaValbenazine (40 mg/1) + Valbenazine (80 mg/1)KitOralNeurocrine Biosciences, Inc.2018-08-142020-03-07US flag
IngrezzaValbenazine (40 mg/1) + Valbenazine (80 mg/1)KitOralNeurocrine Biosciences, Inc.2018-12-14Not applicableUS flag
IngrezzaValbenazine (40 mg/1) + Valbenazine (80 mg/1)KitOralNeurocrine Biosciences, Inc.2018-08-142020-03-07US flag
IngrezzaValbenazine (40 mg/1) + Valbenazine (80 mg/1)KitOralNeurocrine Biosciences, Inc.2018-12-14Not applicableUS flag

Categories

ATC Codes
N07XX13 — Valbenazine
Drug Categories
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
show 5 more
Substituents
Alkyl aryl ether / Alpha-amino acid ester / Amine / Anisole / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carbonyl group / Carboxylic acid ester
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

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[C@H]3C[C@@H](OC(=O)[C@@H](N)C(C)C)[C@H](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. [Article]
  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. [Article]
  3. FDA Approved Drug Products: Ingrezza (valbenazine) oral capsules [Link]
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
PhaseStatusPurposeConditionsCount
4CompletedTreatmentTardive Dyskinesia (TD)2
3CompletedTreatmentTardive Dyskinesia (TD)3
3Enrolling by InvitationTreatmentChorea, Huntington1
3RecruitingTreatmentChorea, Huntington1
2CompletedTreatmentGilles de la Tourette's Syndrome5
2CompletedTreatmentTardive Dyskinesia (TD)4
2TerminatedTreatmentGilles de la Tourette's Syndrome2
2, 3CompletedTreatmentTardive Dyskinesia (TD)1
1CompletedBasic ScienceEffect of Ketoconazole on the PK of NBI-98854 in Healthy Subjects1
1CompletedBasic ScienceGilles de la Tourette's Syndrome1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral40 mg/1
CapsuleOral60 mg/1
CapsuleOral80 mg/1
KitOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8039627No2011-10-182029-10-06US flag
US8357697No2013-01-222027-11-08US flag
US10065952No2018-09-042036-10-28US flag
US10874648No2017-10-102037-10-10US flag
US10857137No2017-10-102037-10-10US flag
US10857148No2017-10-102037-10-10US flag
US10844058No2016-10-282036-10-28US flag
US10851103No2016-10-282036-10-28US flag
US10851104No2016-10-282036-10-28US flag
US10912771No2017-10-102037-10-10US flag
US10919892No2016-12-222036-12-22US flag
US10906902No2016-12-222036-12-22US flag
US10906903No2016-12-222036-12-22US flag
US10952997No2017-10-102037-10-10US flag
US10940141No2020-08-102040-08-10US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0383 mg/mLALOGPS
logP3.63ALOGPS
logP3.65ChemAxon
logS-4ALOGPS
pKa (Strongest Basic)8.41ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area74.02 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity118.4 m3·mol-1ChemAxon
Polarizability48.97 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Not Available
Specific Function
Not Available
Gene Name
VMAT2
Uniprot ID
Q99870
Uniprot Name
Vesicle monoamine transporter type 2
Molecular Weight
17291.525 Da

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da

Drug created on October 20, 2016 21:00 / Updated on February 21, 2021 18:53