Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands.
Department of Clinical Pharmacy & Toxicology, Leiden University Medical Centre, Leiden, The Netherlands.
Eur J Hum Genet. 2020 Apr;28(4):508-517. doi: 10.1038/s41431-019-0540-0. Epub 2019 Nov 19.
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.
尽管药物基因组学（PGx）领域取得了进展，但临床接受程度仍然有限。荷兰药物基因组学工作组（DPWG）旨在通过制定基于证据的药物基因组学指南来优化药物治疗，以促进 PGx 的实施。本指南描述了三种抗癌药物（氟嘧啶类：5-氟尿嘧啶、卡培他滨和替加氟）起始剂量的优化，以降低严重的、潜在致命的毒性（如腹泻、手足综合征、粘膜炎或骨髓抑制）风险。二氢嘧啶脱氢酶（DPD，由 DPYD 基因编码）酶缺乏会增加氟嘧啶类药物引起毒性的风险。DPYD 基因活性评分由四个 DPYD 变体决定，可预测 DPD 活性，可用于优化个体的起始剂量。基因活性评分范围从 0（无 DPD 活性）到 2（正常 DPD 活性）。如果无法根据 DPYD 基因型计算基因活性评分，则建议测定 DPD 活性，并根据现有数据调整初始剂量。对于开始使用 5-氟尿嘧啶或卡培他滨的患者：建议基因活性评分为 0 的患者避免全身和皮肤用 5-氟尿嘧啶或卡培他滨；基因活性评分为 1 或 1.5 的患者建议用 5-氟尿嘧啶或卡培他滨标准剂量的 50%起始治疗。对于开始使用替加氟的患者：基因活性评分为 0、1 或 1.5 的患者建议避免使用替加氟。基因活性评分为 2（参考）的患者应接受标准剂量。根据 DPWG 临床意义评分，DPYD 基因分型被认为是“必需的”，因此在开始使用氟嘧啶类药物之前应进行 DPYD 检测。
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