Valbenazine

Valbenazine is a selective vesicular monoamine transporter 2 (VMAT2) inhibitor marketed under the brand name Ingrezza.

It is approved for the treatment of tardive dyskinesia, a condition characterized by involuntary, repetitive movements. By inhibiting VMAT2 in presynaptic neurons, valbenazine decreases the release of monoamines, thereby reducing overactive signaling responsible for these abnormal movements.

Valbenazine is administered orally once daily with or without food and is primarily metabolized in the liver by cytochrome P450 enzymes, notably CYP2D6.

The primary pharmacogenetic gene associated with valbenazine is CYP2D6, which encodes a liver enzyme responsible for metabolizing many drugs, including active metabolites of valbenazine. CYP2D6 is part of the cytochrome P450 family and influences how quickly valbenazine is cleared from the body.

Variants in CYP2D6 can result in different metabolizer phenotypes—ranging from poor to ultrarapid—which affect drug levels and response. In pharmacogenetics, a “phenotype” refers to an individual’s drug‐metabolizing capacity based on inherited gene variants.

Genetic variations in CYP2D6 determine metabolizer status—ultrarapid, normal, intermediate, or poor—which directly influence plasma concentrations of valbenazine and its active metabolites. For instance, poor metabolizers may have higher drug exposure and increased risk of QT prolongation, whereas ultrarapid metabolizers may experience reduced efficacy.

Ultrarapid Metabolizer

• Effect on drug levels: Increased CYP2D6 activity leads to lower active metabolite concentrations.
• Clinical consequence: Potential reduced efficacy and persistence of symptoms.
• Side effects: Lower risk of adverse effects; side effects not typically reported.

Normal Metabolizer

• Effect on drug levels: Expected drug and metabolite levels within target range.
• Clinical consequence: Standard response as seen in clinical trials.
• Side effects: Side effect profile as described in the prescribing information; generally well-tolerated.

Intermediate Metabolizer

• Effect on drug levels: Moderate CYP2D6 activity may lead to slightly elevated metabolite levels.
• Clinical consequence: Generally similar efficacy with possible slight increase in side effects.
• Side effects: Mild side effects such as somnolence or headache may be more noticeable.

Poor Metabolizer

• Effect on drug levels: Reduced CYP2D6 activity causes higher systemic concentrations of active metabolites.
• Clinical consequence: Increased risk of QT prolongation and other adverse reactions.
• Side effects: Higher incidence of cardiac effects and common adverse events; monitor closely.

Indeterminate/Not Available

• Effect on drug levels: Unknown impact.
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.
• Side effects: Unpredictable; follow standard monitoring protocols.

The following dosing guidelines are based on the available FDA pharmacogenomic guidance for valbenazine and its metabolism by CYP2D6.

CYP2D6 Dosing Guideline

There are no specific alternate treatments or dosing strategies for valbenazine based on CYP2D6 phenotype mentioned in the FDA guidance. Clinicians may consider other VMAT2 inhibitors under clinical discretion.

• FDA – Table of Pharmacogenetic Associations