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

Pharmacology

Indication

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

Structured Indications
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% [FDA Label]. Tmax of 0.5-1h.

Volume of distribution

92 Liters [FDA Label].

Protein binding

Valbenazine is >99% bound to plasma proteins [FDA 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 [FDA 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 [FDA 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 [FDA Label].

Clearance

7.2 Liters/hour [FDA Label].

Toxicity

No carcinogenicity, mutagenicity, or impairment of fertility has been observed [FDA 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
DrugInteractionDrug group
AbirateroneThe serum concentration of Valbenazine can be increased when it is combined with Abiraterone.Approved
AmiodaroneThe metabolism of Valbenazine can be decreased when combined with Amiodarone.Approved, Investigational
AprepitantThe serum concentration of Valbenazine can be increased when it is combined with Aprepitant.Approved, Investigational
ArtemetherThe metabolism of Valbenazine can be decreased when combined with Artemether.Approved
AtazanavirThe metabolism of Valbenazine can be decreased when combined with Atazanavir.Approved, Investigational
AtomoxetineThe metabolism of Valbenazine can be decreased when combined with Atomoxetine.Approved
BetaxololThe metabolism of Valbenazine can be decreased when combined with Betaxolol.Approved
BoceprevirThe metabolism of Valbenazine can be decreased when combined with Boceprevir.Approved, Withdrawn
BortezomibThe metabolism of Valbenazine can be decreased when combined with Bortezomib.Approved, Investigational
BosentanThe serum concentration of Valbenazine can be decreased when it is combined with Bosentan.Approved, Investigational
BupropionThe metabolism of Valbenazine can be decreased when combined with Bupropion.Approved
CarbamazepineThe metabolism of Valbenazine can be increased when combined with Carbamazepine.Approved, Investigational
CelecoxibThe metabolism of Valbenazine can be decreased when combined with Celecoxib.Approved, Investigational
CeritinibThe serum concentration of Valbenazine can be increased when it is combined with Ceritinib.Approved
ChloroquineThe metabolism of Valbenazine can be decreased when combined with Chloroquine.Approved, Vet Approved
ChlorpromazineThe metabolism of Valbenazine can be decreased when combined with Chlorpromazine.Approved, Vet Approved
CholecalciferolThe metabolism of Valbenazine can be decreased when combined with Cholecalciferol.Approved, Nutraceutical
CimetidineThe metabolism of Valbenazine can be decreased when combined with Cimetidine.Approved
CinacalcetThe metabolism of Valbenazine can be decreased when combined with Cinacalcet.Approved
CitalopramThe metabolism of Valbenazine can be decreased when combined with Citalopram.Approved
ClarithromycinThe metabolism of Valbenazine can be decreased when combined with Clarithromycin.Approved
ClemastineThe metabolism of Valbenazine can be decreased when combined with Clemastine.Approved
ClobazamThe metabolism of Valbenazine can be decreased when combined with Clobazam.Approved, Illicit
ClomipramineThe metabolism of Valbenazine can be decreased when combined with Clomipramine.Approved, Vet Approved
ClotrimazoleThe metabolism of Valbenazine can be decreased when combined with Clotrimazole.Approved, Vet Approved
ClozapineThe metabolism of Valbenazine can be decreased when combined with Clozapine.Approved
CobicistatThe serum concentration of Valbenazine can be increased when it is combined with Cobicistat.Approved
CocaineThe metabolism of Valbenazine can be decreased when combined with Cocaine.Approved, Illicit
ConivaptanThe serum concentration of Valbenazine can be increased when it is combined with Conivaptan.Approved, Investigational
CrizotinibThe metabolism of Valbenazine can be decreased when combined with Crizotinib.Approved
CyclosporineThe metabolism of Valbenazine can be decreased when combined with Cyclosporine.Approved, Investigational, Vet Approved
DabrafenibThe serum concentration of Valbenazine can be decreased when it is combined with Dabrafenib.Approved
DarifenacinThe metabolism of Valbenazine can be decreased when combined with Darifenacin.Approved, Investigational
DarunavirThe serum concentration of Valbenazine can be increased when it is combined with Darunavir.Approved
DasatinibThe serum concentration of Valbenazine can be increased when it is combined with Dasatinib.Approved, Investigational
DeferasiroxThe serum concentration of Valbenazine can be decreased when it is combined with Deferasirox.Approved, Investigational
DelavirdineThe metabolism of Valbenazine can be decreased when combined with Delavirdine.Approved
DesipramineThe metabolism of Valbenazine can be decreased when combined with Desipramine.Approved
DihydroergotamineThe metabolism of Valbenazine can be decreased when combined with Dihydroergotamine.Approved
DiltiazemThe metabolism of Valbenazine can be decreased when combined with Diltiazem.Approved
DiphenhydramineThe metabolism of Valbenazine can be decreased when combined with Diphenhydramine.Approved
DosulepinThe metabolism of Valbenazine can be decreased when combined with Dosulepin.Approved
DoxycyclineThe metabolism of Valbenazine can be decreased when combined with Doxycycline.Approved, Investigational, Vet Approved
DronedaroneThe metabolism of Valbenazine can be decreased when combined with Dronedarone.Approved
DuloxetineThe metabolism of Valbenazine can be decreased when combined with Duloxetine.Approved
EliglustatThe metabolism of Valbenazine can be decreased when combined with Eliglustat.Approved
EnzalutamideThe serum concentration of Valbenazine can be decreased when it is combined with Enzalutamide.Approved
ErythromycinThe metabolism of Valbenazine can be decreased when combined with Erythromycin.Approved, Vet Approved
FluconazoleThe metabolism of Valbenazine can be decreased when combined with Fluconazole.Approved
FluoxetineThe metabolism of Valbenazine can be decreased when combined with Fluoxetine.Approved, Vet Approved
FluvoxamineThe metabolism of Valbenazine can be decreased when combined with Fluvoxamine.Approved, Investigational
FosamprenavirThe metabolism of Valbenazine can be decreased when combined with Fosamprenavir.Approved
FosaprepitantThe serum concentration of Valbenazine can be increased when it is combined with Fosaprepitant.Approved
FosphenytoinThe metabolism of Valbenazine can be increased when combined with Fosphenytoin.Approved
Fusidic AcidThe serum concentration of Valbenazine can be increased when it is combined with Fusidic Acid.Approved
HaloperidolThe metabolism of Valbenazine can be decreased when combined with Haloperidol.Approved
ImatinibThe metabolism of Valbenazine can be decreased when combined with Imatinib.Approved
ImipramineThe metabolism of Valbenazine can be decreased when combined with Imipramine.Approved
IndinavirThe metabolism of Valbenazine can be decreased when combined with Indinavir.Approved
IsavuconazoniumThe metabolism of Valbenazine can be decreased when combined with Isavuconazonium.Approved, Investigational
IsoniazidThe metabolism of Valbenazine can be decreased when combined with Isoniazid.Approved
IsradipineThe metabolism of Valbenazine can be decreased when combined with Isradipine.Approved
ItraconazoleThe metabolism of Valbenazine can be decreased when combined with Itraconazole.Approved, Investigational
IvacaftorThe serum concentration of Valbenazine can be increased when it is combined with Ivacaftor.Approved
KetoconazoleThe metabolism of Valbenazine can be decreased when combined with Ketoconazole.Approved, Investigational
LopinavirThe metabolism of Valbenazine can be decreased when combined with Lopinavir.Approved
LorcaserinThe metabolism of Valbenazine can be decreased when combined with Lorcaserin.Approved
LovastatinThe metabolism of Valbenazine can be decreased when combined with Lovastatin.Approved, Investigational
LuliconazoleThe serum concentration of Valbenazine can be increased when it is combined with Luliconazole.Approved
LumacaftorThe metabolism of Valbenazine can be increased when combined with Lumacaftor.Approved
LumefantrineThe metabolism of Valbenazine can be decreased when combined with Lumefantrine.Approved
ManidipineThe metabolism of Valbenazine can be decreased when combined with Manidipine.Approved, Investigational
MethadoneThe metabolism of Valbenazine can be decreased when combined with Methadone.Approved
MethotrimeprazineThe metabolism of Valbenazine can be decreased when combined with Methotrimeprazine.Approved
MetoprololThe metabolism of Valbenazine can be decreased when combined with Metoprolol.Approved, Investigational
MidostaurinThe metabolism of Valbenazine can be decreased when combined with Midostaurin.Approved
MifepristoneThe serum concentration of Valbenazine can be increased when it is combined with Mifepristone.Approved, Investigational
MirabegronThe metabolism of Valbenazine can be decreased when combined with Mirabegron.Approved
MitotaneThe serum concentration of Valbenazine can be decreased when it is combined with Mitotane.Approved
NefazodoneThe metabolism of Valbenazine can be decreased when combined with Nefazodone.Approved, Withdrawn
NelfinavirThe metabolism of Valbenazine can be decreased when combined with Nelfinavir.Approved
NetupitantThe serum concentration of Valbenazine can be increased when it is combined with Netupitant.Approved
NevirapineThe metabolism of Valbenazine can be increased when combined with Nevirapine.Approved
NicardipineThe metabolism of Valbenazine can be decreased when combined with Nicardipine.Approved
NilotinibThe metabolism of Valbenazine can be decreased when combined with Nilotinib.Approved, Investigational
OlaparibThe metabolism of Valbenazine can be decreased when combined with Olaparib.Approved
OsimertinibThe serum concentration of Valbenazine can be increased when it is combined with Osimertinib.Approved
PalbociclibThe serum concentration of Valbenazine can be increased when it is combined with Palbociclib.Approved
PanobinostatThe serum concentration of Valbenazine can be increased when it is combined with Panobinostat.Approved, Investigational
ParoxetineThe metabolism of Valbenazine can be decreased when combined with Paroxetine.Approved, Investigational
Peginterferon alfa-2bThe serum concentration of Valbenazine can be decreased when it is combined with Peginterferon alfa-2b.Approved
PentobarbitalThe metabolism of Valbenazine can be increased when combined with Pentobarbital.Approved, Vet Approved
PhenobarbitalThe metabolism of Valbenazine can be increased when combined with Phenobarbital.Approved
PhenytoinThe metabolism of Valbenazine can be increased when combined with Phenytoin.Approved, Vet Approved
PosaconazoleThe metabolism of Valbenazine can be decreased when combined with Posaconazole.Approved, Investigational, Vet Approved
PrimidoneThe metabolism of Valbenazine can be increased when combined with Primidone.Approved, Vet Approved
PromazineThe metabolism of Valbenazine can be decreased when combined with Promazine.Approved, Vet Approved
QuinidineThe metabolism of Valbenazine can be decreased when combined with Quinidine.Approved
QuinineThe metabolism of Valbenazine can be decreased when combined with Quinine.Approved
RanolazineThe metabolism of Valbenazine can be decreased when combined with Ranolazine.Approved, Investigational
RifabutinThe metabolism of Valbenazine can be increased when combined with Rifabutin.Approved
RifampicinThe metabolism of Valbenazine can be increased when combined with Rifampicin.Approved
RifapentineThe metabolism of Valbenazine can be increased when combined with Rifapentine.Approved
RitonavirThe metabolism of Valbenazine can be decreased when combined with Ritonavir.Approved, Investigational
RolapitantThe metabolism of Valbenazine can be decreased when combined with Rolapitant.Approved
RopiniroleThe metabolism of Valbenazine can be decreased when combined with Ropinirole.Approved, Investigational
SaquinavirThe metabolism of Valbenazine can be decreased when combined with Saquinavir.Approved, Investigational
SertralineThe metabolism of Valbenazine can be decreased when combined with Sertraline.Approved
SildenafilThe metabolism of Valbenazine can be decreased when combined with Sildenafil.Approved, Investigational
SiltuximabThe serum concentration of Valbenazine can be decreased when it is combined with Siltuximab.Approved
SimeprevirThe serum concentration of Valbenazine can be increased when it is combined with Simeprevir.Approved
St. John's WortThe serum concentration of Valbenazine can be decreased when it is combined with St. John&#39;s Wort.Investigational, Nutraceutical
StiripentolThe serum concentration of Valbenazine can be increased when it is combined with Stiripentol.Approved
SulfisoxazoleThe metabolism of Valbenazine can be decreased when combined with Sulfisoxazole.Approved, Vet Approved
TelaprevirThe metabolism of Valbenazine can be decreased when combined with Telaprevir.Approved, Withdrawn
TelithromycinThe metabolism of Valbenazine can be decreased when combined with Telithromycin.Approved
TerbinafineThe metabolism of Valbenazine can be decreased when combined with Terbinafine.Approved, Investigational, Vet Approved
ThioridazineThe metabolism of Valbenazine can be decreased when combined with Thioridazine.Approved, Withdrawn
TiclopidineThe metabolism of Valbenazine can be decreased when combined with Ticlopidine.Approved
TipranavirThe metabolism of Valbenazine can be decreased when combined with Tipranavir.Approved, Investigational
TocilizumabThe serum concentration of Valbenazine can be decreased when it is combined with Tocilizumab.Approved
TranylcypromineThe metabolism of Valbenazine can be decreased when combined with Tranylcypromine.Approved
VenlafaxineThe metabolism of Valbenazine can be decreased when combined with Venlafaxine.Approved
VerapamilThe metabolism of Valbenazine can be decreased when combined with Verapamil.Approved
VoriconazoleThe metabolism of Valbenazine can be decreased when combined with Voriconazole.Approved, Investigational
ZiprasidoneThe metabolism of Valbenazine can be decreased when combined with Ziprasidone.Approved
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 Syndrome2
2CompletedTreatmentTardive Dyskinesia4
2Enrolling by InvitationTreatmentGilles de la Tourette's Syndrome1
2RecruitingTreatmentGilles de la Tourette's Syndrome1
2, 3RecruitingTreatmentTardive Dyskinesia1
3CompletedTreatmentTardive Dyskinesia2
3Enrolling by InvitationTreatmentTardive Dyskinesia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral40 mg/1
CapsuleOral80 mg/1
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 December 01, 2017 17:38