Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu, Gifu 501-1196 Japan; Laboratory of Community Healthcare Pharmacy, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu, Gifu 501-1196 Japan; Laboratory of Home Team Care Pharmacy, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu, Gifu 501-1196 Japan; Department of Pharmacy, Gifu University Hospital, 1-1 Yanagito, Gifu, Gifu 501-1112 Japan.
Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu, Gifu 501-1196 Japan; Department of Pharmacy, Gifu University Hospital, 1-1 Yanagito, Gifu, Gifu 501-1112 Japan.
Lung Cancer. 2019 Aug;134:1-6. doi: 10.1016/j.lungcan.2019.05.013. Epub 2019 May 18.
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) represent the first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer. Afatinib is a second-generation EGFR-TKI with excellent therapeutic effects. However, severe diarrhea and skin disorders are observed at high frequencies, often leading to treatment interruption because of low quality of life (QOL). The relationship between individual variations and the onset of these side effects remains to be elucidated. This study aimed to reveal the association among these side effects, pharmacokinetics, and related genetic polymorphisms.
In total, 33 patients were recruited between July 2014 and June 2017. Afatinib plasma concentrations were measured at day 9 when the concentrations reached a steady state (early phase) and when the prescription dose was stable for more than 1 month (stable phase). We analyzed single nucleotide polymorphisms in the genes ATP-binding cassette sub-family B member 1 (ABCB1), ABCG2, and flavin-containing monooxygenase 3.
The incidences of both diarrhea and acneiform eruption were greater than 80%. Afatinib plasma concentration and the severity of diarrhea in the early phase were correlated. Pharmacokinetics-related genetic polymorphisms influenced the severity of diarrhea. Particularly, the afatinib plasma concentration was higher and diarrhea was more severe in patients carrying the A allele of ABCG2 C421A. Onset of side effects, genetic polymorphisms, and diarrhea in the maintenance phase or acneiform eruption in the early or maintenance phases were not correlated. The severity of diarrhea is influenced by drug plasma concentrations in the early phase and genetic polymorphisms related to afatinib pharmacokinetics.
Particular genetic polymorphisms can be screened before afatinib administration and the dose adapted to individual patients can be controlled, leading to reduced side effects, improved QOL, and better patient compliance to maintain the therapeutic effects.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）是治疗 EGFR 突变阳性晚期非小细胞肺癌患者的一线药物。阿法替尼是一种具有良好疗效的第二代 EGFR-TKI。然而，严重腹泻和皮肤疾病的发生率较高，常因生活质量（QOL）低而导致治疗中断。个体差异与这些副作用的发生之间的关系仍有待阐明。本研究旨在揭示这些副作用、药代动力学和相关遗传多态性之间的关系。
本研究共招募了 33 名患者，时间为 2014 年 7 月至 2017 年 6 月。在第 9 天（早期）和处方剂量稳定超过 1 个月时（稳定期）测量阿法替尼的血浆浓度。我们分析了 ATP 结合盒亚家族 B 成员 1（ABCB1）、ABCG2 和黄素单加氧酶 3 基因的单核苷酸多态性。
腹泻和痤疮样皮疹的发生率均大于 80%。早期阿法替尼的血浆浓度与腹泻的严重程度相关。与药代动力学相关的遗传多态性影响腹泻的严重程度。特别是，ABCG2 C421A 的 A 等位基因携带者的阿法替尼血浆浓度更高，腹泻更严重。副作用的发作、遗传多态性、维持期腹泻或早期或维持期痤疮样皮疹之间无相关性。腹泻的严重程度受早期药物血浆浓度和与阿法替尼药代动力学相关的遗传多态性的影响。
在开始使用阿法替尼之前，可以筛选特定的遗传多态性，并根据患者的个体情况调整剂量，从而减少副作用，提高 QOL，并提高患者对治疗效果的依从性。
