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
Structure for Valbenazine (DB11915)
- 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.
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- Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- 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) antagonistHumans - 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
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.Improve decision support & research outcomes with our structured adverse effects data.- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir 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. 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. Acetazolamide Acetazolamide may increase the excretion rate of Valbenazine which could result in a lower serum level and potentially a reduction in efficacy. 
Identify potential medication risksEasily compare up to 40 drugs with our drug interaction checker.Get severity rating, description, and management advice.Learn more - 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
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- 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 Ingrezza Capsule 60 mg/1 Oral Neurocrine Biosciences, Inc. 2021-04-23 Not applicable US 
Ingrezza Capsule 40 mg/1 Oral Neurocrine Biosciences, Inc. 2017-04-20 2021-02-25 US Ingrezza Capsule 40 mg/1 Oral Neurocrine Biosciences, Inc. 2018-12-14 Not applicable US Ingrezza Capsule 80 mg/1 Oral Neurocrine Biosciences, Inc. 2017-10-04 Not applicable US - 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. 2018-12-14 Not applicable US Ingrezza Valbenazine (40 mg/1) + Valbenazine (80 mg/1) Kit Oral Neurocrine Biosciences, Inc. 2018-08-14 2020-03-07 US Ingrezza Valbenazine (40 mg/1) + Valbenazine (80 mg/1) Kit Oral Neurocrine Biosciences, Inc. 2018-12-14 Not applicable US Ingrezza Valbenazine (40 mg/1) + Valbenazine (80 mg/1) Kit Oral Neurocrine Biosciences, Inc. 2018-08-14 2020-03-07 US
Categories
- ATC Codes
- N07XX13 — Valbenazine
- Drug Categories
- Amino Acids
- Amino Acids, Branched-Chain
- 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 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
- 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]
- 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]
- FDA Approved Drug Products: Ingrezza (valbenazine) oral capsules [Link]
- External Links
- PubChem Compound
- 24795069
- PubChem Substance
- 347828246
- ChemSpider
- 28536134
- 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) 2 3 Active Not Recruiting Treatment Huntington's Disease (HD) 1 3 Completed Treatment Tardive Dyskinesia (TD) 3 3 Enrolling by Invitation Treatment Huntington's Disease (HD) 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 1 Completed Basic Science Gilles de la Tourette's Syndrome 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 40 mg/1 Capsule Oral 60 mg/1 Capsule Oral 80 mg/1 Kit Oral - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8039627 No 2011-10-18 2029-10-06 US US8357697 No 2013-01-22 2027-11-08 US US10065952 No 2018-09-04 2036-10-28 US US10874648 No 2017-10-10 2037-10-10 US US10857137 No 2017-10-10 2037-10-10 US US10857148 No 2017-10-10 2037-10-10 US US10844058 No 2016-10-28 2036-10-28 US US10851103 No 2016-10-28 2036-10-28 US US10851104 No 2016-10-28 2036-10-28 US US10912771 No 2017-10-10 2037-10-10 US US10919892 No 2016-12-22 2036-12-22 US US10906902 No 2016-12-22 2036-12-22 US US10906903 No 2016-12-22 2036-12-22 US US10952997 No 2017-10-10 2037-10-10 US US10940141 No 2020-08-10 2040-08-10 US US10993941 No 2017-10-10 2037-10-10 US US11026931 No 2019-08-14 2039-08-14 US US11026939 No 2018-09-18 2038-09-18 US US11040029 No 2017-10-10 2037-10-10 US
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
Targets
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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