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GTR Home > Conditions/Phenotypes > Deutetrabenazine response

Summary

Deutetrabenazine (brand name Austedo) is used to treat chorea associated with Huntington disease (HD) and tardive dyskinesia (TD). Both HD and TD are types of involuntary movement disorders. The recommended starting dose is 6 mg once daily for individuals with HD and 12 mg per day (6 mg twice daily) for individuals with TD. The maximum recommended daily dosage for both conditions is 48 mg (24 mg, twice daily). The active metabolites of deutetrabenazine are reversible inhibitors of vesicular monoamine transporter 2 (VMAT2). The VMAT2 protein transports the uptake of monoamines, such as dopamine, into the nerve terminal. The inhibition of VMAT2 leads to a depletion of pre-synaptic dopamine and reduces the amount of dopamine realized when that neuron fires. This is thought to lead to fewer abnormal, involuntary movements. The CYP2D6 enzyme converts the active metabolites of deutetrabenazine to minor, reduced activity metabolites. Individuals who have no CYP2D6 activity (“CYP2D6 poor metabolizers”) are likely to have a 3- to 4-fold increased exposure to active metabolites, compared with normal metabolizers, following the recommended standard doses of deutetrabenazine. The 2018 FDA-approved drug label for deutetrabenazine states that the daily dose of deutetrabenazine should not exceed 36 mg (maximum single dose of 18 mg) for individuals who are CYP2D6 poor metabolizers or concurrently taking a strong CYP2D6 inhibitor (e.g., quinidine, antidepressants such as paroxetine, fluoxetine, and bupropion). In addition, the drug label cautions that tetrabenazine, a closely related VMAT2 inhibitor, causes QT prolongation. Therefore, a clinically relevant QT prolongation may occur in some individuals treated with deutetrabenazine who are CYP2D6 poor metabolizers or are co-administered a strong CYP2D6 inhibitor. [from Medical Genetics Summaries]

Available tests

5 tests are in the database for this condition.

Genes See tests for all associated and related genes

  • Also known as: CPD6, CYP2D, CYP2D7AP, CYP2D7BP, CYP2D7P2, CYP2D8P2, CYP2DL1, CYPIID6, P450-DB1, P450C2D, P450DB1, CYP2D6
    Summary: cytochrome P450 family 2 subfamily D member 6 (gene/pseudogene)

Therapeutic recommendations

From Medical Genetics Summaries

This section contains excerpted1information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2017 Statement from the US Food and Drug Administration (FDA)

2.4 Dosage Adjustment in Poor CYP2D6 Metabolizers

In patients who are poor CYP2D6 metabolizers, the total daily dosage of deutetrabenazine should not exceed 36 mg (maximum single dose of 18 mg).

[...]

5.3 QTc Prolongation

Tetrabenazine, a closely related VMAT2 inhibitor, causes an increase (about 8 msec) in the corrected QT (QTc) interval. A clinically relevant QT prolongation may occur in some patients treated with deutetrabenazine who are CYP2D6 poor metabolizers or are co-administered a strong CYP2D6 inhibitor.

For patients who are CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose reduction may be necessary. The use of deutetrabenazine in combination with other drugs that are known to prolong QTc may result in clinically significant QT prolongations.

[...]

8.7 Poor CYP2D6 Metabolizers

Although the pharmacokinetics of deutetrabenazine and its metabolites have not been systematically evaluated in patients who do not express the drug metabolizing enzyme, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similarly to taking a strong CYP2D6 inhibitor (approximately 3-fold).

Please review the complete therapeutic recommendations that are located here: (1).

1 The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance to nomenclature standards, where necessary. We have given the full name of abbreviations, shown in square brackets, where necessary.

Practice guidelines

Consumer resources

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