阿瓦斯丁，英文名Avastin，是治疗直肠癌的新药。
阿瓦斯丁详细介绍
阿瓦斯丁，英文名Avastin，是治疗直肠癌的新药。
治疗直肠癌的新药Avastin
人类基因知识突飞猛进，令开发癌症药物的研究有大突破。三种由生物技术发展出来的抗癌新药，专门对付体内某种助长癌瘤生长扩散的物质，它们在消灭癌细胞的同时，并不损害健康细胞，因此比普通的化疗高出一筹。其中最瞩目的是治疗直肠癌的新药Avastin ，它能阻止癌瘤自制血管，使其无法吸收养分「饿死」。临床测试证明，它将可用来治疗晚期病人，令其生存率大增50 ％，平均寿命延长5 个月。研究结果本月初在美国临床肿瘤学会年会上公布时，与会者都振奋地交头接耳，因为他们知道这些研究成果的划时代意义。
明报报道，在1970 年代，哈佛大学研究员福尔曼首次指出，癌症肿瘤似乎能够在人体内自制新血管，供其吸取氧气和养分之用，毒瘤藉此不断扩散，由一个器官扩散至另一个器官，最终夺命。他因此推断，废去肿瘤制造血管的能力，使其「饿死」，便能减慢甚或停止肿瘤扩散。
平均延长寿命5 个月
一直以来，科学家的研究皆不甚成功，直至最近，科学家终於以其理论制成新药Avastin ，并首次以大规模临床测试证实福尔曼的假设。Avastin 是一种蛋白质，也是一种人造抗体，专门对付被某些癌瘤用来诱使血管形成的物质。
令化疗效果更快更持久
Avastin 的临? 测试有800 人参与，在标准化疗之外再服用Avastin 的结肠直肠癌（Colorectal cancer ）病人，证实比那些只接受化疗的病人，在研究期间的生存机会高出一半。
要指出某疗法是否有效的指标繁多而复杂，不过一项令人易於理解的计算方法是有否令病人寿命延长，而Avastin 被发现令平均寿命由15.6 个月延长到20.3 个月。《纽约时报》说，若一种新抗癌药能延长病人寿命两三个月便等於成功，Avastin 延命5 个月，已超出期望。
参与临床试验的加州大学三藩市分校胃肠肿瘤专家韦洛克说：你看到的是病人彷佛马上受惠，在感觉上以及肿瘤负荷上都减轻了。我想它真的使化疗效果加快，而且可能令效果更持久。
研究人员说，副作用基本上可以控制，只是会令许多病人血压上升，这可用普通方法治疗。Avastin 已显示对乳癌效果不佳，但该公司正研究它对胰脏癌、前列腺癌、卵巢癌和肾癌的效用。 可望明年推出市场
目前，多家生物技术公司共同研发出近10 种类似药理的药物，Avastin 被视为样板，备受业界关注。由於临? 测试结果理据充足，研发出Avastin 的美国著名基因工程公司Genentech 可能会在明年内向美国食品及药物管理局申请推出市场，而不像惯例那样再作第二次大型研究。
另外两种药物，包括纽约生物科技制药公司ImClone 研发的治疗结肠直肠癌药Erbitux ，以及AstraZeneca 公司的肺癌药Iressa ，都是用以阻挡一种体内分子，使其无法协助癌肿瘤发展起对化疗的抵抗能力。临? 实验都证实，它们能令濒死病人的癌瘤缩小，只是尚未能如Avastin 那样延长病人寿命。
癌症医生绝少说「治愈」，因为癌症随时都会复发，但现在很多医生都希望，若把这两三种目前世界上最先进的抗癌药物结合现有的化疗方法，或能长久抑制肿瘤。因此医学界都欢呼，他们即将踏入治癌新纪元。专家相信，以深厚基因知识为基础的疗法，已开始有效对付各大癌症杀手，例如肺癌、乳癌、直肠癌和前列腺癌等。
医学界：标志治癌新纪元
对癌病的临床研究已有15 年的加州大学肿瘤专家韦洛克说：我向来对所谓研究进展有保留，但也不得不说这是划时代的。它令研究者、病人和生物医药公司而言都是一大鼓舞，真是令人兴奋得不得了。
AVASTIN(Bevacizumab)英文说明书
U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
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1.14.1.3 Labeling Text 1
AVASTIN™ 2
(Bevacizumab) 3
For Intravenous Use 4
WARNINGS 5
Gastrointestinal Perforations/Wound Healing Complications 6
AVASTIN administration can result in the development of gastrointestinal 7
perforation and wound dehiscence, in some instances resulting in fatality. 8
Gastrointestinal perforation, sometimes associated with intra-abdominal 9
abscess, occurred throughout treatment with AVASTIN (i.e., was not 10
correlated to duration of exposure). The incidence of gastrointestinal 11
perforation in patients receiving bolus-IFL with AVASTIN was 2%. The 12
typical presentation was reported as abdominal pain associated with 13
symptoms such as constipation and vomiting. Gastrointestinal perforation 14
should be included in the differential diagnosis of patients presenting with 15
abdominal pain on AVASTIN. AVASTIN therapy should be permanently 16
discontinued in patients with gastrointestinal perforation or wound 17
dehiscence requiring medical intervention. The appropriate interval 18
between termination of AVASTIN and subsequent elective surgery 19
required to avoid the risks of impaired wound healing/wound dehiscence 20
has not been determined. (See WARNINGS: Gastrointestinal 21
Perforations/Wound Healing Complications and DOSAGE AND 22
ADMINISTRATION: Dose Modifications.) 23
Hemorrhage 24
Serious, and in some cases fatal, hemoptysis has occurred in patients with 25
non–small cell lung cancer treated with chemotherapy and AVASTIN. In 26
a small study, the incidence of serious or fatal hemoptysis was 31% in 27
patients with squamous histology and 4% in patients with adenocarcinoma 28
receiving AVASTIN as compared to no cases in patients treated with 29
chemotherapy alone. Patients with recent hemoptysis should not receive 30
AVASTIN. (See WARNINGS: Hemorrhage and DOSAGE AND 31
ADMINISTRATION: Dose Modifications .) 32
U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
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DEscriptION 33
AVASTINä (Bevacizumab) is a recombinant humanized monoclonal 34
IgG1 antibody that binds to and inhibits the biologic activity of human 35
vascular endothelial growth factor (VEGF) in in vitro and in vivo assay 36
systems. Bevacizumab contains human framework regions and the 37
complementarity-determining regions of a murine antibody that binds to 38
VEGF (1). Bevacizumab is produced in a Chinese Hamster Ovary 39
mammalian cell expression system in a nutrient medium containing the 40
antibiotic gentamicin and has a molecular weight of approximately 41
149 kilodaltons. AVASTIN is a clear to slightly opalescent, colorless to 42
pale brown, sterile, pH 6.2 solution for intravenous (IV) infusion. 43
AVASTIN is supplied in 100 mg and 400 mg preservative- free, single- use 44
vials to deliver 4 mL or 16 mL of AVASTIN (25 mg/mL). The 100 mg 45
product is formulated in 240 mg a,a-trehalose dihydrate, 23.2 mg sodium 46
phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, 47
anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 48
400 mg product is formulated in 960 mg a,a-trehalose dihydrate, 92.8 mg 49
sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate 50
(dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, 51
USP. 52
CLINICAL PHARMACOLOGY 53
Mechanism of Action 54
Bevacizumab binds VEGF and prevents the interaction of VEGF to its 55
receptors (Flt-1 and KDR) on the surface of endothelial cells. The 56
interaction of VEGF with its receptors leads to endothelial cell 57
proliferation and new blood vessel formation in in vitro models of 58
angiogenesis. Administration of Bevacizumab to xenotransplant models 59
of colon cancer in nude (athymic) mice caused reduction of microvascular 60
growth and inhibition of metastatic disease progression. 61
Pharmacokinetics 62
The pharmacokinetic profile of Bevacizumab was assessed using an assay 63
that measures total serum Bevacizumab concentrations (i.e., the assay did 64
U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
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not distinguish between free Bevacizumab and Bevacizumab bound to 65
VEGF ligand). based on a population pharmacokinetic analysis of 66
491 patients who received 1 to 20 mg/kg of AVASTIN weekly, every 67
2 weeks, or every 3 weeks, the estimated half-life of Bevacizumab was 68
approximately 20 days (range 11-50 days). The predicted time to reach 69
steady state was 100 days. The accumulation ratio following a dose of 70
10 mg/kg of Bevacizumab every 2 weeks was 2.8. 71
The clearance of Bevacizumab varied by body weight, by gender, and by 72
tumor burden. After correcting for body weight, males had a higher 73
Bevacizumab clearance (0.262 L/day vs. 0.207 L/day) and a larger Vc 74
(3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or 75
above median value of tumor surface area) had a higher Bevacizumab 76
clearance (0.249 L/day vs. 0.199 L/day) than patients with tumor burdens 77
below the median. In a randomized study of 813 patients (Study 1), there 78
was no evidence of lesser efficacy (hazard ratio for overall survival) in 79
males or patients with higher tumor burden treated with AVASTIN as 80
compared to females and patients with low tumor burden. The 81
relationship between Bevacizumab exposure and clinical outcomes has not 82
been explored. 83
Special Populations 84
Analyses of demographic data suggest that no dose adjustments are 85
necessary for age or sex. 86
Patients with renal impairment. No studies have been conducted to 87
examine the pharmacokinetics of Bevacizumab in patients with renal 88
impairment. 89
Patients with hepatic dysfunction. No studies have been conducted to 90
examine the pharmacokinetics of Bevacizumab in patients with hepatic 91
impairment. 92
U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
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CLINICAL STUDIES 93
The safety and efficacy of AVASTIN in the initial treatment of patients 94
with metastatic carcinoma of the colon and rectum were studied in two 95
randomized, controlled clinical trials in combination with intravenous 96
5-fluorouracil–based chemotherapy. 97
AVASTIN in Combination with Bolus-IFL 98
Study 1 was a randomized, double-blind, active-controlled clinical trial 99
evaluating AVASTIN as first- line treatment of metastatic carcinoma of the 100
colon or rectum. Patients were randomized to bolus-IFL (irinotecan 101
125 mg/m2 IV, 5-fluorouracil 500 mg/m2 IV, and leucovorin 20 mg/m2 IV 102
given once weekly for 4 weeks every 6 weeks) plus placebo (Arm 1), 103
bolus-IFL plus AVASTIN (5 mg/kg every 2 weeks) (Arm 2), or 5-FU/LV 104
plus AVASTIN (5 mg/kg every 2 weeks) (Arm 3). Enrollment in Arm 3 105
was discontinued, as pre-specified, when the toxicity of AVASTIN in 106
combination with the bolus-IFL regimen was deemed acceptable. 107
Of the 813 patients randomized to Arms 1 and 2, the median age was 60, 108
40% were female, and 79% were Caucasian. Fifty-seven percent had an 109
ECOG performance status of 0. Twenty-one percent had a rectal primary 110
and 28% received prior adjuvant chemotherapy. In the majority of 111
patients, 56%, the dominant site of disease was extra-abdominal, while the 112
liver was the dominant site in 38% of patients. The patient characteristics 113
were similar across the study arms. The primary endpoint of this trial was 114
overall survival. Results are presented in Table 1 and Figure 1. 115
U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
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Table 1
Study 1 Efficacy Results
IFL + Placebo
IFL + AVASTIN
5 mg/kg q 2 wks
Number of Patients 411 402
Overall Survivala
Median (months) 15.6 20.3
Hazard ratio 0.66
Progression-Free Survivala
Median (months) 6.4 10.6
Hazard ratio 0.54
Overall Response Rateb
Rate (percent) 35% 45%
Duration of Response
Median (months) 7.1 10.4
......
Avastin获准作为晚期结肠癌二线治疗药 (2006-6-22)
生物制药公司Genentech在6月20日称，FDA已批准Avastin的扩大适应症，即作为晚期结肠癌的二线治疗药物。
此前，Avastin+化疗联用已获准作为晚期结肠癌的一线治疗药。
FONT color=#733c29>vastin的扩大适应症，即作为晚期结肠癌的二线治疗药物。
此前，Avastin+化疗联用已获准作为晚期结肠癌的一线治疗药。
