Rational application of gefitinib in NSCLC patients with sensitive EGFR mutations based on pharmacokinetics and metabolomics.
Rational application of gefitinib in NSCLC patients with sensitive EGFR mutations based on pharmacokinetics and metabolomics.
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基于药代动力学和代谢组学的吉非替尼在EGFR敏感突变NSCLC患者中的合理应用
DOI：
10.1038/s41401-021-00791-5
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发表时间：
2021
影响因子：
8.2
通讯作者：
Zhang Li
中科院分区：
文献类型：
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作者：
Feng Wei;Chen Xi;Guan Shao-Xing;Ruan Hong-Lian;Huang Yan;Zhang Hui-Zhen;Yang Yun-Peng;Fang Wen-Feng;Zhao Hong-Yun;Zhuang Wei;Xin Shuang;Chen You-Hao;Wang Fei;Gao Yue;Huang Min;Wang Xue-Ding;Zhang Li
吉非替尼上市已有20年的历史，但其药代动力学机制鲜为人知。在这项研究中，我们研究了具有敏感EGFR突变的非小细胞肺癌(NSCLC)患者的药代动力学和代谢学特征。共有2 16例晚期非小细胞肺癌患者入选，吉非替尼的标准剂量为2 5 0 mg/d，这是在具有非敏感突变的异质性受试者中建立的。对患者血浆中的3种主要代谢物(M1、M2和M3)进行了鉴定和定量，分析了吉非替尼/代谢物浓度与疗效的关系。在探索性和验证性试验中，吉非替尼浓度与临床疗效无关。考虑到在多中心临床试验中，250 mg/2天的疗效优于250 mg/天的疗效，根据假设的剂量-反应曲线，标准剂量可能高于最大疗效剂量。在三种代谢产物中，M2在HCC827和PC9细胞中的IC50明显低于Gefitinib，而在小鼠体内的Conc.Brain/Conc.血浆中M2的IC50值明显高于Gefitinib，提示其具有更高的血脑屏障穿透能力，在治疗脑转移瘤方面可能比Gefitinib更有效。在脑转移瘤患者中，持续且具有吸引力的是，较高的M2血浆浓度与较好的临床预后无关(Cm2<、 12 ng/m l和Cm 2≥ 12 ng/m l的中位无病生存率分别为17.0和27.1月，P= 0.038)。血浆M2 ≥ 浓度为12 ng/mL是预测非小细胞肺癌患者预后的重要指标。总之，对于有EGFR敏感突变的非小细胞肺癌患者，标准剂量是值得怀疑的，可以合理减少。M2在疗效上有重要作用，在治疗转移性肿瘤方面可能比吉非替尼更有效。
Gefitinib has been available in the market for 20 years, but its pharmacokinetic mechanism of response is little known. In this study, we examined the pharmacokinetic and metabolomic profiles in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. A total of 216 advanced NSCLC patients were enrolled, and administered gefitinib at the standard dosage of 250 mg/day, which was established in heterogeneous subjects with non-sensitive mutations. We identified and quantified three main metabolites (named as M1, M2 and M3) in the plasma of patients, the correlations between the concentration of gefitinib/metabolites and efficacy were analyzed. In exploratory and validation set, gefitinib concentration was not correlated with clinical effects. Considering the result that the therapeutic effects of 250 mg/2-day was better than that of 250 mg/day in a multiple center clinical trial, the standard dose might be higher than that for maximal efficacy according to the hypothetical dose-response curve. Among the three metabolites, the IC50of M2 in HCC827 and PC9 cell lines was significantly lower, and Conc.brain/Conc.plasmaof M2 in mice was significantly higher than those of gefitinib, suggesting its higher potential to penetrate blood–brain barrier and might be more effective in the treatment of brain metastatic tumor than gefitinib. Consistently and attractively, higher M2 plasma concentration was found to be correlated with better clinical outcome in patients with brain metastases (the median PFS of CM2< 12 ng/mL and CM2≥ 12 ng/mL were 17.0 and 27.1 months, respectively,P= 0.038). The plasma concentration of M2 ≥ 12 ng/mL was a strong predictor of the PFS of NSCLC patients. In conclusion, for NSCLC patients with EGFR sensitive mutations, the standard dose is suspectable and could be decreased reasonably. M2 plays an important role in efficacy and may be more effective in the treatment of metastatic tumor than gefitinib.