U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C24H38N2O4
Molecular Weight 418.5704
Optical Activity UNSPECIFIED
Defined Stereocenters 4 / 4
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of VALBENAZINE

SMILES

CC(C)C[C@]1([H])CN2CCc3cc(c(cc3[C@@]2([H])C[C@@]1([H])OC(=O)[C@]([H])(C(C)C)N)OC)OC

InChI

InChIKey=GEJDGVNQKABXKG-CFKGEZKQSA-N
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

HIDE SMILES / InChI

Molecular Formula C24H38N2O4
Molecular Weight 418.5704
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 4 / 4
E/Z Centers 0
Optical Activity UNSPECIFIED

(+)-alpha-Dihydrotetrabenazine (HTBZ) is an active component of tetrabenazine. Tetrabenazine is a mixture of closely-related compounds (isomers) and is readily metabolized in the human body to HTBZ and related isomers. Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorder and is marketed under the trade names Nitoman in Canada and Xenazine in New Zealand and some parts of Europe, and is also available in the USA as an orphan drug. (+)-alpha-Dihydrotetrabenazine and related benzo[a]quinolizines have been labeled with tritium and carbon-11 radioisotopes and used for in vitro and in vivo studies of the VMAT2 in animal and human brain. Adeptio Pharmaceuticals is developing alpha-dihydrotetrabenazine (HTBZ) for the treatment of neurological disorders. It acts by inhibiting vesicular monoamine transporter 2 (VMAT2), thereby blocking the transport of dopamine into axon terminals or into storage vesicles.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
0.97 nM [Ki]
Target ID: Q05940
Gene ID: 6571.0
Gene Symbol: SLC18A2
Target Organism: Homo sapiens (Human)
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
INGREZZA

Approved Use

INGREZZA is indicated for the treatment of adults with tardive dyskinesia

Launch Date

1.49178234E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
0.19 ng/mL
1 mg single, oral
dose: 1 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
39.4 ng/mL
80 mg 1 times / day steady-state, oral
dose: 80 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NBI-98782 unknown
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
64 ng/mL
100 mg 1 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
35.1 ng/mL
50 mg 1 times / day steady-state, oral
dose: 50 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
31.7 ng/mL
75 mg single, oral
dose: 75 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
56.2 ng/mL
150 mg single, oral
dose: 150 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
9.22 ng × h/mL
1 mg single, oral
dose: 1 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
695 ng × h/mL
80 mg 1 times / day steady-state, oral
dose: 80 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NBI-98782 unknown
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
1110 ng × h/mL
100 mg 1 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
630 ng × h/mL
50 mg 1 times / day steady-state, oral
dose: 50 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
1150 ng × h/mL
75 mg single, oral
dose: 75 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
1840 ng × h/mL
150 mg single, oral
dose: 150 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
32 h
1 mg single, oral
dose: 1 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
18.5 h
80 mg 1 times / day steady-state, oral
dose: 80 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NBI-98782 unknown
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
19 h
100 mg 1 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
21 h
50 mg 1 times / day steady-state, oral
dose: 50 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
21 h
75 mg single, oral
dose: 75 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
19 h
150 mg single, oral
dose: 150 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
NBI-98782 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
36%
80 mg 1 times / day steady-state, oral
dose: 80 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
NBI-98782 unknown
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources:
unhealthy, 18 - 85 years
n = 110
Health Status: unhealthy
Condition: schizophrenia or schizoaffective disorder, or mood disorder
Age Group: 18 - 85 years
Sex: M+F
Population Size: 110
Sources:
Disc. AE: Syncope...
AEs leading to
discontinuation/dose reduction:
Syncope (1 patient)
Sources:
80 mg 1 times / day steady, oral
Recommended
Dose: 80 mg, 1 times / day
Route: oral
Route: steady
Dose: 80 mg, 1 times / day
Sources:
unhealthy, 18 - 85 years
n = 112
Health Status: unhealthy
Condition: schizophrenia or schizoaffective disorder, or mood disorder
Age Group: 18 - 85 years
Sex: M+F
Population Size: 112
Sources:
Disc. AE: Syncope, Cardiac failure...
AEs leading to
discontinuation/dose reduction:
Syncope (1 patient)
Cardiac failure (1 patient)
Sources:
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: Table 1
unhealthy, 26 - 84 years
n = 262
Health Status: unhealthy
Condition: tardive dyskinesia
Age Group: 26 - 84 years
Sex: unknown
Population Size: 262
Sources: Page: Table 1
Other AEs: Somnolence, Anticholinergic syndrome...
Other AEs:
Somnolence (10.9%)
Anticholinergic syndrome (5.4%)
Balance disorder (4.1%)
Headache (3.4%)
Akathisia (2.7%)
Vomiting (2.6%)
Nausea (2.3%)
Arthralgia (2.3%)
Sources: Page: Table 1
80 mg 1 times / day steady, oral
Recommended
Dose: 80 mg, 1 times / day
Route: oral
Route: steady
Dose: 80 mg, 1 times / day
Sources: Page: 8.1
unhealthy, 26 - 84 years
Health Status: unhealthy
Condition: tardive dyskinesia
Age Group: 26 - 84 years
Sex: unknown
Sources: Page: 8.1
AEs

AEs

AESignificanceDosePopulation
Syncope 1 patient
Disc. AE
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources:
unhealthy, 18 - 85 years
n = 110
Health Status: unhealthy
Condition: schizophrenia or schizoaffective disorder, or mood disorder
Age Group: 18 - 85 years
Sex: M+F
Population Size: 110
Sources:
Cardiac failure 1 patient
Disc. AE
80 mg 1 times / day steady, oral
Recommended
Dose: 80 mg, 1 times / day
Route: oral
Route: steady
Dose: 80 mg, 1 times / day
Sources:
unhealthy, 18 - 85 years
n = 112
Health Status: unhealthy
Condition: schizophrenia or schizoaffective disorder, or mood disorder
Age Group: 18 - 85 years
Sex: M+F
Population Size: 112
Sources:
Syncope 1 patient
Disc. AE
80 mg 1 times / day steady, oral
Recommended
Dose: 80 mg, 1 times / day
Route: oral
Route: steady
Dose: 80 mg, 1 times / day
Sources:
unhealthy, 18 - 85 years
n = 112
Health Status: unhealthy
Condition: schizophrenia or schizoaffective disorder, or mood disorder
Age Group: 18 - 85 years
Sex: M+F
Population Size: 112
Sources:
Somnolence 10.9%
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: Table 1
unhealthy, 26 - 84 years
n = 262
Health Status: unhealthy
Condition: tardive dyskinesia
Age Group: 26 - 84 years
Sex: unknown
Population Size: 262
Sources: Page: Table 1
Arthralgia 2.3%
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: Table 1
unhealthy, 26 - 84 years
n = 262
Health Status: unhealthy
Condition: tardive dyskinesia
Age Group: 26 - 84 years
Sex: unknown
Population Size: 262
Sources: Page: Table 1
Nausea 2.3%
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: Table 1
unhealthy, 26 - 84 years
n = 262
Health Status: unhealthy
Condition: tardive dyskinesia
Age Group: 26 - 84 years
Sex: unknown
Population Size: 262
Sources: Page: Table 1
Vomiting 2.6%
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: Table 1
unhealthy, 26 - 84 years
n = 262
Health Status: unhealthy
Condition: tardive dyskinesia
Age Group: 26 - 84 years
Sex: unknown
Population Size: 262
Sources: Page: Table 1
Akathisia 2.7%
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: Table 1
unhealthy, 26 - 84 years
n = 262
Health Status: unhealthy
Condition: tardive dyskinesia
Age Group: 26 - 84 years
Sex: unknown
Population Size: 262
Sources: Page: Table 1
Headache 3.4%
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: Table 1
unhealthy, 26 - 84 years
n = 262
Health Status: unhealthy
Condition: tardive dyskinesia
Age Group: 26 - 84 years
Sex: unknown
Population Size: 262
Sources: Page: Table 1
Balance disorder 4.1%
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: Table 1
unhealthy, 26 - 84 years
n = 262
Health Status: unhealthy
Condition: tardive dyskinesia
Age Group: 26 - 84 years
Sex: unknown
Population Size: 262
Sources: Page: Table 1
Anticholinergic syndrome 5.4%
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: Table 1
unhealthy, 26 - 84 years
n = 262
Health Status: unhealthy
Condition: tardive dyskinesia
Age Group: 26 - 84 years
Sex: unknown
Population Size: 262
Sources: Page: Table 1
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
unlikely
unlikely
unlikely
unlikely
unlikely
unlikely
unlikely
unlikely
unlikely
unlikely
unlikely
unlikely
unlikely
unlikely
unlikely
unlikely
yes [IC50 14.2 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
no
yes
yes
yes
yes
yes (co-administration study)
Comment: administered with ketoconazole: (similar PK parameters with parent drug) approximately 1.5-fold and 2-fold increase in the Cmax and AUC0-inf, respectively; administered with rifampin: about 50% decrease in Cmax and 80% decrease in AUC0-inf
Page: 22;30
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
A ring-closing metathesis-based approach to the synthesis of (+)-tetrabenazine.
2012 Jul 20
Lessons from 11C-dihydrotetrabenazine imaging in a xenograft mouse model of rat insulinoma: is PET imaging of pancreatic beta cell mass feasible?
2017 Dec
Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson's disease.
2017 Jul 25
Pharmacologic Characterization of Valbenazine (NBI-98854) and Its Metabolites.
2017 Jun
Differences in Dihydrotetrabenazine Isomer Concentrations Following Administration of Tetrabenazine and Valbenazine.
2017 Sep
Patents

Sample Use Guides

Single dose administration of (+)-alpha-Dihydrotetrabenazine (HTBZ), escalating dosage amounts 7.5 - 30 mg orally
Route of Administration: Oral
In Vitro Use Guide
(+)-alpha-Dihydrotetrabenazine is a vesicular monoamine transporter (VMAT2) inhibtior with an Ki value of 0.97 nM. IC50 value: 0.97± 0.48 nM. The (+)-isomer showed high affinity in vitro (Ki = 0.97 +/- 0.48 nM) for the vesicular monoamine transporter (VMAT2) in rat brain striatum, whereas the (-)-isomer was inactive (Ki = 2.2 +/- 0.3 uM).
Substance Class Chemical
Created
by admin
on Sat Jun 26 12:53:20 UTC 2021
Edited
by admin
on Sat Jun 26 12:53:20 UTC 2021
Record UNII
54K37P50KH
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
VALBENAZINE
INN   USAN   WHO-DD  
INN   USAN  
Official Name English
MT-5199
Common Name English
VALBENAZINE [MI]
Common Name English
NBI-98854
Code English
VALBENAZINE [INN]
Common Name English
VALBENAZINE [WHO-DD]
Common Name English
(2R,3R,11BR)-9,10-DIMETHOXY-3-(2-METHYLPROPYL)-1,3,4,6,7,11B-HEXAHYDRO-2H- BENZO(A)QUINOLIZIN-2-YL L-VALINATE
Common Name English
L-VALINE, (2R,3R,11BR)-1,3,4,6,7,11B-HEXAHYDRO-9,10-DIMETHOXY-3-(2-METHYLPROPYL)-2H-BENZO(A)QUINOLIZIN-2-YL ESTER
Common Name English
VALBENAZINE [USAN]
Common Name English
INGREZZA
Brand Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 608317
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
WHO-ATC N07XX13
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
NDF-RT N0000190856
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
Code System Code Type Description
RXCUI
1918219
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
PRIMARY
PUBCHEM
24795069
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
PRIMARY
ChEMBL
CHEMBL2364639
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
PRIMARY
DRUG BANK
DB11915
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
PRIMARY
CAS
1025504-45-3
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
PRIMARY
INN
9744
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
PRIMARY
MERCK INDEX
M11996
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
PRIMARY
EVMPD
SUB182496
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
PRIMARY
DRUG CENTRAL
5227
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
PRIMARY
NCI_THESAURUS
C152815
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
PRIMARY
FDA UNII
54K37P50KH
Created by admin on Sat Jun 26 12:53:21 UTC 2021 , Edited by admin on Sat Jun 26 12:53:21 UTC 2021
PRIMARY
Related Record Type Details
EXCRETED UNCHANGED
FECAL
METABOLIC ENZYME -> SUBSTRATE
TARGET -> INHIBITOR
VMAT2 inhibitors that cause reversible reduction of dopamine release at the presynaptic nerve terminal by selectively inhibiting presynaptic VMAT2.
BINDING
Ki
SALT/SOLVATE -> PARENT
EXCRETED UNCHANGED
URINE
SALT/SOLVATE -> PARENT
METABOLIC ENZYME -> SUBSTRATE
BINDER->LIGAND
BINDING
Related Record Type Details
METABOLITE LESS ACTIVE -> PARENT
METABOLITE ACTIVE -> PRODRUG
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Volume of Distribution PHARMACOKINETIC