Aripiprazole Lauroxil

Aripiprazole lauroxil (brand name Aristada) is a long-acting injectable prodrug of aripiprazole developed for intramuscular administration. After injection, it is gradually converted to active aripiprazole, allowing extended dosing intervals.

It is indicated for the treatment of schizophrenia and for maintenance treatment of bipolar I disorder, helping to reduce the frequency of psychotic episodes and stabilize mood.

Mechanistically, aripiprazole acts as a partial agonist at dopamine D2 and serotonin 5-HT_1A receptors and as an antagonist at serotonin 5-HT_2A receptors, modulating neurotransmitter activity to achieve antipsychotic and mood-stabilizing effects.

The primary gene involved in the metabolism of aripiprazole lauroxil is CYP2D6.

CYP2D6 is a liver enzyme belonging to the cytochrome P450 family that converts aripiprazole lauroxil into its active form and clears aripiprazole from the bloodstream. Variations in CYP2D6 activity affect how quickly the drug is processed.

CYP2D6 genetic variations categorize patients into ultrarapid, normal, intermediate, or poor metabolizers, altering systemic aripiprazole levels. Ultrarapid metabolizers may clear the drug too quickly, risking subtherapeutic exposure, while poor metabolizers may have elevated concentrations and increased side-effect risk.

Genetic variations in CYP2D6 influence aripiprazole exposure and can lead to differences in efficacy and safety profiles among patients based on metabolic activity.

Ultrarapid Metabolizer

• Effect on drug levels: Decreased systemic concentrations
• Clinical consequence: Potential reduced efficacy and symptom recurrence
• Side effects: Lower risk of dose-related adverse effects; efficacy may be inadequate

Normal Metabolizer

• Effect on drug levels: Expected therapeutic concentrations
• Clinical consequence: Standard efficacy and tolerability
• Side effects: Typical side-effect profile as per drug labeling

Intermediate Metabolizer

• Effect on drug levels: Moderately increased concentrations
• Clinical consequence: Slightly higher risk of dose-related adverse effects
• Side effects: Mild to moderate side effects may occur more frequently

Poor Metabolizer

• Effect on drug levels: Significantly increased systemic concentrations
• Clinical consequence: Elevated risk of adverse effects, such as extrapyramidal symptoms
• Side effects: More frequent and severe side effects; consider monitoring closely

Indeterminate/Not Available

• Effect on drug levels: Unknown
• Clinical consequence: No specific guidance; standard monitoring applies
• Side effects: Not established; follow usual safety monitoring

CYP2D6 Dosing Guideline

The FDA guidelines do not specify alternative medications for CYP2D6 poor metabolizers of aripiprazole lauroxil. Clinicians may consider antipsychotics less dependent on CYP2D6 metabolism (for example, paliperidone or ziprasidone) based on individual patient factors. These are examples from guidelines and not direct medical advice.

• FDA – Table of Pharmacogenetic Associations