Review

Deutetrabenazine Therapy andCYP2D6 Genotype

Victoria M. Pratt^{1 2}, Stuart A. Scott^{3 4}, Munir Pirmohamed^{5 6 7}, Bernard Esquivel^{8 9}, Brandi L. Kattman¹⁰, Adriana J. Malheiro¹¹

, editors.

In: Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012.

2019 May 1.

Affiliations

Affiliation

¹ NCBI

Book Affiliations

¹ Adjunct Professor, Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN 46202
² Director, Scientific Affairs Pharmacogenetics, Agena Bioscience, San Diego CA 92121
³ Professor, Department of Pathology Stanford University, Palo Alto, CA 94305
⁴ Director, Stanford Medicine Clinical Genomics Laboratory, Stanford, CA 94305
⁵ David Weatherall Chair of Medicine and UK National Health Service Chair of Pharmacogenetics, University of Liverpool, Liverpool, UK
⁶ Director, MRC Centre for Drug Safety Science and Wolfson Centre for Personalized Medicine, University of Liverpool, Liverpool, UK
⁷ Director, Health Data Research UK North, Liverpool, UK
⁸ CEO, GenXys, Vancouver, BC V6B 1B8, Canada
⁹ VP, Clinical Innovation, ixlayer, San Francisco, CA 94105
¹⁰ Chief, Medical Genetics and Human Variation, National Center forBiotechnology Information (NCBI), National Library of Medicine, National Institutesof Health, Bethesda, MD 20894
¹¹ Project Lead, Medical Genetics and Human Variation, National Center forBiotechnology Information (NCBI), National Library of Medicine, National Institutesof Health, Bethesda, MD 20894

PMID:31046213
Bookshelf ID: NBK540716

Free Books & Documents

Review

Deutetrabenazine Therapy andCYP2D6 Genotype

Laura Dean.

Free Books & Documents

In: Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012.

2019 May 1.

Author

Laura Dean¹

Book Editors

Victoria M. Pratt^{1 2}, Stuart A. Scott^{3 4}, Munir Pirmohamed^{5 6 7}, Bernard Esquivel^{8 9}, Brandi L. Kattman¹⁰, Adriana J. Malheiro¹¹

Affiliation

¹ NCBI

Book Affiliations

¹ Adjunct Professor, Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN 46202
² Director, Scientific Affairs Pharmacogenetics, Agena Bioscience, San Diego CA 92121
³ Professor, Department of Pathology Stanford University, Palo Alto, CA 94305
⁴ Director, Stanford Medicine Clinical Genomics Laboratory, Stanford, CA 94305
⁵ David Weatherall Chair of Medicine and UK National Health Service Chair of Pharmacogenetics, University of Liverpool, Liverpool, UK
⁶ Director, MRC Centre for Drug Safety Science and Wolfson Centre for Personalized Medicine, University of Liverpool, Liverpool, UK
⁷ Director, Health Data Research UK North, Liverpool, UK
⁸ CEO, GenXys, Vancouver, BC V6B 1B8, Canada
⁹ VP, Clinical Innovation, ixlayer, San Francisco, CA 94105
¹⁰ Chief, Medical Genetics and Human Variation, National Center forBiotechnology Information (NCBI), National Library of Medicine, National Institutesof Health, Bethesda, MD 20894
¹¹ Project Lead, Medical Genetics and Human Variation, National Center forBiotechnology Information (NCBI), National Library of Medicine, National Institutesof Health, Bethesda, MD 20894

PMID:31046213
Bookshelf ID: NBK540716

Excerpt

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) (Table 1).

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 (1).

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References

1. AUSTEDO- deutetrabenazine tablet, coated [package insert]; Available from:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7ea3c60a-45c7-4...
1. Jankovic J., Jimenez-Shahed J., Budman C., Coffey B., et al. Deutetrabenazine in Tics Associated with Tourette Syndrome. Tremor Other Hyperkinet Mov (N Y) 2016;6:422. - PMC - PubMed
1. Quezada J., Coffman K.A. Current Approaches and New Developments in the Pharmacological Management of Tourette Syndrome. CNS Drugs. 2018 Jan;32(1):33–45. - PMC - PubMed
1. Fernandez H.H., Factor S.A., Hauser R.A., Jimenez-Shahed J., et al. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study. Neurology. 2017 May 23;88(21):2003–2010. - PMC - PubMed
1. Geschwind M.D., Paras N. Deutetrabenazine for Treatment of Chorea in Huntington Disease. JAMA. 2016 Jul 5;316(1):33–5. - PubMed

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