Annotation of CPIC Guideline for capecitabine and DPYD

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

• The 2017 update of CPIC guidelines regarding 5-fluorouracil and capecitabine has been accepted for publication in Clinical Pharmacology and Therapeutics. Literature up to March 2017 was reviewed, and recommendations and supplemental information were updated. In particular, the dosing recommendations were modified to only apply to 5-fluorouracil and capecitabine; they no longer apply to tegafur. Additionally, dosing recommendations are now given in the context of DPYD activity score.
• Excerpts from the 2017 dosing guideline update:
  • "The strength of the prescribing recommendations is based on the known impact of some variants (c.1905+1G>A, c.1679T>G, c.2846A>T, c.1129– 5923C>G) on DPD activity, the demonstrated relationship between DPD activity and 5-fluorouracil clearance, and between 5-fluorouracil exposure and its toxic effects."
  • "At the time of this writing, data on the possible role of DPYD genetic variation in 5-fluorouracil toxicity in pediatric patient populations is extremely scarce; however, there is no evidence to suggest that 5-fluorouracil pharmacokinetics differ from adult patients, and thus no evidence that DPYD variants would affect 5-fluorouracil metabolism differently in children."
• Download and read:
  • Clinical Pharmacogenetics Implementation Consortium Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update
  • 2017 supplement
  • Gene-specific Information Tables for DPYD
  • Capecitabine Drug Resource Mapping
  • Capecitabine Pre and Post Test Alerts
  • Capecitabine Clinical Decision Support Flow Chart

Table 1: Recommended dosing of fluoropyrimidines by genotype/phenotype.

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

• The CPIC authors recommend that the DPYD*4, *5, *6 and *9A alleles be categorized as "normal" activity, in part based upon the recent publication Comparative Functional Analysis of DPYD Variants of Potential Clinical Relevance to Dihydropyrimidine Dehydrogenase Activity.

December 2013 Publication

Advance online publication October 2013.

• Guidelines regarding the use of pharmacogenomic tests in dosing for fluoropyrimidines have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
• Download and read:
  • Clinical Pharmacogenetics Implementation Consortium Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing
  • 2013 supplement