Identification

Name
Deutetrabenazine
Accession Number
DB12161
Type
Small Molecule
Groups
Approved, Investigational
Description

Deutetrabenazine is a novel, highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the management of chorea associated with Huntington’s disease. It is a hexahydro-dimethoxybenzoquinolizine derivative and a deuterated Tetrabenazine [5]. The presence of deuterium in deutetrabenazine increases the half-lives of the active metabolite and prolongs their pharmacological activity by attenuating CYP2D6 metabolism of the compound [5]. This allows less frequent dosing and a lower daily dose with improvement in tolerability [2]. Decreased plasma fluctuations of deutetrabenazine due to attenuated metabolism may explain a lower incidence of adverse reactions associated with deutetrabenazine [1]. Deutetrabenazine is a racemic mixture containing RR-Deutetrabenazine and SS-Deutetrabenazine [Label].

Huntington's disease (HD) is a hereditary, progressive neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and neuropsychiatric disturbances [2] that interfere with daily functioning and significantly reduce the quality of life. The most prominent physical symptom of HD that may increase the risk of injury is chorea, which is an involuntary, sudden movement that can affect any muscle and flow randomly across body regions [5]. Psychomotor symptoms of HD, such as chorea, are related to hyperactive dopaminergic neurotransmission [6]. Deutetrabenazine depletes the levels of presynaptic dopamine by blocking VMAT2, which is responsible for the uptake of dopamine into synaptic vesicles in monoaminergic neurons and exocytotic release [6]. As with other agents for the treatment of neurodegenerative diseases, deutetrabenazine is a drug to alleviate the motor symptoms of HD and is not proposed to halt the progression of the disease [7]. In clinical trials of patients with HD, 12 weeks of treatment of deutetrabenazine resulted in overall improvement in mean total maximal chorea scores and motor signs than placebo [5]. It was approved by FDA in April 2017 and is marketed under the trade name Austedo as oral tablets.

Structure
Thumb
Synonyms
Not Available
External IDs
SD-809
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AustedoTablet, coated6 mg/1OralTeva Neuroscience, Inc.2017-04-12Not applicableUs
AustedoTablet, coated12 mg/1OralTeva Neuroscience, Inc.2017-04-12Not applicableUs
AustedoTablet, coated9 mg/1OralTeva Neuroscience, Inc.2017-04-12Not applicableUs
Categories
UNII
P341G6W9NB
CAS number
1392826-25-3
Weight
Average: 323.466
Monoisotopic: 323.236754209
Chemical Formula
C19H27NO3
InChI Key
MKJIEFSOBYUXJB-WEZHFFAMSA-N
InChI
InChI=1S/C19H27NO3/c1-12(2)7-14-11-20-6-5-13-8-18(22-3)19(23-4)9-15(13)16(20)10-17(14)21/h8-9,12,14,16H,5-7,10-11H2,1-4H3/t14-,16-/m0/s1/i3D3,4D3
IUPAC Name
(3S,11bS)-9,10-di(2H3)methoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-one
SMILES
[2H]C([2H])([2H])OC1=CC2=C(C=C1OC([2H])([2H])[2H])[C@@H]1CC(=O)[C@@H](CC(C)C)CN1CC2

Pharmacology

Indication

Indicated for the treatment of chorea associated with Huntington’s disease [Label].

Associated Conditions
Pharmacodynamics

In clinical trials, there was an evidence of clinical effectiveness of deutetrabenazine in improving the symptoms of involuntary movements in patient with tardive dyskinesia by reducing the mean Abnormal Involuntary Movement Scale (AIMS) score [3, 4]. In a randomized, double-blind, placebo-controlled crossover study in healthy male and female subjects, single dose administration of 24 mg deutetrabenazine results in an approximately 4.5 msec mean increase in QTc [Label]. Effects at higher exposures to deutetrabenazine or its metabolites have not been evaluated [Label]. Deutetrabenazine and its metabolites were shown to bind to melanin-containing tissues including eyes, skin and fur in pigmented rats. After a single oral dose of radiolabeled deutetrabenazine, radioactivity was still detected in eye and fur at 35 days following dosing [Label].

Mechanism of action

The precise mechanism of action of deutetrabenazine in mediating its anti-chorea effects is not fully elucidated. Deutetrabenazine reversibly depletes the levels of monoamines, such as dopamine, serotonin, norepinephrine, and histamine, from nerve terminals via its active metabolites. The major circulating metabolites are α-dihydrotetrabenazine [HTBZ] and β-HTBZ that act as reversible inhibitors of VMAT2. Inhibition of VMAT2 results in decreased uptake of monoamines into synaptic terminal and depletion of monoamine stores from nerve terminals [Label].

Deutetrabenazine contains the molecule deuterium, which is a naturally-occurring, nontoxic hydrogen isotope but with an increased mass relative to hydrogen [5]. Placed at key positions, deuterium forms a stronger hydrogen bond with carbon that requires more energy for cleavage, thus attenuating CYP2D6-mediated metabolism without having any effect on the therapeutic target [5].

TargetActionsOrganism
ASynaptic vesicular amine transporter
inhibitor
Human
Absorption

The extent of absorption is 80% with oral deutetrabenazine. As deutetrabenazine is extensively metabolized to its main active metabolites following administration, linear dose dependence of peak plasma concentrations (Cmax) and AUC was observed for the metabolites after single or multiple doses of deutetrabenazine (6 mg to 24 mg and 7.5 mg twice daily to 22.5 mg twice daily) [Label]. Cmax of deuterated α-HTBZ and β-HTBZ are reached within 3-4 hours post-dosing [Label]. Food may increase the Cmax of α-HTBZ or β-HTBZ by approximately 50%, but is unlikely to have an effect on the AUC [Label].

Volume of distribution

The median volume of distribution (Vc/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 500 L and 730 L, respectively [Label]. Human PET-scans of tetrabenazine indicate rapid distribution to the brain, with the highest binding in the striatum and lowest binding in the cortex [Label]. Similar distribution pattern is expected for deutetrabenazine.

Protein binding

At doses ranging from 50 to 200 ng/mL in vitro, tetrabenazine protein binding ranged from 82% to 85%, α-HTBZ binding ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63% [Label]. Similar protein binding pattern is expected for deutetrabenazine and its metabolites.

Metabolism

Deutetrabenazine undergoes extensive hepatic biotransformation mediated by carbonyl reductase to form its major active metabolites, α-HTBZ and β­-HTBZ. These metabolites may subsequently metabolized to form several minor metabolites, with major contribution of CYP2D6 and minor contributions of CYP1A2 and CYP3A4/5 [Label].

Route of elimination

Deutetrabenazine is mainly excreted in the urine as metabolites. In healthy subjects, about 75% to 86% of the deutetrabenazine dose was excreted in the urine, and fecal recovery accounted for 8% to 11% of the dose [Label]. Sulfate and glucuronide conjugates of the α-HTBZ and β-HTBZ, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine [Label]. α-HTBZ and β-HTBZ metabolites accounted for less than 10% of the administered dose in the urine [Label].

Half life

The half-life of total (α+β)-HTBZ from deutetrabenazine is approximately 9 to 10 hours [Label].

Clearance

In patients with Huntington's disease, the median clearance values (CL/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 47 L/hour and 70 L/hour, respectively [Label].

Toxicity

Adverse reactions associated with overdosage include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor [Label]. In case of an overdose, general supportive and symptomatic measures are recommended while monitoring cardiac rhythm and vital signs. In managing overdosage, the possibility of multiple drug involvement should always be considered [Label].

No carcinogenicity studies were performed with deutetrabenazine. In p53+/– transgenic mice, there were no detectable tumors following oral administration of deutetrabenazine at doses of 0, 5, 15, and 30 mg/kg/day for 26 weeks [Label]. Findings from in vitro assays and in vivo mice micronucleus assay suggest that deutetrabenazine and its metabolites are unlikely to be mutagenic [Label]. The effects of deutetrabenazine on fertility have not been evaluated. Oral administration of tetrabenazine had no effects on mating and reproductive systems of male and female rats [Label].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of adverse effects can be increased when 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline is combined with Deutetrabenazine.
AbirateroneThe serum concentration of Deutetrabenazine can be increased when it is combined with Abiraterone.
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Deutetrabenazine.
AceprometazineThe risk or severity of adverse effects can be increased when Aceprometazine is combined with Deutetrabenazine.
AcetaminophenAcetaminophen may decrease the excretion rate of Deutetrabenazine which could result in a higher serum level.
AcetophenazineThe risk or severity of adverse effects can be increased when Acetophenazine is combined with Deutetrabenazine.
Acetyl sulfisoxazoleThe metabolism of Deutetrabenazine can be decreased when combined with Acetyl sulfisoxazole.
Acetylglycinamide chloral hydrateThe risk or severity of sedation and somnolence can be increased when Acetylglycinamide chloral hydrate is combined with Deutetrabenazine.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Deutetrabenazine which could result in a higher serum level.
AgomelatineThe risk or severity of sedation and somnolence can be increased when Agomelatine is combined with Deutetrabenazine.
Food Interactions
Not Available

References

General References
  1. Paton DM: Deutetrabenazine: Treatment of hyperkinetic aspects of Huntington's disease, tardive dyskinesia and Tourette syndrome. Drugs Today (Barc). 2017 Feb;53(2):89-102. doi: 10.1358/dot.2017.53.2.2589164. [PubMed:28387387]
  2. Rodrigues FB, Duarte GS, Costa J, Ferreira JJ, Wild EJ: Tetrabenazine Versus Deutetrabenazine for Huntington's Disease: Twins or Distant Cousins? Mov Disord Clin Pract. 2017 Jul-Aug;4(4):582-585. doi: 10.1002/mdc3.12483. Epub 2017 Mar 29. [PubMed:28920068]
  3. Anderson KE, Stamler D, Davis MD, Factor SA, Hauser RA, Isojarvi J, Jarskog LF, Jimenez-Shahed J, Kumar R, McEvoy JP, Ochudlo S, Ondo WG, Fernandez HH: Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry. 2017 Aug;4(8):595-604. doi: 10.1016/S2215-0366(17)30236-5. Epub 2017 Jun 28. [PubMed:28668671]
  4. Fernandez HH, Factor SA, Hauser RA, Jimenez-Shahed J, Ondo WG, Jarskog LF, Meltzer HY, Woods SW, Bega D, LeDoux MS, Shprecher DR, Davis C, Davis MD, Stamler D, Anderson KE: Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study. Neurology. 2017 May 23;88(21):2003-2010. doi: 10.1212/WNL.0000000000003960. Epub 2017 Apr 26. [PubMed:28446646]
  5. Frank S, Testa CM, Stamler D, Kayson E, Davis C, Edmondson MC, Kinel S, Leavitt B, Oakes D, O'Neill C, Vaughan C, Goldstein J, Herzog M, Snively V, Whaley J, Wong C, Suter G, Jankovic J, Jimenez-Shahed J, Hunter C, Claassen DO, Roman OC, Sung V, Smith J, Janicki S, Clouse R, Saint-Hilaire M, Hohler A, Turpin D, James RC, Rodriguez R, Rizer K, Anderson KE, Heller H, Carlson A, Criswell S, Racette BA, Revilla FJ, Nucifora F Jr, Margolis RL, Ong M, Mendis T, Mendis N, Singer C, Quesada M, Paulsen JS, Brashers-Krug T, Miller A, Kerr J, Dubinsky RM, Gray C, Factor SA, Sperin E, Molho E, Eglow M, Evans S, Kumar R, Reeves C, Samii A, Chouinard S, Beland M, Scott BL, Hickey PT, Esmail S, Fung WL, Gibbons C, Qi L, Colcher A, Hackmyer C, McGarry A, Klos K, Gudesblatt M, Fafard L, Graffitti L, Schneider DP, Dhall R, Wojcieszek JM, LaFaver K, Duker A, Neefus E, Wilson-Perez H, Shprecher D, Wall P, Blindauer KA, Wheeler L, Boyd JT, Houston E, Farbman ES, Agarwal P, Eberly SW, Watts A, Tariot PN, Feigin A, Evans S, Beck C, Orme C, Edicola J, Christopher E: Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial. JAMA. 2016 Jul 5;316(1):40-50. doi: 10.1001/jama.2016.8655. [PubMed:27380342]
  6. Wimalasena K: Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry. Med Res Rev. 2011 Jul;31(4):483-519. doi: 10.1002/med.20187. Epub 2010 Feb 4. [PubMed:20135628]
  7. 39. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 489-490). Edinburgh: Elsevier/Churchill Livingstone. [ISBN:978-0-7020-3471-8]
External Links
PubChem Compound
73442840
PubChem Substance
347828453
ChemSpider
32700662
Wikipedia
Deutetrabenazine
FDA label
Download (754 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentGilles de la Tourette's Syndrome1
2, 3CompletedTreatmentTardive Dyskinesia1
2, 3RecruitingTreatmentGilles de la Tourette's Syndrome1
3Active Not RecruitingTreatmentTardive Dyskinesia1
3CompletedTreatmentChorea1
3CompletedTreatmentChorea Associated With Huntington Disease1
3CompletedTreatmentTardive Dyskinesia1
3RecruitingTreatmentGilles de la Tourette's Syndrome2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, coatedOral12 mg/1
Tablet, coatedOral6 mg/1
Tablet, coatedOral9 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8524733No2011-03-272031-03-27Us
US9296739No2013-09-182033-09-18Us
US9233959No2013-09-182033-09-18Us
US9550780No2013-09-182033-09-18Us
US9814708No2013-09-182033-09-18Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.361 mg/mLALOGPS
logP3.23ALOGPS
logP3.4ChemAxon
logS-2.9ALOGPS
pKa (Strongest Acidic)18.26ChemAxon
pKa (Strongest Basic)7.33ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area38.77 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity91.31 m3·mol-1ChemAxon
Polarizability36.83 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
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 tetrahydroisoquinolines. These are tetrahydrogenated isoquinoline derivatives.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Tetrahydroisoquinolines
Sub Class
Not Available
Direct Parent
Tetrahydroisoquinolines
Alternative Parents
Anisoles / Piperidinones / Aralkylamines / Alkyl aryl ethers / Trialkylamines / Cyclic ketones / Azacyclic compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Tetrahydroisoquinoline / Anisole / Phenol ether / Alkyl aryl ether / Piperidinone / Aralkylamine / Piperidine / Benzenoid / Tertiary aliphatic amine / Tertiary amine
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Prostaglandin-e2 9-reductase activity
Specific Function
NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. ...
Gene Name
CBR1
Uniprot ID
P16152
Uniprot Name
Carbonyl reductase [NADPH] 1
Molecular Weight
30374.73 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Nadph binding
Specific Function
Has low NADPH-dependent oxidoreductase activity towards 4-benzoylpyridine and menadione (in vitro).
Gene Name
CBR3
Uniprot ID
O75828
Uniprot Name
Carbonyl reductase [NADPH] 3
Molecular Weight
30849.97 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
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
Yes
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
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
Kind
Protein
Organism
Human
Pharmacological action
Yes
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

Drug created on October 20, 2016 15:30 / Updated on September 17, 2018 21:05