Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines

Abstract

Despite advances in the field of pharmacogenetics (PGx), clinical acceptance has remained limited. The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity (such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression). Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) enzyme deficiency increases risk of fluoropyrimidine-induced toxicity. The DPYD-gene activity score, determined by four DPYD variants, predicts DPD activity and can be used to optimize an individual's starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). In case it is not possible to calculate the gene activity score based on DPYD genotype, we recommend to determine the DPD activity and adjust the initial dose based on available data. For patients initiating 5-fluorouracil or capecitabine: subjects with a gene activity score of 0 are recommended to avoid systemic and cutaneous 5-fluorouracil or capecitabine; subjects with a gene activity score of 1 or 1.5 are recommended to initiate therapy with 50% the standard dose of 5-fluorouracil or capecitabine. For subjects initiating tegafur: subjects with a gene activity score of 0, 1 or 1.5 are recommended to avoid tegafur. Subjects with a gene activity score of 2 (reference) should receive a standard dose. Based on the DPWG clinical implication score, DPYD genotyping is considered "essential", therefore directing DPYD testing prior to initiating fluoropyrimidines.

Fig. 1

Schematic overview of fluoropyrimidine metabolism. In brief: tegafur, 5FU, capecitabine are metabolised into three major metabolites. FdUMP, which inhibits TS and prevents conversion of dUMP to dTMP, which is necessary for pyrimidine and DNA synthesis. FdUTP is incorporated in DNA, FdUTP is incorporated in RNA, both resulting in cell death. CES carboxylesterase, CDA cytidine deaminase, 5′dFCR 5′-deoxy-5-fluorocytidine, 5′dFUR 5′-deoxy-5-fluorouridine, 5-FU 5-fluorouracil, TP thymidine phosphorylase, DPYD gene encoding DPD, DPD dihydropyrimidine dehydrogenase, DHFU 5,6-dihydrofluorouracil, FUPA fluoro-ß-ureidopropionate, F-ß-AL Fluoro-ß-alanine, FUMP fluorouridine monophosphate, FUDP fluorouridine diphosphate, FUTP fluorouridine triphosphate, FUDR fluorodeoxyuridine, FdUMP fluorodeoxyuridine monophosphate, FdUDP fluorodeoxyuridine diphosphate, FdUTP fluorodeoxyuridine triphosphate, dUMP deoxyuridine monophosphate, dTMP deoxythymidine monophosphate, TS thymidylate synthase, TYMS gene encoding TS