Page 60 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
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 enzyme (DPD) deficiency (encoded by the DPYD gene) 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). Subjects with a gene activity score of 0 are recommended not to initiate fluoropyrimidines. Alternatively, DPD activity may be determined to adjust the dose accordingly. Subjects with a gene activity score of 0.5, 1 or 1.5 are recommended to initiate therapy with 25%, 50% or 75% of the normal dose of 5-fluorouracil or capecitabine, respectively. When initiating tegafur, an alternative chemotherapeutic agent, or a low dose is recommended. Dose may be increased in subsequent cycles in patients experiencing no or clinically tolerable toxicity. Subjects with a gene activity score of 2 (reference) should receive a normal dose. In case it is not possible to calculate the gene activity score based on DPYD genotype, we recommend to determine the DPD activity. Based on the DPWG clinical implication score, DPYD genotyping is considered “essential”, therefore directing DPYD testing prior to initiating treatment with fluoropyrimidines.
Disclaimer
The Pharmacogenetics Working Group of the KNMP (DPWG) formulates the optimal recommendations for each phenotype group based on the available evidence. If this optimal recommendation cannot be followed due to practical restrictions, e.g. therapeutic drug monitoring or a lower dose is not available, then the health care professional should consider the next best option.
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