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Deutetrabenazine

Involuntary Movement Reducers

Drug Overview

Deutetrabenazine (brand name Austedo) is a medication approved by the U.S. Food and Drug Administration for the treatment of involuntary movements. It belongs to a class of drugs known as vesicular monoamine transporter 2 (VMAT2) inhibitors and works by modulating neurotransmitter levels in the brain.

It is primarily prescribed for chorea associated with Huntington’s disease and for tardive dyskinesia. By reversibly inhibiting VMAT2, deutetrabenazine reduces the uptake of monoamines—such as dopamine—into synaptic vesicles, thereby decreasing excessive neuronal signaling that leads to involuntary movements.

Relevant Genes and Their Roles

The key gene involved in the metabolism of deutetrabenazine is CYP2D6. CYP2D6 is an enzyme in the liver that chemically modifies many drugs to aid in their breakdown and elimination. It plays a critical role in determining how quickly a medication is processed in the body.

Genetic variations in CYP2D6 can lead to different “metabolizer” statuses—such as poor, intermediate, normal, or ultrarapid—which affect the speed of drug clearance. A poor metabolizer may have reduced enzyme activity and process the drug more slowly, while an ultrarapid metabolizer may clear it too quickly.

Impact of Genetics on Drug Response

Individuals who are poor metabolizers of CYP2D6 may experience higher blood levels of deutetrabenazine, increasing the risk of side effects such as QT prolongation, while ultrarapid metabolizers may have reduced exposure and potentially diminished therapeutic effect. Intermediate and normal metabolizers generally exhibit expected drug levels and typical responses.

Expected Clinical Effects of Genetic Variation

Ultrarapid Metabolizer

  • Effect on drug levels: Decreased systemic exposure
  • Clinical consequence: Potential subtherapeutic response
  • Side effects: Lower likelihood; generally infrequent

Normal Metabolizer

  • Effect on drug levels: Expected systemic exposure
  • Clinical consequence: Typical therapeutic response
  • Side effects: Standard risk profile; occurs at expected frequency

Intermediate Metabolizer

  • Effect on drug levels: Moderately increased exposure
  • Clinical consequence: Slightly higher risk of side effects
  • Side effects: Mild to moderate; less frequent than in poor metabolizers

Poor Metabolizer

  • Effect on drug levels: Significantly increased exposure
  • Clinical consequence: Elevated risk of adverse reactions, including QT prolongation
  • Side effects: Severe potential; monitor for cardiac events

Indeterminate / Not Available

  • Effect: Unknown
  • Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring
  • Side effects: Unknown

Dosing Guidelines

The following dosing guidelines are based on the FDA’s pharmacogenetic guidance for deutetrabenazine.

CYP2D6 Dosing Guideline

Phenotype Clinical Consequence Guideline Recommendation
Ultrarapid Metabolizer No specific FDA guidance; drug may be cleared too quickly, risking reduced efficacy Use standard dosing; monitor clinical response
Normal Metabolizer Expected drug clearance and typical efficacy Use standard dosing
Intermediate Metabolizer Slightly reduced clearance; modestly increased exposure Use standard dosing; monitor for side effects
Poor Metabolizer Results in higher systemic concentrations and increased risk of QT prolongation Reduce total daily dose to ≤36 mg (max single dose 18 mg); monitor ECG
Indeterminate Unknown impact Initiate therapy with recommended starting dose
Not available Unknown impact Initiate therapy with recommended starting dose

Alternative Treatment Options

Alternative VMAT2 inhibitors such as tetrabenazine (Xenazine) and valbenazine (Ingrezza) may be considered. These are examples cited in broader pharmacogenetic discussions and not individual treatment advice.

Sources and References

Disclaimer: This document is for informational purposes only and is not a substitute for medical advice. Clinical decisions should be made by a qualified healthcare professional.

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