Safety, Tolerability, and Pharmacokinetics of Multiple Ascending Doses of Simotinib Hydrochloride in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

The primary objective is to assess the safety and tolerability of multiple doses of Simotinib Hydrochloride in NSCLC patients. The secondary objective is to determine the pharmacokinetic (PK) profile and explore the preliminary anti-tumor activity.

开始日期2012-12-01

申办/合作机构

江苏先声药业有限公司

NCT01469910 / Completed临床1期

Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of Simotinib Hydrochloride in Healthy Subjects

The purpose of this study is to assess the safety and pharmacokinetics of single ascending doses of Simotinib Hydrochloride in healthy subjects.

开始日期2011-09-01

申办/合作机构

江苏先声药业有限公司

100 项与盐酸西莫替尼相关的临床结果

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100 项与盐酸西莫替尼相关的转化医学

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100 项与盐酸西莫替尼相关的专利（医药）

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项与盐酸西莫替尼相关的文献（医药）

2016-04-01·Anti-Cancer Drugs4区 · 医学

Simotinib as a modulator of P-glycoprotein

4区 · 医学

Article

作者: Chen, Yanfen ; Zhu, Qubo ; Huang, Lingling ; Shen, Cheng ; Cheng, Zeneng ; Yan, Huiwen

As a new antitumor drug, simotinib hydrochloride is prescribed for prolonged periods, often to patients with comorbidities. Therefore, the risk for developing drug resistance and drug-drug interactions between simotinib and other agents has to be taken into consideration. As P-glycoprotein (P-gp) is an efflux transporter, which plays a significant role in drug resistance and influences the pharmacological properties and toxicities of the drugs it interacts with, the interactions between simotinib and P-gp were investigated. Cytotoxicity was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Intracellular drug concentrations were detected by high-performance liquid chromatography, fluorescence-activated cell sorting and using a fluorescence reader. P-gp ATPase activity was measured using the Pgp-Glo assay, and intracellular pH was assessed using the fluorescent probe 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl. The expression and transcription of P-gp were detected by western blotting and the luciferase assay. Simotinib has no cross-resistance to P-gp substrates, and its efflux rate was independent of either the P-gp expression or the coadministered P-gp substrate. Simotinib reversed chemotherapeutic agent resistance in a short time by increasing the intracellular concentration of the chemotherapeutic agent and blocked rhodamine 123 efflux. Further studies demonstrated that simotinib inhibited P-gp activity by modulating its ATPase activity and the intracellular pH. Although simotinib induced P-gp expression after extended treatment, the induced expression of P-gp had little impact on drug resistance. Simotinib is not a substrate of P-gp. As a modulator, it functions mainly as an inhibitor of P-gp by modulating the intracellular pH and ATPase activity, although it also induces P-gp expression after extended treatment.

2014-02-01·Journal of Chromatography B3区 · 医学

LC-ESI-MS/MS determination of simotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor: Application to a pharmacokinetic study

3区 · 医学

Article

作者: Cheng, Zeneng ; Liu, Xingling ; Yu, Peng ; Li, Sanwang ; He, Lihua ; Xie, Feifan ; Ran, Liling

Simotinib is a novel epidermal growth factor receptor tyrosine kinase inhibitor. This study presented a sensitive and specific liquid chromatography-electrospray ionization-mass spectrometry method using erlotinib as internal standard for the determination of simotinib in human plasma. The method involved a simple liquid-liquid extraction using diethyl ether. The analytes were separated with isocratic gradient elution on an Agilent TC-C18 column (4.6 × 150 mm, 5 μm). Mass spectrometric detector equipped with electrospray ionization source was carried out in the mode of multiple reaction monitoring (MRM). The monitored transitions were m/z 501.2→182.1 for simotinib and m/z 394.4→278.1 for erlotinib. The calibration curve of simotinib was established over the range of 2.058-3000 μg L(-1) (r(2)=0.9924). The intra- and inter-day precisions were all less than 10%, and all the biases were not more than 7%. This validated method was then successfully applied to a pharmacokinetic study involving twelve healthy Chinese volunteers. The mean Cmax and Tmax for simotinib were 254.79±98.30 μg L(-1) and 1.71±0.48 h, respectively. Plasma concentrations declined with a t1/2 of 5.37±2.32 h. AUC0-t and AUC0→∞ values obtained were 1262.59±501.41 μg L(-1) h and 1329.95±517.42 μg L(-1) h, respectively.

2014-02-01·Analytical and Bioanalytical Chemistry2区 · 化学

Development and validation of a UPLC–MS/MS assay for the quantification of simotinib in human plasma

2区 · 化学

Article

作者: Ping Du ; Yuankai Shi ; Xiaohong Han ; Sheng Yang ; Yuanyuan Song ; Xingsheng Hu ; Ning Li

Simotinib is a novel oral small-molecule tyrosine kinase inhibitor that has demonstrated equal or superior antineoplastic activities to erlotinib in preclinical studies. In support of a clinical pharmacokinetic study, a sensitive and accurate liquid chromatography (LC) method with mass spectrometry detection using multiple reaction monitoring (MRM) in positive ion mode was developed and validated for the quantification of simotinib in human plasma. The sample preparation procedure involved a simple protein precipitation with methanol. Erlotinib was used as the internal standard. The optimal chromatographic behavior was achieved on a Zorbax SB-C8 column (2.1 mm × 100 mm, 3.5 μm) using a mixture of 0.1% formic acid with 10 mM ammonium formate/methanol (20:80, v/v) as the mobile phase. The total LC analysis time per injection was 4 min with a flow rate of 0.2 mL/min. The recovery was greater than 90% and no significant matrix effect was observed. The assay was validated over the concentration range of 1-1,000 ng/mL. The intra- and interday precision and accuracy of the quality control samples at low, medium, and high concentration levels showed at most 9.4% relative standard deviation (RSD) and -7.4 to 7.4% relative errors (RE). Assay selectivity, freeze/thaw stability, storage stability, and dilution effects were also assessed. The method is now used to support clinical pharmacokinetic studies in patients with non-small cell lung cancer (NSCLC) after oral administration of simotinib.

项与盐酸西莫替尼相关的新闻（医药）

2023-02-22

·生物谷

类器官立大功！我国科学家发表全球最大样本量研究，证实肺癌类器官药敏测试预测临床疗效总体准确率高达83.3%！

肺癌有着极高的死亡率，晚期肺癌患者的预后常常较差。目前已经开发出基于基因检测技术的分子靶向治疗，可以明显延长晚期肺癌患者的总生存期并提高生活质量。为了提出个性化治疗方案，临床医生需要依据检测到的肿瘤驱动因子突变，来选择特定的分子靶向药物用于癌症治疗。然而肺癌治疗仍存在诸多难题，因此，亟需建立一个模拟原始肿瘤形态学和基因组特征的体外药敏试验模型来预测肺癌靶向和化疗的疗效。近日，广东省肺癌研究所的研究人员及其合作者在《细胞》子刊《细胞报告医学》（Cell Reports Medicine）上，发表了题目为“Using patient-derived organoids to predict locally advanced or metastatic lung cancer tumor response: A real-world study”的研究论文，研究结果显示，基于肺癌类器官的药物敏感性测试结果可准确预测肺癌靶向或化疗的临床疗效。这也是目前国际上肺癌类器官领域预测靶向和化疗疗效的最大样本量真实世界研究。在这项研究中，研究人员从107名晚期癌症患者中生成了214个癌症类器官，总成功率为75.7%（162/214），其中212个是肺癌类器官（LCO），主要来源于恶性浆液性渗出液（MSE），研究流程如下图所示。另外，研究人员还在真实世界研究中进行了针对化疗和靶向治疗的肺癌类器官药物敏感性测试（LCO-DST），用于预测相应治疗的临床反应。图注：研究流程图和本研究中肺癌类器官培养的成功率。（来源：Wang, H., et al. 2023）为了验证恶性浆液性渗出液和恶性浆液性渗出液来源的肺癌类器官之间基因组图谱的一致性，研究人员对25名患者进行了二代测序，并对积液和肺癌类器官样本进行了体细胞突变分析，如下图所示。这些数据显示肺癌类器官样本的变异敏感性为70.5%（93/132），阳性预测值为69.4%（93/134）（图C）。而且，基于肺癌类器官的肿瘤突变负荷（TMB）与基于积液的肿瘤突变负荷呈正相关（Pearson r=0.68，p=0.02，图E），说明积液和肺癌类器官样本之间的基因组图谱具有一致性，即类器官可以反应其同源组织的遗传背景。图注：肺癌类器官样本的基因组分析。（来源：Wang, H., et al. 2023）研究人员将36名患者临床方案与LCO-DST结果相同的肺癌类器官分为四类：奥西莫替尼、化疗、双靶向治疗和其他靶向治疗组。使用接受者操作特征（ROC）分析来确定LCO-DST区分临床敏感或耐药患者的能力。LCO-DST的总体灵敏度为84.0%（95%可信区间，63.08%-94.75%），特异性为82.8%（95%可信区间，63.51%-93.47%），准确性为83.3%（图A、B）。这些结果表明，肺癌类器官可以预测未治疗和治疗患者对靶向治疗的临床反应。图注：肺癌类器官样本的基因组分析。（来源：Wang, H., et al. 2023）为了验证肿瘤类器官药物反应的实验稳定性和异质性，研究人员在同一患者上验证了在不同采样时间获得的肿瘤类器官基因组图谱高度一致（图A），验证了组织样本、积液样本和肿瘤类器官的基因组图谱的一致性（图B）图注：肺癌类器官样本的稳定性和异质性。（来源：Wang, H., et al. 2023）本研究中纳入了两例晚期肺腺癌双靶向基因变异患者：编号60的患者被诊断为IVB期肺腺癌（图A），基线时脑脊液中检测到EGFR L858R突变和MET拷贝数增加（5.0）。编号61的患者被诊断为IVA期肺腺癌（图F），基线时检测到EGFR 19del。相比于单一靶向药物，两例患者的LCO-DST结果均显示联合靶向治疗（奥希替尼+赛沃替尼/卡博替尼）的肿瘤控制率更高，且临床中证实双靶联合治疗均达到了部分缓解（PR）。这些病例表明，LCO-DST可以很好地预测有效的联合治疗方案。图注：肺癌类器官预测耐药病例的双靶向治疗。（来源：Wang, H., et al. 2023）为了研究EGFR和RET抑制剂联合治疗的潜在分子机制，研究人员进行了4D无标记高通量蛋白质组学分析。主成分分析（PCA）的结果表明，不同治疗组的表达水平不同，即治疗效果不同。三个处理组均表现出相同的蛋白表达趋势，且核蛋白变化的数量最多，其次是细胞质和细胞膜蛋白。表明所有这三种治疗的蛋白质表达改变主要在于调节细胞核的功能，包括基因表达。综合这些分析，可见药物敏感性与临床反应的总体一致性可达83.33%，LCO-DST在预测晚期癌症治疗反应中有极高的准确性，其在精确医学中具有巨大的潜力，后续可进行大规模临床试验，确定不同类型疗法的精确截止值。个性化抗癌药物离不开人们对于基因突变的了解，而药物的疗效离不开准确的药物敏感性测试。癌症治疗是极其复杂的，不过科学家们也在不断开发新技术来实现越来越好的治疗策略。参考来源：Wang, Han-Min, et al. "Using patient-derived organoids to predict locally advanced or metastatic lung cancer tumor response: A real-world study." Cell Reports Medicine (2023): 100911.撰文 | 拉缇莎编辑 | cici会议推荐RECOMMENDATIONS点击了解详情点击了解详情精彩推荐：1、大学生捐精合格率不足20%？真相来了！大型荟萃研究证实，近50年全球男性精子数量下降超60%，且下降速度不断加快！2、200万中国人群新发现：保持健康生活方式有助延长寿命，全因死亡率下降52%3、类器官重大进展！Cell子刊：复旦大学夏明宇团队成功建立首个具有功能性突触的耳蜗类器官，再现听觉单元早期发育！4、别把电子烟不当烟！首次发现：使用电子烟时间越长，口腔细胞发生DNA损伤越多，甜味烟损害更高！5、癌细胞真的能被饿死吗？《Nature》: 重磅！普林斯顿研究人员发现肿瘤代谢比预想的慢！

临床研究

2023-02-06

·生物谷

Pharmacological Research: 安洛替尼联合奥希替尼通过靶向c-MET/MYC/AXL轴逆转NSCLC获得性奥希替尼耐药

非小细胞肺癌(NSCLC)是世界范围内最常见的恶性肿瘤之一，确诊时约70%的患者处于晚期，晚期NSCLC患者预后较差。非小细胞肺癌(NSCLC)是世界范围内最常见的恶性肿瘤之一，确诊时约70%的患者处于晚期，晚期NSCLC患者预后较差。近年来，靶向治疗已成为癌症最重要的治疗方案之一，第三代EGFR-TKI的奥西美替尼(AZD9291)已取代以吉非替尼和厄洛替尼为代表的第一代EGFR-TKI，作为转移性EGFR突变的NSCLC患者的一线治疗方案，由于良好和持久的治疗反应显示出优越的生存益处，并改善了生活质量。然而，在大多数患者中出现获得性耐药是一个普遍存在的关键挑战。获得性奥西美替尼耐药的机制是异质性的，既涉及EGFR依赖的机制，也涉及EGFR非依赖的机制，包括EGFR苏氨酸到C797S的突变，c-met扩增，HER2突变和上皮到间充质的转变(EMT)。总之，发现一种逆转EGFR-TKI耐药的疗法对于应对获得性治疗耐药至关重要。图片来源：https://doi.org/10.1016/j.phrs.2023.106668 近日，来自南京医科大学附属第二医院的研究者们在Pharmacological Research杂志上发表了题为“Anlotinib combined with osimertinib reverses acquired osimertinib resistance in NSCLC by targeting the c-MET/MYC/AXL axis”的文章，该研究的结果提供了强有力的支持，该联合疗法可能在提高晚期非小细胞肺癌患者的治疗效果方面有效。有利的临床证据表明，晚期非小细胞肺癌(NSCLC)新疗法的下一个趋势将是联合疗法。然而，不可避免的表皮生长因子受体酪氨酸激酶抑制物(EGFR-TKI)耐药性极大地限制了携带EGFR激活突变的患者的临床疗效。在这项研究中，研究者发现了一名临床上对奥西美替尼耐药的患者，他在奥西美替尼和安洛替尼联合治疗后恢复了阳性反应。构建了两个奥西美替尼耐药细胞系，Ax1在非小细胞肺癌细胞系中对奥西美替尼具有抗性。安罗替尼和奥昔替尼的联合作用在两个耐奥昔替尼的NSCLC细胞系和异种移植瘤中恢复了对奥昔替尼的敏感性。此外，安洛替尼可抑制两种耐药细胞株Axl的磷酸化。在机制上，研究者证实MYC与AXL启动子结合促进其在非小细胞肺癌细胞中的转录，本研究证明了安洛替尼联合奥西莫替尼治疗通过失活c-MET/MYC/AXL轴逆转Osimertinib耐药而增强了抗肿瘤作用。安洛替尼与奥西美替尼联合治疗的体内抗肿瘤效果图片来源：https://doi.org/10.1016/j.phrs.2023.106668 综上所述，本研究显示安洛替尼与奥西美替尼具有协同抗肿瘤作用，并通过靶向c-MET/MYC/Ax1及其下游的MAPK和PI3K/AKT信号通路，逆转AX1高表达的奥西美替尼耐药细胞的获得性耐药。此外，研究者在裸鼠模型体内的发现为联合治疗的有效性和安全性提供了证据。综上所述，本研究的结果提示安洛替尼和奥西美替尼联合应用对EGFR突变的晚期NSCLC患者是有效的，为晚期DRIVE基因阳性的NSCLC提供了一种有前景的联合治疗策略，并为未来的临床试验设计奠定了坚实的基础。（生物谷 Bioon.com）参考文献 Tianyao Lei et al. Anlotinib combined with osimertinib reverses acquired osimertinib resistance in NSCLC by targeting the c-MET/MYC/AXL axis. Pharmacol Res. 2023 Jan 18;188:106668. doi: 10.1016/j.phrs.2023.106668.

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适应症	最高研发状态	国家/地区	公司	日期
非小细胞肺癌	临床1期	中国	先声药业有限公司	2013-04-15
乳腺癌	临床1期	中国	先聲藥業集團有限公司	-
乳腺癌	临床1期	-	Advenchen Laboratories LLC	-
结肠癌	临床1期	-	Advenchen Laboratories LLC	-
结肠癌	临床1期	中国	先聲藥業集團有限公司	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01772732 (Pubmed \| Cancer Manag Res) 人工标引	临床1期	EGFR突变的非小细胞肺癌 EGFR Mutation	41	simotinib	(壓夢憲製網築簾艱構製) = 餘夢遞簾繭夢艱膚簾顧繭鹽範廠糧淵鹽鹹醖鏇 (繭構窪淵壓膚廠艱願願 ) 更多	积极	2019-05-13
NCT01772732 (ASCO2017)	临床1期	晚期非小细胞肺癌一线	41	Simotinib	(鏇鏇製鹹鏇鏇壓積構繭) = Simotinib was well tolerated, with encouraging efficacy observed in NSCLC patients with EGFR sensitive mutations, particularly in those with BM 夢蓋鬱遞選襯製齋廠觸 (獵衊鬱鑰餘鏇顧鏇糧製 )	-	2017-05-30