DEUTETRABENAZINE

Details

Stereochemistry	RACEMIC
Molecular Formula	C19H27NO3
Molecular Weight	323.4596
Optical Activity	( + / - )
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

[2H]C([2H])([2H])OC1=CC2=C(C=C1OC([2H])([2H])[2H])[C@@H]3CC(=O)[C@@H](CC(C)C)CN3CC2

InChI

InChIKey=MKJIEFSOBYUXJB-WEZHFFAMSA-N

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

HIDE SMILES / InChI

Molecular Formula	C19H27NO3
Molecular Weight	323.4596
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Deutetrabenazine (trade name Austedo) is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of chorea associated with Huntington’s disease. The drug was developed by Auspex Pharmaceuticals and is being commercialized by Teva Pharmaceuticals. Deutetrabenazine is a deuterated derivative of tetrabenazine. The incorporation of deuterium in place of hydrogen at the sites of primary metabolism results in metabolic clearance being slowed, allowing less frequent dosing and better tolerability.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Synaptic vesicular amine transporter 57	Inhibitor 8,504		3.8 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Huntington's disease 28	Primary		Approved 8,583	AUSTEDO
Tardive dyskinesia 15	Primary		Approved 8,583	AUSTEDO

C_max

Value	Dose	Co-administered	Analyte	Population
0.3 ng/mL	25 mg single, oral		DEUTETRABENAZINE plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
0.26 ng × h/mL	25 mg single, oral		DEUTETRABENAZINE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
12 mg 2 times / day multiple, oral Recommended	unhealthy, 18 to 75 years	Disc. AE: Suicidal ideation, Sudden cardiac death...
18 mg 2 times / day multiple, oral Recommended	unhealthy, 18 to 75 years	Disc. AE: Insomnia, Cardio-respiratory arrest...
6 mg 2 times / day multiple, oral Recommended	unhealthy, 18 to 75 years	Disc. AE: QT prolonged, Vesicular rash...
15 mg 2 times / day multiple, oral Recommended	unhealthy, 25 to 75 years	Disc. AE: Confusional state...
12 mg 2 times / day multiple, oral Recommended	unhealthy, 32 years	Disc. AE: Mental status changes...

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AEs

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AE	Significance	Dose	Population
Sudden cardiac death	Disc. AE	12 mg 2 times / day multiple, oral Recommended	unhealthy, 18 to 75 years
Suicidal ideation	Disc. AE	12 mg 2 times / day multiple, oral Recommended	unhealthy, 18 to 75 years
Cardio-respiratory arrest	Disc. AE	18 mg 2 times / day multiple, oral Recommended	unhealthy, 18 to 75 years
Insomnia	Disc. AE	18 mg 2 times / day multiple, oral Recommended	unhealthy, 18 to 75 years
Psychomotor hyperactivity	Disc. AE	18 mg 2 times / day multiple, oral Recommended	unhealthy, 18 to 75 years

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1,087	inhibitor 2,438	substrate 1,388 inhibitor 2,507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 2,153 CYP2B6 926 CYP2C8 1,057 CYP2C19 2,057 CYP3A4/5 296 P-gp 1,741 BCRP 910 OATP1B1 1,079 OATP1B3 961 OCT2 779 OAT1 725 OAT3 747	carbonyl reductase 3 CYP1A2 1,197 OAT3 391 P-gp 2,052 BCRP 697 OATP1B1 503 OATP1B3 435 OCT2 434 OAT1 395	CYP1A2 832 CYP2B6 669

Drug as perpetrator

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Target	Modality	Activity	Metabolite
BCRP 985	inhibitor 4,027	no	SD-1018 1
BCRP 985	inhibitor 4,027	no	SD-1021 1
CYP1A2 2,333	inducer 1,966	no	SD-1018 1
CYP1A2 2,333	inducer 1,966	no	SD-1021 1
CYP1A2 2,333	inhibitor 4,027	no	SD-1018 1

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Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
CYP2D6 1,388	substrate 4,014	major		yes (co-administration study)
BCRP 697	substrate 4,014	no	SD-1018 1
BCRP 697	substrate 4,014	no	SD-1021 1
OAT1 395	substrate 4,014	no	SD-1018 1
OAT1 395	substrate 4,014	no	SD-1021 1

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PubMed

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Title	Date	PubMed
Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial.	2016 Jul 5	27380342

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Patents

Sample Use Guides

In Vivo Use Guide

The dose of Austedo is determined individually for each patient based on the reduction of chorea or tardive dyskinesia and tolerability. When first prescribed to patients who are not being switched from tetrabenazine (a related VMAT2 inhibitor), the recommended starting dose of Austedo is 6 mg administered orally once daily for patients with Huntington’s disease and 12 mg per day (6 mg twice daily) for patients with tardive dyskinesia.

Route of Administration: Oral

In Vitro Use Guide

The in vitro binding affinity for the active metabolites of tetrabenazine (α- and β- dihydrotetrabenazine) and the deuterated versions of these metabolites to the vesicular monoamine transporter 2 (VMAT2) was examined in competitive binding assays. Deuterated α-dihydrotetrabenazine binds to VMAT2 with Ki of 3.8 nM, non-deuterated α-dihydrotetrabenazine binds with Ki of 3.1 nM.