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CPIC® Guideline for Ondansetron and Tropisetron based on CYP2D6 genotype

Most recent guideline publication:

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 Genotype and Use of Ondansetron and Tropisetron (December 2016)

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 and CYP2D6 diplotype-phenotype table:

  • Diplotypes giving rise to activity scores of 1 changed from CYP2D6 normal metabolizer to CYP2D6 intermediate metabolizer assignments.
    • Impact on the recommendations in this guideline: Because the recommendations in this guideline do not differ between a CYP2D6 normal and intermediate metabolizer, the current published recommendations for normal and intermediate metabolizers will remain unchanged.
  • All activity scores for diplotypes containing a CYP2D6*10 allele have been updated accordingly (activity scores changed to reflect the lower value of 0.25 for *10). Prior to the consensus projects, the combination of a duplicated normal function allele with a *10 allele resulted in an activity score of 2.5 which translates to an ultrarapid metabolizer. The lower value of 0.25 for CYP2D6*10 results in an activity score of 2.25 for these allele combinations, which based on the new consensus project, now translates to a normal metabolizer. See table of all previous and new phenotype groupings.
    • Impact on the recommendations in this guideline: The authors of this guideline are currently reviewing evidence for the affected activity score (AS of 2.25) and will update this webpage and relevant tables accordingly.

Tables provided in the main manuscript of the guideline:

Table 1. Assignment of likely CYP2D6 phenotypes based on diplotypes
Table 2. Dosing recommendations for ondansetron and tropisetron based on CYP2D6 genotype

Supplement to: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 Genotype and Use of Ondansetron and Tropisetron (December 2016)

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

Supplemental Table S1. Association between allelic variants and CYP2D6 enzyme activity
Supplemental Table S2. Evidence linking CYP2D6 to ondansetron and tropisetron phenotype
Supplemental Table S3. Cytochrome P450 enzymes involved in the metabolism of 5-HT3 receptor antagonist
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

Ondansetron

Tropisetron

Clinical Decision Support:b

Ondasetron/Tropisetron pre- and post-test alerts and flow chart

aSome of the tables included in the guideline may have been updated on-line, 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.