CYP2C9 and Phenytoin, Fosphenytoin

Normal Metabolizer

Clinical Implication

  • Normal CYP2C9 enzyme activity.
  • Normal response expected based on CYP2C9 genotype. Risk of SJS/TEN dependent on HLA-B*15:02 (not tested).

Therapeutic Recommendation

  • Use standard dose and adjust based on clinical factors.

Intermediate Metabolizer with an enzyme Activity Score of 1.5

Clinical Implication

  • Decreased CYP2C9 enzyme activity.
  • Normal response expected based on CYP2C9 genotype. Risk of SJS/TEN dependent on HLA-B*15:02 (not tested).

Therapeutic Recommendation

  • Use standard dose and adjust based on clinical factors

Intermediate Metabolizer with an enzyme Activity Score 1

Clinical Implication

  • Decreased CYP2C9 enzyme activity.
  • Increased risk of adverse effects (e.g., sedation, ataxia, dizziness, leukopenia, suicidal ideation). Risk of SJS/TEN dependent on HLA-B*15:02 (not tested).

Therapeutic Recommendation

  • Use standard initial or loading dose for first dose, then use a ~25% dose reduction for subsequent doses. Thereafter, adjust according to therapeutic drug monitoring, response, and adverse effects.

Poor Metabolizer

Clinical Implication

  • Little to no CYP2C9 enzyme activity.
  • Increased risk of adverse effects (e.g., sedation, ataxia, dizziness, leukopenia, suicidal ideation). Risk of SJS/TEN dependent on HLA-B*15:02 (not tested).

Therapeutic Recommendation

  • Use standard initial or loading dose for first dose, then use a ~50% dose reduction for subsequent doses. Thereafter, adjust according to therapeutic drug monitoring, response, and adverse 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.

Reference

  • Karnes JH et al. Clin Pharmacol Ther. 2021 Feb;109(2):302-309. PMID: 32779747.

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