What are the recommendations for prescribing medications like atomoxetine (Strattera) to individuals who are poor CYP2D6 (cytochrome P450 2D6) metabolizers?

Prescribing Atomoxetine for Poor CYP2D6 Metabolizers

For poor CYP2D6 metabolizers, atomoxetine should be initiated at 0.5 mg/kg/day in children and adolescents up to 70 kg, or 40 mg/day in individuals over 70 kg, with increases only if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. 1

Understanding CYP2D6 Metabolism and Atomoxetine

• CYP2D6 is a genetically polymorphic enzyme responsible for the primary metabolism of atomoxetine, with approximately 5-8% of the Caucasian population being poor metabolizers (PMs) 2
• Poor metabolizers have significantly higher plasma concentrations of atomoxetine (approximately 10-fold higher) compared to extensive metabolizers due to reduced clearance 3
• The half-life of atomoxetine is substantially longer in poor metabolizers (21.6 hours) compared to extensive metabolizers (5.2 hours) 3

FDA-Approved Dosing Recommendations for Poor CYP2D6 Metabolizers

Children and Adolescents up to 70 kg:

• Initial dose: 0.5 mg/kg/day (compared to standard 0.5 mg/kg/day) 1
• Target dose: Only increase to 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and initial dose is well tolerated 1
• Maximum dose: 1.4 mg/kg or 100 mg daily, whichever is less 1

Children over 70 kg and Adults:

• Initial dose: 40 mg/day (same as standard starting dose) 1
• Target dose: Only increase to 80 mg/day if symptoms fail to improve after 4 weeks and initial dose is well tolerated 1
• Maximum dose: 100 mg daily 1

Clinical Considerations for Poor Metabolizers

• Poor metabolizers taking atomoxetine may experience:

  • Greater efficacy at equivalent doses compared to extensive metabolizers 4
  • Greater increases in heart rate and diastolic blood pressure 4, 5
  • Higher risk of certain adverse effects including decreased appetite and tremor 4

• A statistically significant increase in QTc interval has been observed with increasing plasma concentrations of atomoxetine, though not considered clinically significant in studies of poor metabolizers 5

Role of CYP2C19 in Atomoxetine Metabolism

• CYP2C19 plays a secondary role in atomoxetine metabolism 6
• Patients with reduced-function CYP2C19 genotypes may have approximately 1.5-fold higher atomoxetine exposure regardless of CYP2D6 status 6
• For patients who are both CYP2D6 poor metabolizers and CYP2C19 reduced function carriers, consider further dose reduction by approximately one-third 6

Monitoring Recommendations

• Monitor closely for adverse effects, particularly cardiovascular effects (heart rate, blood pressure) 4
• Assess efficacy and tolerability before considering dose increases 1
• Periodically reevaluate the long-term usefulness of atomoxetine for the individual patient 1

Common Pitfalls to Avoid

• Failing to identify CYP2D6 metabolizer status before initiating therapy 2, 1
• Using standard dosing protocols in poor metabolizers, which may lead to excessive drug exposure and adverse effects 3, 4
• Co-prescribing strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) which can convert normal metabolizers into functional poor metabolizers 1
• Overlooking the potential impact of CYP2C19 genotype on atomoxetine metabolism 6

By following these guidelines, clinicians can optimize atomoxetine therapy for poor CYP2D6 metabolizers, maximizing efficacy while minimizing adverse effects.