Annotation of CPIC Guideline for tropisetron and CYP2D6

This annotation is based on the CPIC® guideline for ondansetron and tropisetron and CYP2D6.

October 2019 Update

CYP2D6 genotype to phenotype translation changes: Up until August 2019, there were a few inconsistencies in the translation of CYP2D6 genotype to phenotype translation across guidelines (i.e. CPIC and DPWG) and between clinical genetic testing laboratories. CPIC recently conducted a modified-Delphi project to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts 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 (access tables below):

• 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 consensus project 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.

December 2016

• Guidelines regarding the use of pharmacogenomic tests in dosing for tropisetron were published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
• Excerpt from the 2016 tropisetron dosing guidelines:
  • "Gene duplication has been shown to be associated with higher metabolism and clearance of ondansetron resulting in lower area under the plasma concentration-time curve. This translates clinically into a decreased response to ondansetron and tropisetron, specifically increased risk of vomiting in CYP2D6 ultrarapid metabolizers. If CYP2D6 genotype is known, alternative 5-HT3 receptor antagonist antiemetics not metabolized by CYP2D6 (e.g., granisetron) should be considered in CYP2D6 ultrarapid metabolizers. "
  • "At the time of this writing, there are no data available on CYP2D6 genotype's effect on ondansetron or tropisetron response in the pediatric populations, although there is no reason to suspect that CYP2D6 genetic variation will affect this drug's metabolism differently in children compared with adults. Because CYP2D6 catalytic activity in neonates (<1 month old) depends strongly on developmental aspects, the impact of CYP2D6 in this patient population might be different than adults or older children."
• Download and read:
• Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 Genotype and Use of Ondansetron and Tropisetron
• 2016 supplement
• Gene-specific Information Tables for CYP2D6
• Tropisetron Drug Resource Mappings
• Tropisetron Pre and Post Test Alerts
• Tropisetron Clinical Decision Support Flow Chart

Table 1: Dosing recommendations for tropisetron based on CYP2D6 phenotype/genotype

Adapted from Tables 1 and 2 of the 2016 guideline manuscript.

^a Assignment of allele function and citations for allele function can be found on PharmGKB: CYP2D6 Allele Definition Table and CYP2D6 Allele Functionality Table.

^b Rating scheme is described in the 2016 Supplement

^c CPIC strength of recommendation: No Recommendation. See rating scheme described in the Supplement.

^d Where xN represents the number of CYP2D6 gene copies. For individuals with CYP2D6 duplications or multiplications, see supplemental data for additional information on how to translate diplotypes into phenotypes.

^e Drug-drug interactions and other patient characteristics (e.g., age, renal function, and liver function) should be considered when selecting alternative therapy.

^f Patients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories.