Takahashi Takayuki, Terazono Hideyuki, Suetsugu Takayuki, Sugawara Hideki, Arima Junko, Nitta Mina, Tanabe Toru, Okutsu Kayu, Ikeda Ryuji, Mizuno Keiko, Inoue Hiromasa, Takeda Yasuo
Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
Cancers (Basel). 2021 Jul 8;13(14):3425. doi: 10.3390/cancers13143425.
Afatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). Early prediction of adverse effects based on the pharmacokinetics of afatinib enables support for quality of life (QOL) in patients with no change in efficacy. We examined the pharmacokinetic relationship between trough plasma concentration and adverse effects and evaluated the utility of measuring the trough plasma concentration of afatinib as the first EGFR-TKI treatment for NSCLC in a prospective multicenter study. Twenty-four patients treated with afatinib were enrolled in this study. All blood samples were collected at the trough point, and plasma concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry. Logistic regression analysis for the dose reduction of afatinib was performed, and the receiver operating characteristic (ROC) curve was plotted. Although all patients started afatinib at 40 mg/day, plasma concentrations were variable, and mean and median trough plasma concentrations were 32.9 ng/mL and 32.5 ng/mL in this study, respectively. Minimum and maximum trough plasma concentrations were 10.4 ng/mL and 72.7 ng/mL, respectively. This variability was speculated to involve personal parameters such as laboratory data. However, no patient characteristics or laboratory data examined correlated with the trough plasma concentration of afatinib, except albumin. Albumin showed a weak correlation with plasma concentration (r = 0.60, = 0.009). The trough plasma concentration of afatinib was significantly associated with the dose reduction of afatinib ( = 0.047). The area under the ROC curve (AUC) for the trough plasma concentration of afatinib was 0.81. The cut-off value was 21.4 ng/mL. The sensitivity and specificity of the cut-off as a risk factor were 0.80 and 0.75. In summary, the trough plasma concentration of afatinib was associated with continued or reduced dosage because of the onset of several adverse effects, and a threshold was seen. Adverse effects not only lower QOL but also hinder continued treatment. Measuring plasma concentrations of afatinib appears valuable to predict adverse effects and continue effective therapy.
阿法替尼作为第二代表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKI），用于治疗携带EGFR突变的非小细胞肺癌（NSCLC）。基于阿法替尼的药代动力学对不良反应进行早期预测，可在不改变疗效的情况下支持患者的生活质量（QOL）。我们在一项前瞻性多中心研究中，研究了谷浓度与不良反应之间的药代动力学关系，并评估了测量阿法替尼谷浓度作为NSCLC的首个EGFR-TKI治疗的实用性。本研究纳入了24例接受阿法替尼治疗的患者。所有血样均在谷值点采集，并使用高效液相色谱-串联质谱法测量血浆浓度。对阿法替尼剂量减少进行了逻辑回归分析，并绘制了受试者工作特征（ROC）曲线。尽管所有患者均以40mg/天开始服用阿法替尼，但血浆浓度存在差异，本研究中平均和中位谷浓度分别为32.9ng/mL和32.5ng/mL。最低和最高谷浓度分别为10.4ng/mL和72.7ng/mL。这种差异推测涉及个人参数，如实验室数据。然而，除白蛋白外，所检查的患者特征或实验室数据与阿法替尼的谷浓度均无相关性。白蛋白与血浆浓度呈弱相关（r = 0.60，P = 0.009）。阿法替尼的谷浓度与阿法替尼的剂量减少显著相关（P = 0.047）。阿法替尼谷浓度的ROC曲线下面积（AUC）为0.81。截断值为21.4ng/mL。作为危险因素的截断值的敏感性和特异性分别为0.80和0.75。总之，阿法替尼的谷浓度与因多种不良反应的发生而持续或减少剂量相关，且存在一个阈值。不良反应不仅会降低生活质量，还会阻碍持续治疗。测量阿法替尼的血浆浓度对于预测不良反应和继续有效治疗似乎具有重要价值。
