Annotation of CPIC Guideline for capecitabine and DPYD

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Summary

The CPIC Dosing Guideline for 5-fluorouracil and capecitabine recommends an alternative drug for patients who are DPYD poor metabolizers with an activity score of 0. In those who are poor metabolizers with an activity score of 0.5, an alternative drug is also recommended, but if this is not considered a suitable therapeutic option, 5-fluorouracil or capecitabine should be administered at a strongly reduced dose with early therapeutic drug monitoring. Patients who are intermediate metabolizers with an activity score of 1 or 1.5 should receive a dose reduction of 50%. Patients with the c.[2846A>T];[2846A>T] genotype may require a >50% dose reduction.

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Annotation

This annotation is based on the CPIC® guideline for fluoropyrimidines and DPYD.

January 2024 Update

  • Recently, individual patients have been reported [Article:38129972] to carry only one of the two SNPs in the HapB3 haplotype (i.e., c.1236G>A without c.1129-5923C>G), suggesting that the two variants are not in complete linkage disequilibrium. To address this, CPIC updated the allele definition and functionality tables to include the c.1129-5923C>G SNP separately as this is likely the causal variant leading to decreased function. CPIC also retained the HapB3 haplotype definition for cases where only the c.1236G>A variant is tested (e.g. whole exome sequencing). While CPIC recommends to directly test the causal SNP if possible, in cases where only c.1236G>A is tested or results are available for, it should be clearly stated in the test report that “decreased function” was inferred by detecting the exonic tag SNP, and disclose that in rare cases, the causal decreased function variant c.1129-5923C>G may not be present despite having this tag SNP.

  • A recent publication [Article:37639651] reported evidence for a potentially reduced treatment effectiveness in DPYD c.1236G>A (HapB3) carriers receiving fluoropyrimidine dosing reduced by 25%. In the same patient group, also significantly increased toxicity was observed. The guideline authors have reviewed this paper and concluded that further studies need to be performed before potentially changing the dosing recommendation for this risk variant. It was noted that in this study, in the majority of patients receiving genotype-based dose reductions, no dose escalation was performed as is recommended in the CPIC guideline. Given this evidence for substantial interpatient variability among heterozygous carriers of a single decreased function variant (activity score 1.5), particular emphasis should be placed on dose titration after the initial dosing in this patient group. This guideline is in the process of being updated and these recommendations will be reviewed based on a complete evidence review.

November 2018 Update

  • The DPYD guideline published in November 2017 recommended to reduce the dose of fluoropyrimidines by 25-50% (from the full standard dose) in DPYD Intermediate Metabolizers with an activity score of 1.5. At the time of the guideline publication, this dose range was recommended due to limited evidence for genotype-guided dosing of decreased function alleles/variants. However, a recent prospective study [Article:30348537] provides evidence to support a recommendation for a 50% dose reduction in heterozygous carriers of the decreased function variants c.2846A>T (rs67376798) or c.1129–5923C>G (rs75017182); HapB3 or its tagging SNP c.1236G>A; rs56038477). These data suggest that all Intermediate Metabolizers with an activity score of 1.5 should receive a 50% dose reduction. Therefore CPIC revised its recommendation such that all DPYD Intermediate Metabolizers should receive a 50% dose reduction from the full standard starting dose, whether the activity score is 1 or 1.5 followed by dose titration, based on clinical judgement and ideally therapeutic drug monitoring.
  • In addition, recent case reports from patients who are homozygous for c.2846A>T (activity score of 1) indicate that a dose reduction of more than 50% may be required in some carriers of this genotype. Therefore, in patients with an activity score of 1 due to a homozygous c.[2846A>T];[2846A>T] genotype, clinicians should be aware that a >50% reduction in starting dose might be warranted.

November 2017 Update

Advance online publication November 2017

Adapted from Tables 1 and 2 of the 2017 guideline manuscript (November 2018 Update on PharmGKB).

a Calculated as the sum of the two lowest individual variant activity scores. See main guideline for further information.
b Allele definitions, assignment of allele function and references can be found using the DPYD Allele Functionality Table.
c HGVS nomenclature using the reference sequence NM_000110.3.
d Rating scheme described in the Supplement.
e Also known as rs1801265 or DPYD*9A
f Also known as rs1801159 or DPYD*5
g Also known as rs3918290 or DPYD*2A
h Also known as rs55886062 or DPYD*13
i Also known as rs67376798
j Also known as rs75017182. Likely HapB3 causal variant. See DPYD Allele Functionality Table for other HapB3 proxy SNPs.
k If available, a phenotyping test (see main text for further details) should be considered to estimate the starting dose. In absence of phenotyping data, a dose of <25% of the normal starting dose is estimated assuming additive effects of alleles on 5-FU clearance.
l Therapeutic drug monitoring should be done at the earliest time point possible (e.g., minimum time point in steady state) in order to immediately discontinue the infusion if the drug level is too high.

May 2014 Update on PharmGKB

December 2013 Publication

Advance online publication October 2013.

PharmGKB ID

PA166109594