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Deutetrabenazine response

MedGen UID:
941225
Concept ID:
CN258189
Sign or Symptom
Synonym: Austedo response
Drug:
deutetrabenazine
MedGen UID:
894187
Concept ID:
C4277781
Pharmacologic Substance
 
Gene (location): CYP2D6 (22q13.2)

Definition

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]

Professional guidelines

PubMed

Bashir HH, Jankovic J
Neurol Clin 2020 May;38(2):379-396. Epub 2020 Feb 28 doi: 10.1016/j.ncl.2020.01.004. PMID: 32279716
Ricciardi L, Pringsheim T, Barnes TRE, Martino D, Gardner D, Remington G, Addington D, Morgante F, Poole N, Carson A, Edwards M
Can J Psychiatry 2019 Jun;64(6):388-399. Epub 2019 Feb 21 doi: 10.1177/0706743719828968. PMID: 30791698Free PMC Article
Bhidayasiri R, Jitkritsadakul O, Friedman JH, Fahn S
J Neurol Sci 2018 Jun 15;389:67-75. Epub 2018 Feb 5 doi: 10.1016/j.jns.2018.02.010. PMID: 29454493

Curated

DailyMed Drug Label, AUSTEDO- deutetrabenazine tablet, coated, deutetrabenazine kit, 2021

Recent clinical studies

Etiology

Makhoul K, Jankovic J
J Neurol 2023 Sep;270(9):4518-4522. Epub 2023 Jun 11 doi: 10.1007/s00415-023-11769-0. PMID: 37301806
Frank S, Testa C, Edmondson MC, Goldstein J, Kayson E, Leavitt BR, Oakes D, O'Neill C, Vaughan C, Whaley J, Gross N, Gordon MF, Savola JM; Huntington Study Group/ARC-HD Investigators and Coordinators
CNS Drugs 2022 Nov;36(11):1207-1216. Epub 2022 Oct 15 doi: 10.1007/s40263-022-00956-8. PMID: 36242718Free PMC Article
Sajatovic M, Finkbeiner S, Wilhelm A, Barkay H, Chaijale N, Gross N, Gordon MF
Am J Geriatr Psychiatry 2022 Mar;30(3):360-371. Epub 2021 Aug 16 doi: 10.1016/j.jagp.2021.08.003. PMID: 34511333
Citrome L
Int J Clin Pract 2017 Nov;71(11) Epub 2017 Oct 12 doi: 10.1111/ijcp.13030. PMID: 29024264
Anderson KE, Stamler D, Davis MD, Factor SA, Hauser RA, Isojärvi J, Jarskog LF, Jimenez-Shahed J, Kumar R, McEvoy JP, Ochudlo S, Ondo WG, Fernandez HH
Lancet Psychiatry 2017 Aug;4(8):595-604. Epub 2017 Jun 28 doi: 10.1016/S2215-0366(17)30236-5. PMID: 28668671

Therapy

Makhoul K, Jankovic J
J Neurol 2023 Sep;270(9):4518-4522. Epub 2023 Jun 11 doi: 10.1007/s00415-023-11769-0. PMID: 37301806
Schneider F, Stamler D, Bradbury M, Loupe PS, Hellriegel E, Cox DS, Savola JM, Gordon MF, Rabinovich-Guilatt L
Clin Pharmacol Drug Dev 2021 Jun;10(6):647-659. Epub 2020 Oct 10 doi: 10.1002/cpdd.882. PMID: 33038289Free PMC Article
Khorassani F, Luther K, Talreja O
Am J Health Syst Pharm 2020 Jan 24;77(3):167-174. doi: 10.1093/ajhp/zxz299. PMID: 31974564
Citrome L
Int J Clin Pract 2017 Nov;71(11) Epub 2017 Oct 12 doi: 10.1111/ijcp.13030. PMID: 29024264
Anderson KE, Stamler D, Davis MD, Factor SA, Hauser RA, Isojärvi J, Jarskog LF, Jimenez-Shahed J, Kumar R, McEvoy JP, Ochudlo S, Ondo WG, Fernandez HH
Lancet Psychiatry 2017 Aug;4(8):595-604. Epub 2017 Jun 28 doi: 10.1016/S2215-0366(17)30236-5. PMID: 28668671

Clinical prediction guides

Frank S, Testa C, Edmondson MC, Goldstein J, Kayson E, Leavitt BR, Oakes D, O'Neill C, Vaughan C, Whaley J, Gross N, Gordon MF, Savola JM; Huntington Study Group/ARC-HD Investigators and Coordinators
CNS Drugs 2022 Nov;36(11):1207-1216. Epub 2022 Oct 15 doi: 10.1007/s40263-022-00956-8. PMID: 36242718Free PMC Article
Sajatovic M, Finkbeiner S, Wilhelm A, Barkay H, Chaijale N, Gross N, Gordon MF
Am J Geriatr Psychiatry 2022 Mar;30(3):360-371. Epub 2021 Aug 16 doi: 10.1016/j.jagp.2021.08.003. PMID: 34511333
Khorassani F, Luther K, Talreja O
Am J Health Syst Pharm 2020 Jan 24;77(3):167-174. doi: 10.1093/ajhp/zxz299. PMID: 31974564
Citrome L
Int J Clin Pract 2017 Nov;71(11) Epub 2017 Oct 12 doi: 10.1111/ijcp.13030. PMID: 29024264
Anderson KE, Stamler D, Davis MD, Factor SA, Hauser RA, Isojärvi J, Jarskog LF, Jimenez-Shahed J, Kumar R, McEvoy JP, Ochudlo S, Ondo WG, Fernandez HH
Lancet Psychiatry 2017 Aug;4(8):595-604. Epub 2017 Jun 28 doi: 10.1016/S2215-0366(17)30236-5. PMID: 28668671

Therapeutic recommendations

From Medical Genetics Summaries

This section contains excerpted 1 information 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.

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