CYP2D6 and Atomoxetine

Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the list below.

Important Instructions: Please use CYP2D6 Activity Score to select the appropriate row in the list below.

Ultrarapid Metabolizer (Activity Score >2.25)

Clinical Implication

  • Increased CYP2D6 enzyme activity.
  • For children and adults:  Increased risk of treatment failure.

Therapeutic Recommendation

  • For children: Use standard dose and titrations of atomoxetine, if no response nor adverse effects after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less.
  • For adults: Use standard dose and titrations of atomoxetine, if no response after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml. Dosages above the maximum 100 mg/day may be needed to achieve target concentrations, though >120 mg/day has not been evaluated.

Normal – Ultrarapid Metabolizer (Activity Score 1.5+ or 2+)*

Clinical Implication

  • Normal to increased CYP2D6 enzyme activity.
  • For children and adults: Increased risk of treatment failure.

Therapeutic Recommendation

  • For children: Use standard dose and titrations of atomoxetine, if no response nor adverse effects after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less.
  • For adults: Use standard dose and titrations of atomoxetine, if no response after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml. Dosages above the maximum 100 mg/day may be needed to achieve target concentrations, though >120 mg/day has not been evaluated.

Normal Metabolizer (Activity Score of 1.25-2.25)*

Clinical Implication

  • Normal CYP2D6 enzyme activity.
  • For children and adults: Increased risk of treatment failure.

Therapeutic Recommendation

  • For children: Use standard dose and titrations of atomoxetine, if no response nor adverse effects after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less.
  • For adults: Use standard dose and titrations of atomoxetine, if no response after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml. Dosages above the maximum 100 mg/day may be needed to achieve target concentrations, though >120 mg/day has not been evaluated.

Intermediate – Ultrarapid Metabolizer with an enzyme Activity Score of 1+* 

Clinical Implication

  • Possible increased, normal, or decreased CYP2D6 enzyme activity. Exact activity cannot be determined because of gene duplication and assay limitations.
  •  For children and adults: Increased risk of treatment failure.

Therapeutic Recommendation

  • For children: Use standard dose and titrations of atomoxetine, if no response nor adverse effects after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less.
  • For adults: Use standard dose and titrations of atomoxetine, if no response after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml. Dosages above the maximum 100 mg/day may be needed to achieve target concentrations, though >120 mg/day has not been evaluated.

Intermediate – Ultrarapid Metabolizer with an enzyme Activity Score of 0.25+, 0.5+, or 0.75+*

Clinical Implication

  • Possible increased, normal, or decreased CYP2D6 enzyme activity. Exact activity cannot be determined because of gene duplication and assay limitations. 
  • For children and adults: Possible increased risk of treatment failure OR increased risk of adverse effects (e.g., increase in HR and DBP) leading to increased risk of treatment discontinuation.

Therapeutic Recommendation

  • For children: Initiate with standard dose (0.5 mg/kg/day) and maintain dose instead of titrating after 3 days, if no response nor adverse effects after 2 weeks, consider obtaining a plasma concentration (2–4 hours after dose administered). If < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less. Reduce dose if experiencing unacceptable adverse effects.
  • For adults: Initiate with standard dose (40 mg/day) and titrate dose after 2 weeks (instead of 3 days) to 80 mg/day if no response.  If response is inadequate after additional 2 weeks, consider obtaining a plasma concentration (2–4 hours after dose administered). If < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml. Dosages above the maximum 100 mg/day may be needed to achieve target concentrations, although >120 mg/day has not been evaluated. Reduce dose if experiencing unacceptable side effects.

Intermediate Metabolizer with an enzyme (Activity Score 1)*

Clinical Implication

  • Decreased CYP2D6 enzyme activity.
  • For children and adults: For children and adults: Increased risk of treatment failure.

Therapeutic Recommendation

  • For children: Use standard dose and titrations of atomoxetine, if no response nor adverse effects after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less.
  • For adults: Use standard dose and titrations of atomoxetine, if no response after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml. Dosages above the maximum 100 mg/day may be needed to achieve target concentrations, though >120 mg/day has not been evaluated.

Intermediate Metabolizer with an enzyme Activity Score of 1.25-2.25*

Clinical Implication

  • Decreased CYP2D6 enzyme activity.
  • For children and adults:
    Increased risk of adverse effects (e.g., increase in HR and DBP) leading to increased risk of treatment discontinuation.

Therapeutic Recommendation

  • For children: Initiate with standard dose (0.5 mg/kg/day) and maintain dose instead of titrating after 3 days, if no response nor adverse effects after 2 weeks, consider obtaining a plasma concentration (2–4 hours after dose administered). If < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml. Reduce dose if experiencing unacceptable adverse effects.
  • For adults: Initiate with standard dose (40 mg/day) and titrate dose after 2 weeks (instead of 3 days) to 80 mg/day if no response.  If response is inadequate after additional 2 weeks, consider obtaining a plasma concentration (2–4 hours after dose administered). If < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml. Reduce dose if experiencing unacceptable side effects.

Poor Metabolizer (Activity Score 0)

Clinical Implication

  • No CYP2D6 enzyme activity.
  • For children and adults: Increased effectiveness of treatment and increased risk of adverse effects (e.g., increase in HR and DBP).

Therapeutic Recommendation

  • PMs will likely require lower doses.
  • For children: Initiate with standard dose (0.5 mg/kg/day) and maintain dose instead of titrating after 3 days, if no response nor adverse effects after 2 weeks, consider obtaining a plasma concentration (2–4 hours after dose administered). If < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml. Reduce dose if experiencing unacceptable adverse effects. 
  • For adults: Initiate with standard dose (40 mg/day) and titrate dose after 2 weeks (instead of 3 days) to 80 mg/day if no response.  If response is inadequate after additional 2 weeks, consider obtaining a plasma concentration (2–4 hours after dose administered). If < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml. Reduce dose if experiencing unacceptable side effects.

Unable to Genotype or Assay Failure

  • The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

  • This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

*Previously some labs have designated an Activity Score of 1 as Normal Metabolizers

Reference

  • Brown JT et al. Clin Pharmacol Ther. 2019 Jul;106(1):94-102. PMID: 30801677.

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