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

• Published in: European journal of human genetics : EJHG Vol. 28; no. 4; pp. 508 - 517
• Main Authors: Lunenburg, Carin A. T. C., van der Wouden, Cathelijne H., Nijenhuis, Marga, Crommentuijn-van Rhenen, Mandy H., de Boer-Veger, Nienke J., Buunk, Anne Marie, Houwink, Elisa J. F., Mulder, Hans, Rongen, Gerard A., van Schaik, Ron H. N., van der Weide, Jan, Wilffert, Bob, Deneer, Vera H. M., Swen, Jesse J., Guchelaar, Henk-Jan
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.04.2020; Springer International Publishing
• Subjects: 5-Fluorouracil; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - adverse effects; Capecitabine - administration & dosage; Capecitabine - adverse effects; Diarrhea; Dihydrouracil Dehydrogenase (NADP) - genetics; Dihydrouracil Dehydrogenase (NADP) - standards; Drug interaction; Drug therapy; Drug Therapy - methods; Drug Therapy - standards; Drug-Related Side Effects and Adverse Reactions - genetics; Drug-Related Side Effects and Adverse Reactions - prevention & control; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Genetic Testing - methods; Genetic Testing - standards; Genotypes; Genotyping; Humans; Mucositis; Myelosuppression; Pharmacogenomic Variants; Practice Guidelines as Topic; Tegafur; Toxicity; Working groups
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/s41431-019-0540-0

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.