CPIC® Guideline for Fluoropyrimidines and DPYD
Most recent guideline publication:
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update (October 2017)
Updates since publication:
February 2020 Update:
The DPYD allele functionality table and DPYD genotype-phenotype table have been updated (see the “change log” in each table for changes).
January 2020 Update:
The DPYD allele functionality table, DPYD frequency table, and DPYD genotype-phenotype table have been updated (see the “change log” in each table for changes).
November 2018 Update:
The current DPYD guideline recommends 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 (PMID: 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 revises 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.
Tables provided in the main manuscript of the guideline:
| Table 1. Assignment of likely DPD phenotype based on DPYD genotype |
| Table 2. Recommended dosing of fluoropyrimidines by DPD phenotype |
Supplement to: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update (October 2017)
Tables included in the supplement or referenced in the guidelinea:
| Supplemental Table S1. Evidence linking DPYD genotype with DPD phenotype and dihydropyrimidine toxicity |
| DPYD allele definition table |
| DPYD allele functionality table |
| DPYD frequency table |
| DPYD genotype-phenotype table |
| Gene resource mapping |
| Drug resource mapping |
| Clinical decision supportb: |
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.
Original guideline publication (December 2013):
- Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing (December 2013)
- 2013 supplement
- May 2014: 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. (Please note this update was incorporated into the 2017 update).