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肺癌靶向药物

ID #1064

泰欣生是什么

  泰欣生(尼妥珠单克隆抗体)单克隆抗体药物能够特异性针对肿瘤细胞进行靶向治疗,从分子水平逆转肿瘤细胞的恶性生物学行为。该类药物具有靶向性强、特异性高和毒副作用低等特点,并能增强放、化疗疗效,代表着肿瘤治疗领域的最新发展方向。
  百泰生物药业有限公司开发的国家Ⅰ类新药泰欣生(尼妥珠单抗,Nimotuzumab) ——人源化抗人表皮生长因子受体(EGFR)单克隆抗体,能够竞争性抑制内源性配体与EGFR的结合,阻断由EGFR介导的下游信号传导通路,从而抑制肿瘤细胞增殖、诱导分化,促进肿瘤细胞凋亡,抑制肿瘤血管生成,增强放、化疗疗效。
  泰欣生(尼妥珠单抗,Nimotuzumab)是全球第一个以EGFR为靶点的人源化单抗药物,由古巴学者率先研制,并由我国学者参与研究正式投产,也是我国正式上市的第一个人源化单克隆抗体药物。目前,泰欣生已在中国、美国、德国、加拿大、日本、古巴、印度等20个多国家进行多项临床研究,已经完成或正在进行的临床试验共计60余项,包括泰欣生联合放疗、化疗,治疗鼻咽癌、头颈部肿瘤、神经胶质瘤、结直肠癌、胰腺癌、非小细胞肺癌等实体瘤,已入组患者逾3000人。
  临床研究证实:泰欣生?能够显著提高放、化疗疗效,不良反应轻微,患者耐受性良好,具有比较广泛的应用前景,无疑成为中国肿瘤分子靶向治疗临床应用新的里程碑。
  【药品名称】
  通用名称:尼妥珠单抗注射液
  商品名称:泰欣生
  英文名称:Nimotuzumab
  汉语拼音: NiTuoZhuDanKang Zhusheye
  【成分】
  每支10 mL含50 mg尼妥珠单抗、4.5 mg磷酸二氢钠、18.0 mg磷酸氢二钠、86.0 mg氯化钠、2.0 mg聚山梨醇酯80。
  【性状】
  外观澄清、无色无味,无不溶物的液体。
  【适应症】
  本品与放疗联合适用于治疗表皮生长因子受体(EGFR)阳性表达的Ⅲ/Ⅳ期鼻咽癌。使用本品前,患者应先确认其肿瘤细胞EGFR表达水平,EGFR中、高表达的患者推荐使用本品。 检验操作应由熟练掌握EGFR检测试剂盒检测技术的实验室完成。检验中的某些失误,如使用较差的组织样本、未能严格遵从操作规程、使用不当的对照等均可能导致不可靠的结果。
  【规格】
  13.5毫升西林瓶装量10毫升(±0.5毫升),尼妥珠单抗浓度为5mg/mL,每支含50毫克。
  【用法用量】
  100mg尼妥珠单抗稀释于250ml生理盐水中,前臂静脉输液给药,进药过程在60分钟以上。第一次给药时间为放射治疗的第一天,于放疗前完成,以后每周一次,共8次。患者同时接受标准的鼻咽癌放射治疗。
  【不良反应】
  该药物的不良反应主要表现为发热、血压下降、恶心、头晕、皮疹。在70例晚期鼻咽癌患者中进行的Ⅱ期临床试验中发现,用药后发热的发生率为4.28%,最高体温39℃,对症处理后缓解,不影响治疗;血压下降,头晕发生率2.86%,最低达80/50mmHg,休息后缓解,不影响治疗;恶心发生率为1.43%,轻度,可自行缓解,不影响治疗;头晕发生率2.86%,时有头晕,可自行缓解,不影响治疗;皮疹发生率1.43%,轻度,可自行缓解,不影响治疗。
  在古巴和加拿大进行的临床试验发现该药常见的不良反应有发热、寒颤、恶心、呕吐、发冷、贫血、血压降低。不常见的不良反应有肌肉痛、运动语言障碍、口干、潮红、下肢无力、嗜睡、丧失方向感、肌酐水平升高、白细胞减少、血尿、胸痛、口腔绀紫。这些不良反应可使用常规剂量的镇痛药和/或抗组织胺药物予以治疗。
  【禁忌】
  对该药品或其任一组分过敏者禁止使用。
  【注意事项】
  1.本品冻融后抗体大部分活性将丧失,故在贮藏过程中严禁冷冻。本品配制的溶液在输液容器中2~8℃时其物理和化学稳定性可保持12个小时,在室温下可保持8个小时。储存时间超过上述时间,则应弃去不宜继续使用。
  2.本品必须在有经验的临床医师指导下使用。
  【孕妇及哺乳期妇女用药】
  本品可透过胎盘屏障,研究提示EGFR与胎儿发育调控、组织分化、器官形成有关,故孕妇或没有采用足够避孕措施的妇女慎用。本品属于IgG类抗体,由于人IgG1能够分泌至人乳汁,建议哺乳期妇女在本品治疗期间以及在最后一次给药60天内中断哺乳。
  【儿童用药】
  18岁以下儿童使用本药的安全性和疗效尚未确立。
  【老年用药】
  尚未确立老年患者使用安全性或疗效方面的特殊差异。
  【药物相互作用】
  未进行该药物与其它任何药物间的相互作用研究。
  【药物过量】
  在每人每次200毫克至400毫克剂量下可以耐受,目前尚未确立使用超过400毫克剂量时的安全性结论。
  【临床试验】
  一项在中国进行的随机、开放多中心的Ⅱ期临床研究评价了本品对局部晚期鼻咽鳞状细胞癌(Ⅲ或ⅣA-B期)的治疗效果。入组病人137例,试验组接受h-R3治疗加根治性放射治疗,对照组接受单纯根治性放射治疗。结果显示:
  1.肿瘤完全缓解率(CR率):对治疗结束时、疗后第5周原发灶、颈部转移淋巴结和总评价的肿瘤完全缓解率(CR率)进行统计分析。治疗结束时试验组的CR率为:原发灶76.56%、淋巴结75.00%、总评价65.63%,对照组的CR率为34.85%、57.58%和27.27%,两组间差异有统计学意义;疗后第5周,试验组的CR率分别为原发灶90.63%、淋巴结89.06%、总评价87.50%,对照组的CR率分别为51.52%、72.73%和42.42%,两组间差异有统计学意义;
  观察了治疗结束后第17周试验组的CR率分别为原发灶92.19%、淋巴结93.75%、总评价90.63%,对照组的CR率分别为63.64%、80.30%和51.52%,两组间差异有统计学意义。
  2.肿瘤有效率(CR+PR):疗后第17周试验组有效率为100%,对照组90.91%,两者比较,其差异有统计学意义。
  3.全部17周观察期内试验组有1例发生骨转移,对照组中有5例发生包括肺、肝和骨在内的远地转移。对于抗肿瘤远处转移作用,仍在继续临床观察。
  4.采用治疗前后卡氏( Karnofsky )评分和体重变化来评价患者的生存质量。试验组治疗后卡氏评分高于对照组,平均体重下降低于对照组,两组间均差异有统计学意义, 显示本品对患者生活质量改善的意义。
  另外,已完成的Ⅱ/Ⅲ期临床试验有:在古巴进行的该药联合放疗治疗头颈癌临床试验;在加拿大进行的头颈癌II期临床试验;在德国进行的单药治疗儿童神经胶质瘤以及合并手术治疗转移性胰腺癌临床试验。
  正在进行的Ⅱ/Ⅲ期临床试验有:在古巴进行的单药以及联合化疗治疗乳腺癌、食管癌、前列腺癌和宫颈癌、非小细胞肺癌的脑部转移的临床试验;在加拿大进行的单药以及联合放、化疗治疗头颈癌(除鼻咽部)、脑转移癌和非小细胞肺癌临床试验;在德国进行的III期儿童脑胶质瘤临床试验。
  本产品拟在中国继续进行转移性结直肠癌、晚期食管癌和胃癌、晚期非小细胞肺癌、神经胶质瘤的研究。
  【药理毒理】
  药理研究:EGFR是分子量为170 KD的跨膜糖蛋白,其胞内区具有特殊的酪氨酸激酶活性。EGF-R的过度表达可改变细胞周期调控(加快细胞增殖),阻止细胞凋亡,促进血管生成,增强细胞移动性、侵袭性和转移性。尼妥珠单抗可在体内或体外培养细胞中阻断EGF与其受体EGFR的结合,并对EGFR过表达的肿瘤具有有效的抗血管生成、抗增殖和促凋亡作用。体内和体外试验结果均显示了本品有抗肿瘤增殖的功能,还具有抗血管生成和促进肿瘤细胞凋亡的特性。
  毒理研究:在两种动物(小鼠和绿猴)中进行尼妥珠单抗的4个单次给药急性毒性试验,剂量是临床剂量0.85倍到34倍,未见到毒性反应。采用两种动物(小鼠和绿猴)单剂量重复给药试验未发现任何毒性迹象。绿猴体内为期6个月的长期毒性试验,采用高低两个剂量,分别是人用剂量的20倍和2倍,血生化检查、心电图、体重、各器官病理组织学检查均未见异常。未见长期静脉注射导致的动物皮肤的损害。用小鼠和家兔进行尼妥珠单抗的局部耐受性试验,注射局部未见静脉刺激作用。用成人不同组织的冷冻切片进行交叉反应性试验,显示尼妥珠单抗和人活体组织(如心脏、血管、肾脏和肺)无交叉反应。尚未进行致癌、致突变和生殖力损害的特殊毒性研究。
  [药代动力学]
  对12名古巴晚期上皮源性癌症患者(11名女性和1名男性,平均年龄59.33岁,卵巢4例、乳房4例、肺2例、胃1例、肾1例)进行了药代动力学观察,各组病人通过静脉分别注射50、100、200和400毫克的尼妥珠单抗,其对应的清除半衰期分别为:62小时、82小时、302小时和304小时。
  生理条件下,不同剂量用药24小时由尿路排出量占注射剂量(ID)的比例分别是,50 mg排出21.1%,100 mg排出28.20%,200 mg排出27.36%,400 mg排出33.57%。
  本品在人体内主要分布的器官为肝脏、脾脏、心脏、肾脏和胆囊,其中肝脏是单抗特异摄取最高的器官。动物药代动力学数据证实给药后24小时以肿瘤组织药物浓度最高。
  尚缺乏在中国人种中进行药代动力学的研究数据。
  【贮藏】
  本品在2~8℃储存,严禁冷冻。
  【包装】
  每个小包装内含4支西林瓶,每个大包装含8个小包装,共32支西林瓶。
  【有效期】
  24个月
  【批准文号】
  国药准字S20080001
  【生产企业】
  企业名称:百泰生物药业有限公司

==== 汉译英 ====

Teshin Health (Nigeria Herceptin monoclonal antibody) monoclonal antibody drugs to specific targeted therapy against tumor cells, from the molecular level, reverse the malignant biological behavior of tumor cells. This class of drugs has a strong target, the specificity and toxicity of high and low side effects and can enhance the radiotherapy and chemotherapy, representing the latest developments in the field of cancer treatment direction.
Bio-Pharmaceutical Co., Ltd. 100 Thai national class Ⅰ developing new drugs Teshin Health (Nigeria properly natalizumab, Nimotuzumab) - humanized anti-human epidermal growth factor receptor (EGFR) monoclonal antibody, can be competitive inhibition of endogenous ligand and the combination of EGFR, blocked by EGFR-mediated downstream signal transduction pathway, thereby inhibiting tumor cell proliferation, induce differentiation and promote apoptosis of tumor cells, inhibit tumor angiogenesis, to enhance radiotherapy and chemotherapy.
Teshin Health (Nigeria properly natalizumab, Nimotuzumab) is the world's first to EGFR as a target of the humanized monoclonal antibody drug, first developed by Cuban scholars by scholars involved in the study of China's officially put into operation, but also the country's official listing of the first a humanized monoclonal antibody drugs. At present, the Teshin Health has been in China, the United States, Germany, Canada, Japan, Cuba, India, more than 20 countries, a number of clinical studies have been completed or ongoing clinical trials in a total of more than 60 items, including Teshin Health combined with radiotherapy , chemotherapy, treatment of nasopharyngeal carcinoma, head and neck cancer, glioma, colorectal, pancreatic cancer, non-small cell lung cancer and other solid tumors, has enrolled more than 3,000 patients.
Clinical studies confirm: Teshin students? Can significantly improve the radiotherapy and chemotherapy efficacy, adverse reactions are mild, well-tolerated in patients with a relatively broad range of applications, will undoubtedly become the clinical application of molecular target therapy for cancer a new milestone.
【Drug name】
Common name: Nepal duly natalizumab injection
Product Name: Teshin Health
English name: Nimotuzumab
Pinyin: NiTuoZhuDanKang Zhusheye
【Composition】
Each 10 mL contains 50 mg Niger properly natalizumab, 4.5 mg sodium dihydrogen phosphate, 18.0 mg disodium hydrogen phosphate, 86.0 mg sodium chloride, 2.0 mg polysorbate 80.
【Properties】
Appearance clarification, colorless, tasteless, non-insoluble liquid.
【Indications】
This product is combined with radiotherapy for the treatment of epidermal growth factor receptor (EGFR) positive expression of Ⅲ / Ⅳ stage nasopharyngeal carcinoma. So that before the FDA, patients should first confirm that the level of tumor cell EGFR expression, EGFR in patients with high expression of recommendation to the FDA. Test operation should be familiar with EGFR detection kit detection laboratory to complete. Inspection of some of the mistakes, such as using less tissue samples failed to strictly comply with operational procedures, improper use of the control of staff may lead to unreliable results.
【Specification】
Volume of 13.5 milliliters Xilin bottle 10 ml (± 0.5 ml), Nepal duly natalizumab concentration 5mg/mL, each containing 50 mg.
【Usage consumption】
Nepal due natalizumab 100mg diluted in 250ml normal saline, forearm intravenous administration, into the medicine course in 60 minutes. The first time for radiation therapy dose on the first day, was completed before radiotherapy, after once a week, a total of 8 times. Patients are also receiving standard radiotherapy of nasopharyngeal carcinoma.
Adverse reactions 【】
The adverse drug reaction is mainly manifested as fever, hypotension, nausea, dizziness, skin rash. In 70 patients with advanced nasopharyngeal carcinoma patients has been conducted Phase Ⅱ clinical trial found that the incidence of fever after administration of 4.28%, the maximum temperature 39 ℃, symptomatic treatment to alleviate does not affect the treatment; blood pressure, dizziness and the incidence of 2.86 %, the lowest reach 80/50mmHg, rest after mitigation, does not affect the treatment; nausea incidence of 1.43%, mild, self-mitigation, does not affect the treatment; dizziness incidence of 2.86%, when there is dizziness, self-mitigation, does not affect the treatment; rash incidence of 1.43%, mild, self-mitigation, does not affect the treatment.
In Cuba and Canada clinical trials found that common adverse drug reactions are fever, chills, nausea, vomiting, chills, anemia, blood pressure reduction. Less common adverse reactions are muscle pain, sports language barriers, dry mouth, flushing, lower limb weakness, lethargy, loss of sense of direction, creatinine levels increased, leukopenia, hematuria, chest pain, oral cyanosis purple. These adverse reactions could be the use of conventional doses of analgesic drugs and / or anti-histamine drugs, treatment.
【Taboo】
Of the drug or any of its component who are allergic prohibited.
【Note】
1. This product is freeze-thaw activity will lose the majority of antibody, it is strictly prohibited during storage freezer. This product is formulated in the infusion solution container 2 ~ 8 ℃, when its physical and chemical stability can be maintained for 12 hours at room temperature can maintain 8 hours. Stored longer than these times, it should be discarded to not continue to be used.
2. This product must all be under the guidance of experienced clinicians to use.
【Pregnant and lactating women drug】
It can be used through the placental barrier, research suggests that EGFR and fetal growth regulation, tissue differentiation and organ formation, so pregnant or not using adequate contraceptive measures for women with caution. This product is part of IgG antibody, because human IgG1 condemns individuals to be able to secrete milk, we recommend breast-feeding during treatment of women in the goods, as well as in the last dose within 60 days of interruption of breastfeeding.
  【儿童用药】
Children under the age of 18 use the drug safety and efficacy have not been established.
【Old medication】
Not yet been established in elderly patients with the use of safety or efficacy of the special differences.
【Drug interactions】
Did not carry out the drug with any other drug-drug interaction studies.
Overdosage
In the per person per 200 mg to 400 mg doses can be tolerated, are yet to establish the use of more than 400 mg doses, the safety conclusions.
【Clinical trials】
One in China randomized, open multi-center Phase Ⅱ clinical study evaluated the product for locally advanced squamous cell carcinoma of the nasopharynx (Ⅲ or Ⅳ A-B period) the therapeutic effect. 137 patients into the group of patients, experimental group received h-R3 therapy plus radical radiotherapy in the control group received radical radiotherapy alone. The results showed that:
1. Tumor complete remission rate (CR rate): the end of treatment, the treatment 5 weeks after the primary lesion, neck lymph node metastasis and overall evaluation of the tumor complete remission rate (CR rate) for statistical analysis. End of treatment, CR rate in the test group as follows: 76.56% primary tumor, lymph nodes 75.00%, with a total assessment of 65.63% in the control group, CR rate was 34.85%, 57.58% and 27.27%, statistically significant difference between the two groups; treatment 5 weeks after the test group CR rates were 90.63% for the primary tumor, lymph nodes 89.06%, 87.50% overall evaluation of the control group CR rates were 51.52%, 72.73% and 42.42%, difference between the two groups was statistically significance;
Observed 17 weeks after the end of treatment trials group CR rates were 92.19% for the primary tumor, lymph nodes 93.75%, with a total assessment of 90.63% in the control group CR rates were 63.64%, 80.30% and 51.52%, difference between the two groups there are statistically significant.
2. Efficient tumor (CR + PR): the first 17 weeks after the treatment the test group was 100% effective in the control group 90.91%, in comparison, the differences were statistically significant.
3. All of the 17-week observation period, test group, 1 case of bone metastasis in the control group, 5 cases occurred, including lung, liver and bone, including distant metastasis. For the role of anti-tumor metastasis are continuing clinical observation.
4. Use of before and after treatment Karnofsky (Karnofsky) score and body weight change to assess the patient's quality of life. The test group after treatment Karnofsky score higher, with an average weight loss than the control group, the difference between the two groups were statistically significant, indicating the goods to improve the quality of life for patients with meaning.
In addition, the completed Ⅱ / Ⅲ clinical trials are: in Cuba the drug combined with radiotherapy for head and neck cancer clinical trials; in Canada's head and neck cancer Phase II clinical trials; in Germany a single-drug treatment of children with glioma as well as the combined surgical treatment of metastatic pancreatic cancer clinical trials.
The ongoing Ⅱ / Ⅲ clinical trials are: in Cuba, as well as single-drug chemotherapy treatment of breast cancer, esophageal cancer, prostate cancer and cervical cancer, non-small cell lung cancer brain metastasis in clinical trials; in Canada, single Drug and joint radiotherapy and chemotherapy for head and neck cancer (excluding nasopharynx), metastatic brain cancer and non-small cell lung cancer clinical trials; in Germany by the phase III clinical trials of children with brain gliomas.
This product is intended to continue in China, metastatic colorectal cancer, advanced esophageal cancer and gastric cancer, advanced non-small cell lung cancer, glioma research.
【Pharmacology and toxicology】
Pharmacological Research: EGFR is a molecular weight of 170 KD transmembrane glycoprotein, which has a special intracellular tyrosine kinase activity. Over-expression of EGF-R can alter cell cycle regulation (accelerated cell proliferation), block apoptosis, promote angiogenesis, enhance cell mobility, invasive and metastatic. Nepal due natalizumab may be in vivo or in vitro cultured cells, blocking the combination of EGF and its receptor EGFR, and EGFR overexpression in tumors with an effective anti-angiogenic, anti-proliferation and promoting apoptosis. In vivo and in vitro test results have shown that this product has anti-tumor proliferation functions, also has anti-angiogenesis and promote tumor cell apoptosis characteristics.
Toxicology: In the two kinds of animals (mice and green monkey) in Nepal due to natalizumab in four single-dose acute toxicity test, the dose is 0.85 times the clinical dose to 34 times, not seen toxicity. Using two kinds of animals (mouse and green monkey) a single dose of repeated dose toxicity test did not find any signs. Green monkey in vivo 6-month period of the long-term toxicity tests, using both high and low doses, respectively, of human dose of 20 times and two times, blood biochemical tests, electrocardiogram, body weight, histopathological examination of various organs were no exception. No long-term intravenous injection of the skin damage caused by animals. Carried out using mice and rabbits due natalizumab Nepal Local tolerance test, intravenous injection site was no stimulating effect. Different organizations using frozen sections of adult cross-reactivity tests showed Niger properly natalizumab and human living tissues (such as the heart, blood vessels, kidneys, and lungs) without cross-reactivity. Yet to be carcinogenic, mutagenic and fertility damage to the special toxicity studies.
[Pharmacokinetics]
Cuba on 12 patients with advanced epithelial cancers (11 females and one male, with an average age of 59.33 years, four cases of ovarian, breast, 4 cases, lung in 2 cases, stomach in 1, kidney 1 case) were pharmacokinetics observation of patients in each group were injected intravenously and 400 mg of Nigeria 50,100,200 due natalizumab, which corresponds to the clearance half-lives are as follows: 62 hours, 82 hours, 302 hours and 304 hours.
Physiological conditions, different doses of medication 24 hours discharge from the urinary tract accounts for doses (ID) ratio, respectively, 50 mg discharge 21.1%, 100 mg discharge 28.20%, 200 mg discharge 27.36%, 400 mg discharged 33.57%.
This product is mainly distributed in the human body's organs as the liver, spleen, heart, kidney and gall bladder, where the liver is the highest intake of monoclonal antibody specific organs. Animal pharmacokinetic data confirm that 24 hours after administration the highest concentration of drug in tumor tissue.
Still lacking in China, carried out ethnic pharmacokinetics of research data.
【Storage】
This product is at 2 ~ 8 ℃ storage, freezing is strictly prohibited.
【Packing】
Each small package contains four vials, each large package containing eight small package, a total of 32 vials.
【Valid Period】
24 months
【Approval number】
State medicine accurate S20080001
【Manufacturer】
Company Name: Bio-Pharmaceutical Co., Ltd. 100 Thai

Tags: 泰新生 泰欣生

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更新日期: 2009-11-24 07:09
作者: : mcyclub
修订: 1.0

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