Identification

Name
Valbenazine
Accession Number
DB11915
Type
Small Molecule
Groups
Approved, Investigational
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).

Structure
Thumb
Synonyms
Not Available
External IDs
MT-5199 / NBI-98854
Product Ingredients
IngredientUNIICASInChI Key
Valbenazine tosylate5SML1T733B1639208-54-0BXGKAGLZHGYAMW-TZYFFPFWSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
IngrezzaCapsule40 mg/1OralNeurocrine Biosciences, Inc.2017-04-20Not applicableUs
IngrezzaCapsule80 mg/1OralNeurocrine Biosciences, Inc.2017-10-04Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
IngrezzaValbenazine (40 mg/1) + Valbenazine (80 mg/1)KitOralNeurocrine Biosciences, Inc.2018-08-14Not applicableUs
IngrezzaValbenazine (40 mg/1) + Valbenazine (80 mg/1)KitOralNeurocrine Biosciences, Inc.2018-08-14Not applicableUs
Categories
UNII
54K37P50KH
CAS number
1025504-45-3
Weight
Average: 418.578
Monoisotopic: 418.283157712
Chemical Formula
C24H38N2O4
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

Pharmacology

Indication

For the treatment of tardive dyskinesia in adults [Label].

Associated Conditions
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
Human
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.

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].

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
DrugInteraction
AbirateroneThe metabolism of Valbenazine can be decreased when combined with Abiraterone.
AcetaminophenAcetaminophen may decrease the excretion rate of Valbenazine which could result in a higher serum level.
AcetazolamideThe metabolism of Valbenazine can be decreased when combined with Acetazolamide.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Valbenazine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Valbenazine which could result in a higher serum level.
Adefovir DipivoxilAdefovir Dipivoxil may decrease the excretion rate of Valbenazine which could result in a higher serum level.
AlbendazoleThe metabolism of Valbenazine can be decreased when combined with Albendazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Valbenazine.
AlfentanilThe metabolism of Alfentanil can be decreased when combined with Valbenazine.
AlfuzosinThe metabolism of Valbenazine can be decreased when combined with Alfuzosin.
Food Interactions
Not Available

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]
External Links
PubChem Compound
24795069
PubChem Substance
347828246
ChemSpider
28536134
ChEMBL
CHEMBL2364639
Wikipedia
Valbenazine
FDA label
Download (358 KB)
MSDS
Download (21.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceGilles de la Tourette's Syndrome1
1CompletedBasic ScienceSafety, Tolerability, and PK of NBI-98854 in Hepatically Impaired Subjects1
2CompletedTreatmentGilles de la Tourette's Syndrome3
2CompletedTreatmentTardive Dyskinesia4
2Enrolling by InvitationTreatmentGilles de la Tourette's Syndrome1
2RecruitingTreatmentGilles de la Tourette's Syndrome2
2, 3RecruitingTreatmentTardive Dyskinesia1
3CompletedTreatmentTardive Dyskinesia2
3Enrolling by InvitationTreatmentTardive Dyskinesia1
4RecruitingTreatmentTardive Dyskinesia (TD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral40 mg/1
CapsuleOral80 mg/1
KitOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8039627No2009-10-062029-10-06Us
US8357697No2007-11-082027-11-08Us

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

Taxonomy

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
Alpha-amino acid ester / Valine or derivatives / Tetrahydroisoquinoline / Anisole / Phenol ether / Alkyl aryl ether / Fatty acid ester / Aralkylamine / Piperidine / Fatty acyl
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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
Human
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
Human
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
Human
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 15:00 / Updated on October 10, 2018 21:57