Dihydropyrimidine Dehydrogenase Deficiency and Implementation of UpfrontDPYDGenotyping

Abstract

Fluoropyrimidines (FP; 5-fluorouracil, capecitabine, and tegafur) are a commonly prescribed class of antimetabolite chemotherapies, used for various solid organ malignancies in over 2 million patients globally per annum. Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the critical enzyme implicated in FP metabolism. DPYD variant genotypes can result in decreased DPD production, leading to the development of severe toxicities resulting in hospitalization, intensive care admission, and even death. Management of toxicity incurs financial burden on both patients and healthcare systems alike. Upfront DPYD genotyping to identify variant carriers allows an opportunity to identify patients who are at high risk to suffer from serious toxicities and allow prospective dose adjustment of FP treatment. This approach has been shown to reduce patient morbidity, as well as improve the cost-effectiveness of managing FP treatment. Upfront DPYD genotyping has been recently endorsed by several countries in Europe and the United Kingdom. This review summarizes current knowledge about DPD deficiency and upfront DPYD genotyping, including clinical and cost-effectiveness outcomes, with the intent of supporting implementation of an upfront DPYD genotyping service with individualized dose-personalization.

Pharmacogenomics in the era of personalised medicine

“…1,8 An example of successful international implementation is the introduction of upfront DPYD genotyping in patients intended to receive fluoropyrimidine chemotherapy (5-fluorouracil and capecitabine). 9 Globally, more than 2 million cancer patients receive fluoropyrimidine per annum, including approximately 10 000 patients in Australia. 10 Serious grade 3 and 4 toxicities 11 resulting in hospitalisation and occasional intensive care admission occur in approximately 30% of treated cases.…”

From Genes to Endogenous Substrates: Towards a Better Understanding of Drug Metabolizing Enzymes

“…The first paper of interest is a comprehensive review in which White et al 1 . describe the role of dihydropyrimidine dehydrogenase (DPD) deficiency and recommend implementation of DPYD genotyping as a way to identify patients at a high risk for severe adverse events and to personalize the use of fluoropyrimidines.…”

Implementation of dihydropyrimidine dehydrogenase deficiency testing in Europe

“…Despite the strong evidence supporting the value of testing for DPD deficiency and inclusion of the EMA recommendations in the drug labels, 1 , 2 DPD testing is not yet used worldwide. 21 , 22 Recently, a survey conducted among 325 US medical oncologists reported that only 17 out of 59 respondents strongly agreed with the usefulness of DPD testing. 22 Koo et al .…”