Valbenazine

Identification

Summary

Valbenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia and chorea associated with Huntington's disease.

Brand Names
Ingrezza
Generic Name
Valbenazine
DrugBank Accession Number
DB11915
Background

Valbenazine is a modified metabolite of tetrabenazine, and it is currently being approved for the treatment of various movement disorders, particularly tardive dyskinesia and chorea associated with Huntington's disease.7,4 Tardive dyskinesia has long been regarded as a consequence of anti-dopamine receptor therapy, and until 2008 with the advent of tetrabenazine, most treatments were ineffective.5 However, challenges in using tetrabenazine as a treatment of tardive dyskinesia included frequent dosing and safety and tolerability concerns.5

On April 2017, valbenazine was approved by the FDA under the brand name INGREZZA as the first and only approved treatment for adults with Tardive Dyskinesia (TD).3 On August 2023, valbenazine was again approved by the FDA for the treatment of chorea associated with Huntington's disease respectively. This approval was supported by positive results in multiple trials, including the KINECT-HD Phase 3 study and the ongoing KINECT-HD2 open-label extension trial. The reduction in chorea severity was observed as early as 2 weeks after starting treatment with an initial dose of 40 mg.8

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 418.578
Monoisotopic: 418.283157712
Chemical Formula
C24H38N2O4
Synonyms
  • Valbenazine
External IDs
  • MT-5199
  • NBI-98854

Pharmacology

Indication

Valbenazine is indicated for the treatment of adults with tardive dyskinesia and chorea associated with Huntington’s disease.7

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofChorea••••••••••••••••••••••••
Management ofTardive dyskinesia••••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Valbenazine inhibits human VMAT2 (Ki ~ 150 nM) with no appreciable binding affinity for VMAT1 (Ki > 10 µM). Valbenazine is converted to the active metabolite [+]-α-dihydrotetrabenazine ([+]-α-HTBZ). [+]-α-HTBZ also binds with relatively high affinity to human VMAT2 (Ki ~ 3 nM). Valbenazine and [+]-αHTBZ have no appreciable binding affinity (Ki > 5000 nM) for dopaminergic (including D2), serotonergic (including 5HT2B), adrenergic, histaminergic or muscarinic receptors, thus limiting off-target receptors binding for a more favorable safety profile.7,2,1

Valbenazine may cause an increase in the corrected QT interval in patients who are CYP2D6-poor metabolizers or who are taking a strong CYP2D6 or CYP3A4 inhibitor. An exposure-response analysis of clinical data from two healthy volunteer studies revealed increased QTc interval with higher plasma concentrations of the active metabolite. Based on this model, patients taking an valbenazine 60 mg or 80 mg dose with increased exposure to the metabolite (e.g., being a CYP2D6 poor metabolizer) may have a mean (upper bound of double-sided 90% CI) QT prolongation of 9.6 (12.0) msec or 11.7 (14.7) msec, respectively as compared to otherwise healthy volunteers given valbenazine, who had a respective mean (upper bound of double-sided 90% CI) QT prolongation of 5.3 (6.7) msec or 6.7 (8.4) msec.7

Mechanism of action

Although the exact mechanism of action of valbenzine is still unknown, it is thought be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release.7

TargetActionsOrganism
ASynaptic vesicular amine transporter
inhibitor
Humans
Absorption

Valbenazine and its active metabolite ([+]-α-HTBZ) demonstrate approximate proportional increases for the area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (Cmax) after single oral doses from 40 mg to 300 mg (i.e., 50% to 375% of the recommended treatment dose).7

Following oral administration, the time to reach maximum valbenazine plasma concentration (Tmax) ranges from 0.5 to 1.0 hours. Valbenazine reaches steady-state plasma concentrations within 1 week. The absolute oral bioavailability of valbenazine is approximately 49%. [+]-α-HTBZ gradually forms and reaches Cmax 4 to 8 hours after administration of valbenazine.7

Ingestion of a high-fat meal decreases valbenazine Cmax by approximately 47% and AUC by approximately 13%. [+]-α-HTBZ Cmax and AUC are unaffected.7

Volume of distribution

The mean steady-state volume of distribution of valbenazine is 92 L.7

Protein binding

The plasma protein binding of valbenazine and [+]-α-HTBZ is greater than 99% and approximately 64%, respectively.7

Metabolism

Valbenazine is extensively metabolized after oral administration by hydrolysis of the valine ester to form the active metabolite ([+]-α-HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form mono-oxidized valbenazine and other minor metabolites. [+]-α-HTBZ appears to be further metabolized in part by CYP2D6.7

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Route of elimination

Following the administration of a single 50-mg oral dose of radiolabeled C-valbenazine (i.e., ~63% of the recommended treatment dose), approximately 60% and 30% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 2% was excreted as unchanged valbenazine or [+]-α-HTBZ in either urine or feces.7

Half-life

Both Valbenazine and [+]-α-HTBZ have half-lives of 15 to 22 hours.7

Clearance

Valbenazine has a mean total plasma systemic clearance value of 7.2 L/hr.7

Adverse Effects
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Toxicity

The limited available data on valbenazine use in pregnant women are insufficient to inform a drug-associated risk. In animal reproductive studies, no malformations were observed when valbenazine was administered orally to rats and rabbits during the period of organogenesis at doses up to 1.8 or 24 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day based on mg/m2 body surface area. However, administration of valbenazine to pregnant rats during organogenesis through lactation produced an increase in the number of stillborn pups and postnatal pup mortalities at doses <1 times the MRHD based on mg/m2. Advise a pregnant woman of the potential risk to a fetus.7

In a fertility study, rats were treated orally with valbenazine at 1, 3, and 10 mg/kg/day prior to mating and through mating, for a minimum of 10 weeks (males) or through Day 7 of gestation (females). These doses are 0.1, 0.4, and 1.2 times the MRHD of 80 mg/day based on mg/m2, respectively. Valbenazine delayed mating in both sexes, which led to a lower number of pregnancies and disrupted estrous cyclicity at the high dose, 1.2 times the MRHD of 80 mg/day based on mg/m2. Valbenazine had no effects on sperm parameters (motility, count, density) or on uterine parameters (corpora lutea, number of implants, viable implants, pre-implantation loss, early resorptions, and post-implantation loss) at any dose.7

Patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) had higher exposure of valbenazine and its active metabolite than patients with normal hepatic function.7

Valbenazine did not increase tumors in rats treated orally for 91 weeks at 0.5, 1, and 2 mg/kg/day. These doses are <1 times (0.06, 0.1, and 0.24 times, respectively) the MRHD of 80 mg/day based on mg/m2.7

Valbenazine did not increase tumors in hemizygous Tg.rasH2 mice treated orally for 26 weeks at 10, 30, and 75 mg/kg/day, which are 0.6, 1.9, and 4.6 times the MRHD of 80 mg/day based on mg/m2.7

Valbenazine was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay.7

No specific antidotes for valbenazine are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certified Poison Control Center.7

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.
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

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Product Ingredients
IngredientUNIICASInChI Key
Valbenazine tosylate5SML1T733B1639208-54-0BXGKAGLZHGYAMW-TZYFFPFWSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
IngrezzaCapsule60 mg/1OralNeurocrine Biosciences, Inc.2021-04-23Not applicableUS flag
IngrezzaCapsule80 mg/1OralNeurocrine Biosciences, Inc.2017-10-04Not 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 tosylate (40 mg/1) + Valbenazine tosylate (60 mg/1)KitOralNeurocrine Biosciences, Inc.2023-08-18Not applicableUS flag
IngrezzaValbenazine (40 mg/1) + Valbenazine (80 mg/1)KitOralNeurocrine Biosciences, Inc.2018-08-142020-03-07US flag
IngrezzaValbenazine tosylate (40 mg/1) + Valbenazine tosylate (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 tosylate (40 mg/1) + Valbenazine tosylate (60 mg/1)KitOralNeurocrine Biosciences, Inc.2023-08-18Not 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. Witek N, Comella C: Valbenazine in the treatment of tardive dyskinesia. Neurodegener Dis Manag. 2019 Apr;9(2):73-81. doi: 10.2217/nmt-2019-0001. Epub 2019 Feb 6. [Article]
  4. Harriott ND, Williams JP, Smith EB, Bozigian HP, Grigoriadis DE: VMAT2 Inhibitors and the Path to Ingrezza (Valbenazine). Prog Med Chem. 2018;57(1):87-111. doi: 10.1016/bs.pmch.2017.12.002. Epub 2018 Mar 7. [Article]
  5. Citrome L: Valbenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication-What is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2017 Jul;71(7). doi: 10.1111/ijcp.12964. Epub 2017 May 12. [Article]
  6. FDA Approved Drug Products: Ingrezza (valbenazine) oral capsules [Link]
  7. FDA Approved Drug Products: INGREZZA® (valbenazine) capsules, for oral use (August 2023) [Link]
  8. Neurocrine Biosciences Announces FDA Approval of INGREZZA® (valbenazine) Capsules for the Treatment of Chorea Associated With Huntington's Disease [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

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral40 mg/1
CapsuleOral60 mg/1
CapsuleOral80 mg/1
KitOral
CapsuleOral73 MG
Capsule, gelatin coatedOral40 mg
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
US10874648No2020-12-292037-10-10US flag
US10857137No2020-12-082037-10-10US flag
US10857148No2020-12-082037-10-10US flag
US10844058No2020-11-242036-10-28US flag
US10851103No2020-12-012036-10-28US flag
US10851104No2020-12-012036-10-28US flag
US10912771No2021-02-092037-10-10US flag
US10919892No2021-02-162036-12-22US flag
US10906902No2021-02-022036-12-22US flag
US10906903No2021-02-022036-12-22US flag
US10952997No2021-03-232037-10-10US flag
US10940141No2021-03-092040-08-10US flag
US10993941No2021-05-042037-10-10US flag
US11026931No2021-06-082039-08-14US flag
US11026939No2021-06-082038-09-18US flag
US11040029No2021-06-222037-10-10US flag
US11311532No2018-09-182038-09-18US flag
US11654142No2018-11-142038-11-14US flag
US11439629No2017-10-102037-10-10US 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/MSsplash10-014i-0000900000-1cadb118dacf8b8fb373
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-0200900000-514a8356e2c8171d1af4
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0uxr-2009700000-d2cde83a552882a3aa52
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-014j-9603100000-ab588e1c17ed1098794f
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0pvl-3179300000-fcbd9204216572e6668b
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-029l-0059100000-2c655f78d0a076010bde
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-202.79527
predicted
DeepCCS 1.0 (2019)
[M+H]+205.19086
predicted
DeepCCS 1.0 (2019)
[M+Na]+211.10338
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Monoamine transmembrane transporter activity
Specific Function
Involved in the ATP-dependent vesicular transport of biogenic amine neurotransmitters. Pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles...
Gene Name
SLC18A2
Uniprot ID
Q05940
Uniprot Name
Synaptic vesicular amine transporter
Molecular Weight
55712.075 Da
References
  1. FDA Approved Drug Products: INGREZZA® (valbenazine) capsules, for oral use (August 2023) [Link]

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
References
  1. FDA Approved Drug Products: INGREZZA® (valbenazine) capsules, for oral use (August 2023) [Link]
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
References
  1. FDA Approved Drug Products: INGREZZA® (valbenazine) capsules, for oral use (August 2023) [Link]
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
References
  1. FDA Approved Drug Products: INGREZZA® (valbenazine) capsules, for oral use (August 2023) [Link]

Drug created at October 20, 2016 21:00 / Updated at February 13, 2024 02:57