本帖最后由 荷花池荒岛 于 2014-5-23 08:44 编辑
Dacomitinib(PF-00299804,达可替尼, 药商:Pfizer)
PF-00299804是美国辉瑞公司作为一线药物治疗晚期非小细胞肺癌(NSCLC)患者使用而研制的第二代人表皮生长因子受体(HER)的不可逆的TK抑制剂,作用于HER-1/EGFR、HER-2、及HER-4。
备注一:
299804是游离碱。临床剂量:非正版剂量=1:1。
剂量和给药方法:最低剂量是30mg每天一次口服,标准剂量为45mg每天一次口服。应空腹(至少进食前1小时或后2小时)。
半衰期是46-72小时,口服6-7小时后到达最高血药浓度,经过5个半衰期达到稳定血药浓度(4-6倍初始血药浓度)。血药浓度与剂量成线性关系。食物或抗酸药对Dacomitinib的血药浓度影响很小。
备注二:
常见副作用:腹泻(diarrhea)和皮疹(rash),恶心呕吐、毛囊炎、皮肤干燥、肝功能异常(丙氨酸转氨酶(ALT)和天门冬氨酸转氨酶(AST)、碱性磷酸酶、胆红素升高)、血小板减少症、心脏毒性(如左心室射血分数(LVEF)减少)、厌食、疲劳、呼吸困难、咳嗽、鼻衄、胃肠道和非-胃肠道出血、便秘、腹痛、发热、口腔炎、甲沟炎等。
副作用处理
- 腹泻:腹泻症状较轻时,可给予蒙脱石散剂(思密达)、洛哌丁胺(易蒙停),同时对症治疗,用口服补液盐(ORS)预防和纠正脱水、补充电解质,口服维生素。注:易蒙停的使用易蒙停4mg,随后2mg/4h,至腹泻停止12h停药;若24h后腹泻未停止,易蒙停增量至2mg/2h,酌情加用口服喹诺酮类抗生素(如氟哌酸);若 48h后腹泻仍未停止,应用奥曲肽,100~150μg SC q8h,用药至腹泻停止24h。不推荐预防性应用易蒙停来预防腹泻。若腹泻严重,或伴呕吐、消化道出血、少尿、无尿甚至休克时,应禁食,立即静脉滴注大量液体维持水和电解质平衡,静脉滴注多种维生素,有低钾血症时还须补钾。重症患者可考虑短期应用糖皮质激素,以减轻中毒症状。避免食用会加速肠蠕动的食物或饮料,如乳制品、果汁、大量的水果和蔬菜、胡椒、辛辣食物等;推荐藕粉、米粉、稀饭、小米粥、不加油的面汤等流质,热苹果泥。注意腹部的保暖,可用暖水袋热敷腹部。清洁臀部和肛周,避免感染。其它推荐药物有:地芬诺酯(Diphenoxylate,苯乙哌啶)、微生态制剂-培菲康(Bifico, 双歧三联活菌胶囊)、丽珠肠乐(口服双歧杆菌活菌制剂)等。
- 皮疹:穿宽松、柔软、低领、棉质的衣服,局部皮肤应避免抓挠,勿用碱性肥皂和刺激性洗涤物及粗糙毛巾擦洗,保持皮肤清洁,外出时避免强烈日光照射,皮肤干燥可涂用润肤剂,皮肤瘙痒可口服抗组胺药物,如息斯敏(阿司咪唑)。轻度皮疹可以局部涂搽百多邦(莫匹罗星软膏)或比亚芬(三乙醇胺乳膏),嘴唇四周可用蜂蜜涂抹。中度皮疹可以口服多西环素(强力霉素)或美满(米诺环素),100mg每日二次,这两种四环素类药物副作用较大,请谨慎使用。
- 肝功能异常:水飞蓟素(德国产的利加隆)、水飞蓟宾(天津天力士产的水林佳)、易善复、阿拓莫兰(还原型谷胱甘肽片)。注:不推荐含五味子或双环醇的保肝药。
- 心脏毒性:阿法替尼会引起心脏毒性,主要表现为胸闷、心悸、呼吸困难、心电图异常、LVEF 下降以及心肌酶的变化,甚至导致致命性的心衰。可以通过临床症状结合心电图、超声心动图等检查进行诊断。可服用心脏保护剂预防,比如辅酶Q10。保健品辅酶Q10分 Ubiquinone(普通型)和Ubiquinol(还原型)二种,还原型的效果强一些;药用辅酶Q10有日本卫材能气朗Q10和上海信宜Q10。
- 胃酸:抗酸剂达喜、嘉胃斯康薄荷味胃片(GAVISCON Strawberry Flavour Tablets)、胃粘膜保护剂瑞巴派特片(膜固思达片)。不建议使用质子泵抑制剂(PPI)如奥美拉唑、兰索拉唑、潘托拉唑和H2受体拮抗剂如西咪替丁等。雷尼替丁和法莫替丁属于较弱的CYP抑制剂,影响较小。埃索美拉唑是奥美拉唑的(S)-型异构体,对CYP2C19依赖性小。上午吃达可替尼,午饭后一小时吃一片GAVISCON,晚饭后一小时吃一片GAVISCON,睡觉前吃一片GAVISCON。其它抗酸药可参考此服法。
- 恶心呕吐:进清淡易消化食物,少量多餐,少吃甜食和易产气的食物,按医嘱予胃复安类药物口服。注:胃复安不可超量服用,并不能连续服用3个月以上。
- 便秘:火龙果、杜密克等。
- 腹痛:消旋山莨菪碱片654-2。
- 口腔炎:保持口腔清洁,早、晚用软毛刷刷牙,餐后用漱口水;口服VC+VB2,避免进刺激性食物,必要时予复达欣、甲硝唑抗炎治疗。口腔局部可用VC+VB2+蜂蜜涂抹。也可以用溃疡散、康复新等。VC可以用拜耳的力度伸泡腾片。
- 甲沟炎:避免向指甲加压,避免剪指/趾甲太短,不要穿紧鞋。轻度可用金银花水泡脚/手,头孢、夫西地酸乳膏或云南白药外涂,每日1~2次。严重者可剪除嵌甲,清除甲下积脓,并用生理盐水清洗,然后用2%碘酊浸润脚趾20分钟,或用硝酸银无菌湿敷。
- 呼吸困难:肺活量锻炼、气功、呼吸操、吸氧。
- 厌食:四磨汤口服液、宜利治(甲地孕酮)。注:甲地孕酮吃6-10天即可,不建议长期服用。
- 体重减轻:雀巢的速愈素、雅培的保康素、安素、乳铁蛋白、海参等。注:糖尿病人应选择无糖型的复合蛋白粉。
- 消化道出血:如出现消化道出血,大便潜血(++)以上、呕血,或鲜血便,应加强观察。判断上消化道出血者应禁食,并给予止酸、保护胃粘膜、止血(止血环酸、立止血等),必要时可以使用奥曲肽等;对于下消化道出血者,应积极给予止血、支持对症治疗,出血无法控制者,必要时需外科处理。
备注三:
药物相互作用:
299804是CYP2D6抑制剂,尽量避免使用强的CYP2D6抑制剂,如:奎尼丁, 西咪替丁、帕罗西汀, 氟西汀等。CYP2D6抑制剂会大大增加达可替尼的血药浓度,从而增加副作用。
同时应避免使用强的CYP3A4抑制剂和CYP3A4诱导剂。强的CYP3A4抑制剂(会增加达可替尼的血药浓度)包括阿扎那韦[atazanavir],环丙沙星[ciprofloxacin],葡萄柚或葡萄柚汁等。强的CYP3A4诱导剂(会减少达可替尼的血药浓度)包括利福平[rifampicin],糖皮质激素药物(强的松>考的松>地塞米松),烟草和酒精等。
备注四:
装药说明
- 胶囊可用普通胃溶胶囊(0号胶囊比较大,如果病人吞不下,可换成小号的)
- 辅料可用药用淀粉(预胶化淀粉),辅料质量是达可替尼的2倍以上即可。作用:促进药物吸收,加快溶出速度。
- 筛子可用50-60目的筛子,作用:过滤掉粗颗粒,混合更加均匀。
- 天平可使用0.001g电子天平,当然0.0001g电子天平更好。
---参考http://www.yuaigongwu.com/thread-8735-3-1.html
备注五:
299804和特罗凯的比较:http://www.ncbi.nlm.nih.gov/pubmed/22753918
http://www.haodf.com/zhuanjiaguandian/drzenghuidr_880407488.htm
备注六:
Pfizer2014年1月27日关于299804试验结果的声明:http://www.pfizer.com/news/press ... ll_cell_lung_cancer
备注七:病友反馈
- 手脚皮肤裂、甲沟炎、脚后跟疼、腹泻、嘴角鼻内发炎。
- 肝功能不好了,转氨酶上去了,人没有力气。
- 影响睡眠,皮肤溃烂,血压高,皮疹,腹泻。
- 感觉浑身无力,说一会话就要躺下来休息。 //乏力可能跟心脏毒性有关,抑制HER2会有心脏毒性。 seacat
- 主要是口腔溃疡,其它都很轻微,大概吃是10天左右口腔溃疡就比较严重了。
- 尿路感染,食欲不振,胃痛、胃痉挛,心慌,皮疹。除了胃痛厉害之外,其他副作用比较小。
---参考http://www.yuaigongwu.com/thread-8735-1-1.html
备注八:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, are effective therapies against mutant non-small cell lung cancers (NSCLCs). Treatment is limited by the development of resistance in part explained by the gain of a secondary EGFR mutation,T790M, at the gatekeeper residue. Irreversible EGFR inhibitors, including PF00299804, are effective in vitro and in vivo against EGFR mutant tumors that contain EGFR T790M and are currently under clinical development. In this study we generate models of resistance to PF00299804, using cell lines with EGFR T790M, and demonstrate that the PF00299804 resistant models develop focal amplification of EGFR that preferentially involves the T790M-containing allele. These PF00299804 resistant cell lines remain dependent on EGFR for growth as downregulation of EGFR by shRNA compromises their viability. We demonstrate that resistance to PF00299804 arises, at least in part, through selection of a pre-existing EGFR T790M amplified clone both in vitro and using a xenograft model in vivo. Our findings demonstrate that EGFR T790M is a common resistance mechanism to both reversible, and when amplified, the irreversible EGFR kinase inhibitors further emphasizing the need to develop more potent therapies against EGFR T790M. The findings can be used to guide studies of patient tumor specimens from ongoing clinical trials of irreversible EGFR kinase inhibitors.
。。。。。。
In lung cancer, EGFR T790M is the most common mechanism of acquired resistance to gefitinib and erlotinib and typically emerges within 9-13 months after initiating therapy(Inoue et al., 2006; Mok et al., 2008; Sequist et al., 2008). However, very little is known about how cancers that developed a gatekeeper mutation after treatment with gefitinib or erlotinib develop acquired resistance to second generation kinase inhibitors. In this study we used EGFR T790M lung cancer as a model to determine how resistance develops against agents aimed specifically at targeting the gatekeeper resistance mutation. Our findings suggest that although irreversible EGFR inhibitors may be transiently effective against cancers harboring EGFR T790M (Figure 1D), clones harboring amplified EGFR T790M will rapidly emerge in vitro and in vivo through selection of pre-existing EGFR T790M amplified or high expressing clones (Figures 5 and 6) leading to clinical drug resistance. These observations provide , mechanistic insight into the origins drug resistance to EGFR targeted therapies. Amplification of the gatekeeper mutation containing allele is a unique mechanism of drug resistance and has not previously been described for other kinase inhibitors targeting drug resistant forms of mutant oncogenes.
。。。。。。
---http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859699/
备注九:
However, all current irreversible inhibitors are less potent in cell line models harboring EGFR T790M compared to those with an EGFR activating mutation alone (Figure S1) and at clinically achievable concentrations, these agents do not inhibit EGFR T790M in vitro. Since the ATP affinity of EGFR T790M is similar to WT EGFR, the concentration of quinazoline-based EGFR inhibitors required to inhibit EGFR T790M, will also effectively inhibit WT EGFR. In patients, this concurrent inhibition of WT EGFR, results in skin rash and diarrhea, and limits the ability to achieve plasma concentrations sufficient to inhibit EGFR T790M. As a consequence the clinical efficacy of the irreversible EGFR inhibitors CI-1033, HKI-272 and PF00299804 has been limited, especially in gefitinib/erlotinib resistant NSCLC patients, and the dose limiting toxicity has been diarrhea and skin rash.
---http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879581/
备注十:
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