Overview of Fluoropyrimidines & DPYD

Fluoropyrimidines, including 5-fluorouracil (5-FU) and capecitabine, are agents used in the treatment of solid tumors, such as gastrointestinal, breast, and head and neck cancers.  DPD, an enzyme in the liver, metabolizes most of 5-FU to inactive metabolites. 

DPYD is a gene that encodes the DPD liver enzyme.  Variation in the DPYD gene results in three DPD metabolizer phenotypes: normal, intermediate, and poor metabolizers. 

The DPD intermediate metabolizer phenotype is observed in approximately 2-8% of the population. The DPD poor metabolizer phenotype is rare, observed in less than 0.2% of the population.  Intermediate and poor metabolizer phenotypes are associated with decreased DPD activity and an increased risk of severe or even fatal drug toxicity with systemic fluoropyrimidine drugs.

Most research has focused on systemic fluoropyrimidines and DPYD genotypes. However, 5-FU is also used as a topical formulation, primarily for the treatment of actinic or solar keratoses and superficial basal cell carcinoma. A case report suggests that patients with the poor metabolizer phenotype may have an increased risk of severe toxicity when prescribed topical fluorouracil (5-FU).

The Clinical Pharmacogenetics Implementation Consortium (CPIC) is a group that evaluates the evidence for the use of pharmacogenetics and then develops clinical practice guidelines. For 5-fluorouracil and capecitabine, extensive guideline information can be found at: https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/, a reference maintained by CPIC.  

Here is a video that reviews the CPIC guideline for fluoropyrimidines: https://www.youtube.com/watch?v=2wB2l4W9x8s&feature=emb_imp_woyt

At UCHealth the use of pharmacogenetics when prescribing fluoropyrimidines will occur in patients who meet the following conditions:

1) Provided a blood or saliva sample to the CCPM biobank, consented for the return of their results, and this sample has undergone genotyping OR the patient is being seen in a clinic which is currently using pharmacogenetic testing as part of standard care (e.g., the UCHealth GI Oncology Clinic). 
2) Are prescribed 5-FU or capecitabine.

For patients enrolled in the biobank, this process takes a minimum of 4-6 weeks but may take several years. Therefore, results will not be available at initial presentation if a patient has not previously enrolled in the biobank.

If you are a provider AND your patient is a DPYD intermediate or poor metabolizer, a best practice advisory (BPA) will alert you in the UCHealth EHR if you attempt to prescribe a systemic fluoropyrimidine. In addition, if you are a provider AND your patient is a DPYD poor metabolizer, a BPA will appear in the EHR if you attempt to prescribe topical 5-FU.  If a BPA alerts, clinical guidance and associated resources will be listed for your reference.  There is patient education text available for UCHealth providers to use in discharge paperwork or the after visit summary (AVS).