Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA.
Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
Clin Pharmacol Ther. 2023 Oct;114(4):768-779. doi: 10.1002/cpt.2978. Epub 2023 Jul 11.
Fluoropyrimidine (FP) chemotherapy is associated with severe, life-threatening toxicities, particularly among patients who carry deleterious germline variants in the DPYD gene. Pretreatment DPYD testing is standard of care throughout most of Europe; however, it has not been recommended in clinical practice guidelines in the United States. Due to increased risk of severe toxicity, a Citizen's Petition asked the US Food and Drug Administration (FDA) to update language in FP drug labels to recommend DPYD testing as part of a boxed warning and recommend FP dose reduction in patients carrying deleterious germline variants. In response, the FDA updated the capecitabine package insert to inform patients about the toxicity risk and test availability and consider DPYD testing. However, the FDA did not include a testing recommendation or requirement, or a boxed warning. Additionally, the FDA did not recommend FP dose adjustment in DPYD variant carriers. This review provides a critical assessment of the DPYD-FP pharmacogenetic association using the FDA's previously published Pharmacogenetic Pyramid, demonstrating that the evidence is compelling for recommending DPYD testing prior to FP treatment. Additionally, the FDA's stated concerns about recommending DPYD testing and DPYD-guided FP dose adjustment are addressed and discussed in the context of the FDA's other genetic testing and dose adjustment recommendations. We call on the FDA to follow our European counterparts in recommending DPYD testing and genotype-based dose adjustment to ensure patients with cancer receive safe and effective FP chemotherapy.
氟嘧啶 (FP) 化疗与严重的、危及生命的毒性有关，特别是在携带 DPYD 基因有害种系变异的患者中。在欧洲大部分地区，治疗前 DPYD 检测是标准的护理方法；然而，在美国的临床实践指南中并没有推荐。由于严重毒性的风险增加，公民请愿书要求美国食品和药物管理局 (FDA) 更新 FP 药物标签中的语言，建议将 DPYD 检测作为盒装警告的一部分，并建议携带有害种系变异的患者减少 FP 剂量。作为回应，FDA 更新了卡培他滨的说明书，告知患者毒性风险和检测可用性，并考虑进行 DPYD 检测。然而，FDA 既没有包括检测建议或要求，也没有盒装警告。此外，FDA 也没有建议在 DPYD 变异携带者中调整 FP 剂量。本综述使用 FDA 之前发布的药物遗传学金字塔对 DPYD-FP 药物遗传学相关性进行了批判性评估，证明在 FP 治疗前进行 DPYD 检测的证据确凿。此外，还针对 FDA 关于推荐 DPYD 检测和基于 DPYD 指导的 FP 剂量调整的担忧进行了讨论，并结合 FDA 对其他基因检测和剂量调整的建议进行了讨论。我们呼吁 FDA 效仿欧洲同行，建议进行 DPYD 检测和基于基因型的剂量调整，以确保癌症患者接受安全有效的 FP 化疗。
