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Tetrabenazine

Involuntary Movement Reducers

Drug Overview

Tetrabenazine (brand name Xenazine) is a prescription medication approved by the U.S. Food and Drug Administration for the treatment of chorea associated with Huntington’s disease and other involuntary movement disorders. By modulating neurotransmitter storage, it helps reduce the intensity and frequency of involuntary movements.

The primary indication for tetrabenazine is the management of chorea in Huntington’s disease and tardive dyskinesia. It works by inhibiting the vesicular monoamine transporter 2 (VMAT2) in nerve terminals, leading to reduced uptake of dopamine and other monoamines into synaptic vesicles.

By decreasing the amount of dopamine released into the synapse, tetrabenazine helps to alleviate excessive motor activity. It is typically administered orally, with dose adjustments based on patient response and tolerability.

Relevant Genes and Their Roles

The CYP2D6 gene encodes an enzyme in the liver responsible for metabolizing tetrabenazine into its active and inactive metabolites. Variations in CYP2D6 activity can alter how quickly or slowly the drug is processed.

People with different CYP2D6 genotypes are classified into metabolizer groups—ultrarapid, normal, intermediate, or poor—based on how much functional enzyme they produce. These differences can affect drug levels, efficacy, and the risk of side effects.

Impact of Genetics on Drug Response

CYP2D6 metabolizer status influences plasma concentrations of tetrabenazine’s active metabolites. Ultrarapid metabolizers clear the drug more quickly, which may reduce efficacy, while poor metabolizers clear it slowly, leading to high drug levels and increased risk of adverse effects. Intermediate and normal metabolizers fall between these extremes.

Expected Clinical Effects of Genetic Variation

Ultrarapid Metabolizer

  • Effect on drug levels: Accelerated clearance; lower plasma concentrations
  • Clinical consequence: Potential reduction in therapeutic benefit
  • Side effects: Fewer side effects due to lower exposure; generally mild if present

Normal Metabolizer

  • Effect on drug levels: Expected plasma concentrations
  • Clinical consequence: Standard efficacy and safety profile
  • Side effects: Typical side effects (e.g., sedation, depression) at expected frequency

Intermediate Metabolizer

  • Effect on drug levels: Slightly increased exposure
  • Clinical consequence: Efficacy similar to normal but with modestly higher risk of side effects
  • Side effects: Mild to moderate side effects (e.g., drowsiness), monitor closely

Poor Metabolizer

  • Effect on drug levels: Markedly increased plasma concentrations
  • Clinical consequence: Higher risk of adverse reactions (e.g., excessive sedation, QT prolongation)
  • Side effects: Severe side effects more likely; monitor for depression, hypotension, or cardiac effects

Indeterminate/Not Available

  • Effect: Unknown
  • Clinical consequence: No genotype-based guidance available; follow standard dosing with monitoring

Dosing Guidelines

The following dosing guidelines are based on FDA pharmacogenetic information for CYP2D6 metabolism of tetrabenazine.

Phenotype Clinical Consequence Guideline Recommendation
Ultrarapid Metabolizer Accelerated drug clearance; potential reduced efficacy No dose adjustment; monitor response and consider dose increase if clinically indicated
Normal Metabolizer Expected drug exposure and effect Initiate standard starting dose
Intermediate Metabolizer Slightly increased drug exposure; modestly higher side effect risk Initiate standard starting dose; monitor for adverse effects
Poor Metabolizer Reduced metabolism leading to high drug levels and increased side effect risk Reduce dose (max single dose 25 mg; do not exceed 50 mg/day) or consider alternative therapy
Indeterminate / Not available Unknown impact Initiate standard starting dose

Alternative Treatment Options

Examples of alternative VMAT2 inhibitors include deutetrabenazine (Austedo) and valbenazine (Ingrezza). These may be considered when genetic testing indicates a high-risk CYP2D6 genotype. This information is provided for reference purposes and is not a substitute for professional medical 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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