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CPIC® Guideline for Atomoxetine based on CYP2D6 genotype

Most recent guideline publication:

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 Genotype and Atomoxetine (February 2019)

Updates since publication:

October 2019: CYP2D6 genotype to phenotype translation changes: Up until August 2019, there were a few inconsistencies in the translation of CYP2D6 genotype to phenotype across guidelines (i.e. CPIC and DPWG) and between clinical genetic testing laboratories. CPIC recently conducted a modified-Delphi project to obtain consensus among a panel of international CYP2D6 experts for a uniform system for translating CYP2D6 genotype to phenotype (more information). Modifications to CPIC’s prior system include downgrading the value assigned to the CYP2D6*10 allele for activity score calculation from 0.5 to 0.25 and changing the phenotype assignment for an activity score of 1 from normal metabolizer to intermediate metabolizer  (table of all previous and new phenotype groupings).

As a result, the following changes have been made in the CYP2D6 allele functionality table, CYP2D6 genotype to phenotype table, Atomoxetine pre- and post-test alerts and flow chart.

  • Activity scores of 1 changed from CYP2D6 normal metabolizer to CYP2D6 intermediate metabolizer.
    • Impact on the recommendations in this guideline: The current guideline has a specific recommendation for AS of 1 (no CYP2D6*10 allele present); thus, the current published recommendations for normal and intermediate metabolizer will remain unchanged.
  • All activity scores for diplotypes containing a CYP2D6*10 allele have been updated accordingly (activity scores changed to reflect activity value of 0.25). See table of all previous and new phenotype groupings.
    • Impact on the recommendations in this guideline: The recommendations for ultrarapid and normal metabolizers are the same so this change does not impact the recommended prescribing recommendations. The recommendations for the activity score of 1 (with a CYP2D6*10 allele present) and 0.5 are the same so the current published recommendations for this diplotype will remain unchanged.

Tables and figure provided in the main manuscript of the guideline:

Table 1. Assignment of likely CYP2D6 phenotypes based on diplotypes
Table 2. Dosing recommendations for atomoxetine based on CYP2D6 genotype for children
Table 3. Dosing recommendations for atomoxetine based on CYP2D6 genotype for adults
Figure 1. Atomoxetine Pathway, Pharmacokinetics

Supplement to: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 Genotype and Atomoxetine (February 2019)

Tables and figures provided in the supplement or referenced in the guidelinea:

Supplemental Table S1. Evidence linking CYP2D6 to atomoxetine phenotype
CYP2D6 allele definition table
CYP2D6 allele functionality table
CYP2D6 frequency table
CYP2D6 diplotype-phenotype table

Gene Resource Mapping

CYP2D6 gene resource mappings

Drug Resource Mapping

Atomoxetine

Clinical Decision Support:b

Atomoxetine pre- and post-test alerts and flow chart

aSome of the tables included in the guideline may have been updated online, particularly to reflect newly described or newly characterized alleles. These include the gene-specific information tables (https://www.pharmgkb.org/page/pgxGeneRef) that support CPIC guidelines by providing information regarding star (*) allele definitions, allele function, allele frequency by major ethnic groups, translations of diplotype to phenotype, and gene resource mappings.

bThese resources support the adoption of CPIC guidelines into the electronic health record with clinical decision support and provide information that clinical implementers find helpful.

This guideline has been endorsed by the American Society for Clinical Pharmacology and Therapeutics.