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Deutetrabenazine Therapy and CYP2D6 Genotype

Abstract
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).

Authors

Director, Pharmacogenomics and Molecular Genetics Laboratories, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Bloomington, IN 47405Medical Director, The DeBartolo Family Personalized Medicine Institute, Senior Member, Division of Population Sciences, Moffitt Cancer Center, Tampa, FL 33612Division Director, Clinical Data Management and Curation, CancerLinQ LLC, Alexandria, VASenior Medical Writer, Medical Genetics and Human Variation, National Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health, Bethesda, MD 20894Chief, Medical Genetics and Human Variation, National Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health, Bethesda, MD 20894Project Lead, Medical Genetics and Human Variation, National Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health, Bethesda, MD 20894

Publisher

National Center for Biotechnology Information (US)
Bethesda (MD)

Language

eng

PubMed ID

31046213

Citation

Dean L: Deutetrabenazine Therapy and CYP2D6 Genotype.Medical Genetics Summaries. Edited by Pratt V, et al: National Center for Biotechnology Information (US), 2012, Bethesda (MD).
Dean L. Deutetrabenazine Therapy and CYP2D6 Genotype. Edited by Pratt V, McLeod H, Rubinstein W, et al. Medical Genetics Summaries. Bethesda (MD): National Center for Biotechnology Information (US); 2012.
Dean L. (2012). Deutetrabenazine Therapy and CYP2D6 Genotype. Edited by Pratt V & McLeod H & Rubinstein W, et al. In Medical Genetics Summaries. Bethesda (MD): National Center for Biotechnology Information (US);
Dean L. Edited by Pratt V, et al. Medical Genetics Summaries. Bethesda (MD): National Center for Biotechnology Information (US); 2012.
* Article titles in AMA citation format should be in sentence-case
TY - CHAP T1 - Deutetrabenazine Therapy and CYP2D6 Genotype BT - Medical Genetics Summaries A1 - Dean,Laura, Y1 - 2012/// PY - 2019/5/4/pubmed PY - 2019/5/4/medline PY - 2019/5/4/entrez KW - deutetrabenazine KW - Austedo KW - CYP2D6 KW - chorea KW - Huntington KW - tardive dyskinesia KW - tetrabenazine KW - Xenozine KW - valbenazine KW - Ingrezza N2 - 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). PB - National Center for Biotechnology Information (US) CY - Bethesda (MD) UR - https://www.unboundmedicine.com/medline/citation/31046213/Medical_Genetics_Summaries:_Deutetrabenazine_Therapy_and_CYP2D6_Genotype L2 - https://www.ncbi.nlm.nih.gov/books/NBK540716 DB - PRIME DP - Unbound Medicine ER -