关于阿法替尼（Bibw 2992）耐药的一些理论和解决方案

阿法替尼的半衰期是33.9小时，口服4小时后到达最高血药浓度，经过7-8天达到稳定血药浓度。
   多次给药后药物达到稳态浓度的时间仅决定于药物的消除半衰期。达稳态水平的某一特定比值所需的时间，它与药物半衰期成正比，与给药次数和间隔无关。
   提高给药频率或增加给药剂量均不能使稳态浓度提前达到，而只能改变体内药物总量（即提高稳态浓度水平）或峰浓度与谷浓度之差。在剂量不变时，加快给药频率使体内的药物总量增加、峰谷浓度之差缩小；延长给药间隔时间使体内药物总量减少、峰谷浓度差加大。
（1）首日加倍给药方案
   血药浓度达到稳态往往要经过较长的时间，例如达稳态99%需要6.64个半衰期，尤其是半衰期长的药物为了不失时机，及早达到稳态水平，此时，可将首次剂量提高到维持剂量的2倍，以后再按给药周期给以维持剂量。
   
（2）药物假期方案     
     对于有T790M突变的易瑞沙、特罗凯耐药病人，Bibw 2992或者PF00299804的效果是短暂的，平均无进展时间只有3.3个月，体外实验证明在空窗情况下T790M扩增细胞能逆转。因此采用间歇方案或者脉冲方案也许能延长药物有效时间。
   有二种方案：a. 吃5天停2天，适合无法耐受bibw 2992副作用的病人。
              b.吃8天停5天，适合肿瘤负荷轻的病人。

注：bibw 2992的临床试验证明，每天一次，连续服药方案的效果最好，对于病情进展的病人，不应该采用药物假期方案。
参考文献：
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859699/
http://mct.aacrjournals.org/cont ... e-8f83-10daa93438e3
http://www.ncbi.nlm.nih.gov/pubmed/22317763
http://protangzm28242.blogbus.com/logs/229173363.html
http://www.ncbi.nlm.nih.gov/pubmed/22789825
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748240/

学习了！多谢老马！

{:soso_e163:}

老马 发表于 2013-4-4 16:16

                               
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阿法替尼的半衰期是33.9小时，口服4小时后到达最高血药浓度，经过7-8天达到稳定血药浓度。
   多次给药后药 ...

老马：我们家易、特都耐药了，目前刚化疗完，接下来我想用BIBW2992和WZ4002,请教老马，哪个先上好呢？或许可以稳定时间长

怪自己英语没学好，中文看懂了，老马前辈前些日子征召的翻译高手给翻译一下多好啊！谢谢，谢谢

咱也 是 一个英文多看不懂。敬请英语高手给翻译下。万分感激。

Her2病人的获得性耐药
http://www.plosone.org/article/i ... ournal.pone.0026760
T798突变是Her2的看门基因（gatekeeper），就像T790突变是Her1的看门基因一样。
体外实验显示WZ4002能对付拉帕替尼( lapatinib)耐药的肿瘤细胞株，有效浓度为200nM。


注：ERBB2-L755S, ERBB2-L755P and ERBB2-T798M 是Her2肿瘤细胞的三种耐药突变。

Differential Sensitivity of ERBB2 Kinase Domain Mutations towards Lapatinib.pdf (1.56 MB, 下载次数: 110)

2013-11-17 23:05 上传

点击文件名下载附件

Irreversible inhibitors potently inhibits drug resistant ERBB2 mutants
CL-387785 is an irreversible EGFR/ERBB2 inhibitor that was shown to overcome gefitinib resistance due to the EGFR-T790M gatekeeper mutation. WZ-4002 was recently reported to have significant in vitro and in vivo activity against both the wild type and mutant EGFR. Moreover, irreversible inhibitors were recently shown to overcome inhibitor resistance caused due to insertion mutations in the ERBB2 kinase. Thus, we tested the efficacy of these irreversible inhibitors CL-387785 and WZ-4002 (Figure S3) on lapatinib-resistant ERBB2 point mutations (L755S, L755P and T798M). Interestingly, both inhibitors potently inhibited proliferation of Ba/F3-ERBB2 mutant cell lines with IC50 values less than 200 nM (Figure 7A and 7B). WZ-4002 was more potent (fold-increase of IC50 of mutant ERBB2 compared to wild type ERBB2) than CL-387785 (Table S2). Biochemical analysis of ERBB2 kinase activity and downstream targets showed that both irreversible inhibitors showed significant activity towards all three resistant ERBB2 mutants (Figure 7C and 7D). The structural basis for the excellent activity of WZ-4002 against lapatinib resistant ERBB2 mutations may be attributed to its ability to bind an active conformation of the ERBB2 kinase in an irreversible manner. Thus, WZ-4002 may be a potential alternative compound to treat cancer patients with either primary or secondary lapatinib resistance due to ERBB2 kinase domain mutations located at L755 or T798 within a clinical trial.

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Functional analysis of mutant receptor tyrosine kinases involved in cancer pathogenesis
http://d-nb.info/1011494124/34

WZ4002的体外实验和动物实验数据

注：DEL E746_A750是19突变，L858R是21突变，ERBB2 Ins G776V是一种20突变（Her2突变）,T790M也是一种20突变。H3255等是非小细胞性肺癌细胞株。BA/F3细胞是小鼠原B淋巴细胞。

参考特罗凯的动物实验数据：特罗凯在老鼠体内的半衰期是5-6小时，在人体内是36.2小时。
估计WZ4002在人体内的半衰期是14小时左右。
1ng/mL÷ 494.97=0.00202 μM =2.02nM

The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor.
Youngwook Kim, Jeonghun Ko, ZhengYun Cui, Amir Abolhoda, Jin Seok Ahn, Sai-Hong Ou, Myung-Ju Ahn, Keunchil Park

Medical Nano-Element Development Center, Samsung Biomedical Research Institute, Seoul, Korea.
Molecular Cancer Therapeutics (impact factor: 5.23). 03/2012; 11(3):784-91. DOI:10.1158/1535-7163.MCT-11-0750
http://www.researchgate.net/publ ... tion_EGFR_inhibitor
Source: PubMed
ABSTRACT Molecular target therapies using first-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib or erlotinib, have been shown to be effective for patients with non-small cell lung cancer (NSCLC) who harbor activating mutations in EGFR. However, these patients eventually develop resistance to the reversible TKIs, and this has led to the development of second-generation, irreversible EGFR inhibitors. Currently, the mechanism of acquired resistance to irreversible EGFR inhibitors is not clear. Using an in vitro cell culture system, we modeled the acquired resistance to first-line treatment with second-generation EGFR-TKIs using an EGFR-mutant NSCLC cell line. Here, we report a mechanism of resistance involving T790M secondary mutation as well as a corresponding clinical case. The results of these findings suggest that inhibition of EGFR by currently available second-generation EGFR-TKIs may not be sufficient to physiologically prevent the emergence of cells that are still dependent on EGFR signaling. This finding bears important implications on the limitations of currently available second-generation EGFR-TKIs.

After prolonged treatment method with afatinib, many independent afatinib-resist
http://topoisomerasesignaling.co ... ent-afatinibresist/
Right after prolonged treatment with afatinib, a number of independent afatinib-resistant clones emerged that persisted and proliferated even inside the presence of 2 ?M afatinib. From these, we established 14 diverse independent clones that acquired resistance to afatinib. Many of the drug responses of your representative resistant clones are selleck product shown in Fig. 1B. To monitor whether or not the acquisition of resistance was irreversible, we cultured all of these clones in ordinary development medium without the RTK inhibitor. These clones remained resistant to afatinib right after incubation in normal growth medium for many months , indicating that these cells underwent an irreversible adjust, perhaps involving chemically stable physical alterations in their genetic space. The signature exon 19 deletion of parental PC9 cells remained unaltered in every one of the r . Complete surgical resection of tumors or liver transplantation is only doable inside a minority of sufferers; for individuals with superior ailment, the prognosis is exceptionally poor, with an overall median survival of only a few months. Response charges to classical chemotherapy are reduced, and in many cases with mixture regimens, tough remission has remained elusive . Thus, there exists a powerful need for supplemental therapeutic choices.
In recent times, rationally designed, molecularly targeted drugs are becoming offered. These agents are designed to target development or survival pathways hyper-activated in cancer cells. Tyrosine kinases are considered to be great molecular oncology targets Phloretin because they transduce development and survival signals and therefore are hyper-activated in most, if not all, human malignancies . The ErbB receptor tyrosine kinase family, comprising EGFR and ErbB2, -3, and -4, has been of central interest during the development of targeted anticancer methods. Trastuzumab , a monoclonal antibody against ErbB2, is effectively being utilized in sufferers with ErbB2-overexpressing breast cancer, and overexpression of ErbB2 by way of gene amplification is usually a superior predictor of favorable response . Several preclinical and clinical scientific studies have addressed the efficacy of EGFR-targeting agents, like tyrosine kinase inhibitors , for instance gefitinib and erlotinib , likewise as monoclonal anti-EGFR antibodies, which include cetuximab, for your remedy of non-small cell lung cancer , head and neck cancer, colon carcinoma, glioblastoma, and other tumors . Though NSCLC sufferers with activating mutations from the kinase domain of EGFR react favorably to EGFR TKIs, leading to their approval for this subset of malignancies, the molecular basis determining the response of tumor cells to EGFR-targeting drugs in other settings is only partially understood and is mentioned controversially.