CYP2D6 and Ondansetron

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.
  • Increased risk of treatment failure (i.e., uncontrolled nausea and vomiting).

Therapeutic Recommendation

  • Select alternative 5-HT3 antagonist not metabolized by CYP2D6 (i.e., granisetron) or alternative anti-emetic as appropriate (e.g., promethazine).

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

Clinical Implication

  • Normal to increased CYP2D6 enzyme activity.
  • Possible increased risk of treatment failure (i.e., uncontrolled nausea and vomiting).

Therapeutic Recommendation

  • Select alternative 5-HT3 antagonist not metabolized by CYP2D6 (i.e., granisetron) or alternative anti-emetic as appropriate (e.g., promethazine).

Normal Metabolizer (Activity Score 1.25–2.25)*

Clinical Implication

  • Normal CYP2D6 enzyme activity.
  • Normal response expected.

Therapeutic Recommendation

  • Use standard dose of ondansetron

Intermediate – Ultrarapid Metabolizer (Activity Score 0.25+, 0.5+, 0.75+, or 1+)*

Clinical Implication

  • Possible increased, normal, or decreased CYP2D6 enzyme activity. Exact activity cannot be determined because of gene duplication and assay limitations.

Therapeutic Recommendation

  • Select alternative 5-HT3 antagonist not metabolized by CYP2D6 (i.e., granisetron) or alternative anti-emetic as appropriate (e.g., promethazine).

Intermediate Metabolizer with an enzyme Activity Score of 1*

Clinical Implication

  • Decreased CYP2D6 enzyme activity.
  • Normal response expected.

Therapeutic Recommendation

  • Use standard dose of ondansetron

Intermediate Metabolizer with an enzyme Activity Score of 0.25-0.75*

Clinical Implication

  • Decreased CYP2D6 enzyme activity.
  • Insufficient evidence demonstrating clinical impact.

Therapeutic Recommendation

  • Use standard dose of ondansetron

Poor Metabolizer (Activity Score 0)

Clinical Implication

  • No CYP2D6 enzyme activity.
  • Insufficient evidence demonstrating clinical impact.

Therapeutic Recommendation

  • Use standard dose of ondansetron.

Unable to Genotype or Assay Failure

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

  • Bell GC et al. Clin Pharmacol Ther. 2017 Aug;102(2):213-218. PMID: 28002639.

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