AvastinBevacizumab商品名Avastin.docx

1、Avastin Bevacizumab商品名AvastinGenentech公司的抗癌新药Bevacizumab（商品名Avastin）于2004年2月26日获得美国食品和药品管理局（FDA)的批准上市用于一线治疗晚期结直肠癌，这是世界上首个批准上市的血管内皮生长因子（VEGF)抑制剂。 Bevacizumab(商品名Avastin)中文说明书 【性状】剂型：水剂。剂量：两种，100mg/4ml或400mg/16ml。 【作用机制】Bevacizumab(商品名Avastin)是一种重组的人类单克隆IgG1抗体，通过抑制人类血管内皮生长因子的生物学活性而起作用。 药理毒理】药物代谢动力学特性：

2、静脉给药后，平均清除半衰期为20天（范围1150天），预测达到稳态的时间为100天。 特殊人群：根据人群用药资料，没有发现稳态血药浓度与患者的年龄、性别之间有相关性。 与处方者有关的临床前安全资料,在兔子中使用超过两倍Avastin人类推荐剂量，出现致畸性。 目前无Avastin在人类和动物致癌性资料。 【适应症】Avastin适用于联合以5FU为基础的化疗方案一线治疗转移性结直肠癌。 【禁忌症】目前不知Avastin的禁忌症。 【用法与用量】推荐剂量为5 mg/kg，每2周静脉注射1次直至疾病进展。Avastin应在术后28天以后使用，且伤口完全愈合。Avastin 需用100ml 0.9%

3、的生理盐水稀释，不能用葡萄糖溶解。Avastin不能静脉推注，第一次静脉滴注应在化疗后，滴注时间应超过90分钟。第一次滴注耐受性好，第二次静脉滴注时间应超过60分钟，仍然耐受好，以后滴注时间超过30分钟即可。 【不良反应】最严重的不良反应为胃肠穿孔/伤口并发症、出血、高血压危象、肾病综合症、充血性心力衰竭。 最常见的严重不良反应(NCI-CTC 3-4级 )为：无力、疼痛、高血压、腹泻、白细胞减少。 最常见不良反应为：无力、疼痛、腹痛、头痛、高血压、腹泻、恶心、呕吐、食欲下降、口腔炎、便秘、上呼吸道感染、鼻衄、呼吸困难、剥脱性皮炎、蛋白尿。 【贮藏】Avastin必须储存在原包装内，冷藏于28

4、 ，避光保存。不能冷冻，不能摇动。Back to TopDESCRIPTION AVASTIN (Bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and in vivo assay systems. Bevacizumab contains human framework regions an

5、d the complementarity-determining regions of a murine antibody that binds to VEGF (1). Bevacizumab is produced in a Chinese Hamster Ovary mammalian cell expression system in a nutrient medium containing the antibiotic gentamicin and has a molecular weight of approximately 149 kilodaltons. AVASTIN is

6、 a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for intravenous (IV) infusion. AVASTIN is supplied in 100 mg and 400 mg preservative-free, single-use vials to deliver 4 mL or 16 mL of AVASTIN (25 mg/mL). The 100 mg product is formulated in 240 mg , -trehalose dihyd

7、rate, 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 400 mg product is formulated in 960 mg , -trehalose dihydrate, 92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate (

8、dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, USP.Back to TopCLINICAL PHARMACOLOGY Mechanism of Action Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors l

9、eads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of Bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.Pharmacoki

10、netics The pharmacokinetic profile of Bevacizumab was assessed using an assay that measures total serum Bevacizumab concentrations (i.e., the assay did not distinguish between free Bevacizumab and Bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 491 patients who r

11、eceived 1 to 20 mg/kg of AVASTIN weekly, every 2 weeks, or every 3 weeks, the estimated half-life of Bevacizumab was approximately 20 days (range 11-50 days). The predicted time to reach steady state was 100 days. The accumulation ratio following a dose of 10 mg/kg of Bevacizumab every 2 weeks was 2

12、.8.The clearance of Bevacizumab varied by body weight, by gender, and by tumor burden. After correcting for body weight, males had a higher Bevacizumab clearance (0.262 L/day vs. 0.207 L/day) and a larger Vc (3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or above median valu

13、e of tumor surface area) had a higher Bevacizumab clearance (0.249 L/day vs. 0.199 L/day) than patients with tumor burdens below the median. In a randomized study of 813 patients (Study 1), there was no evidence of lesser efficacy (hazard ratio for overall survival) in males or patients with higher

14、tumor burden treated with AVASTIN as compared to females and patients with low tumor burden. The relationship between Bevacizumab exposure and clinical outcomes has not been explored.Special Populations Analyses of demographic data suggest that no dose adjustments are necessary for age or sex.Patien

15、ts with renal impairment. No studies have been conducted to examine the pharmacokinetics of Bevacizumab in patients with renal impairment.Patients with hepatic dysfunction. No studies have been conducted to examine the pharmacokinetics of Bevacizumab in patients with hepatic impairment.Back to TopCL

16、INICAL STUDIES The safety and efficacy of AVASTIN in the treatment of patients with metastatic carcinoma of the colon or rectum were studied in three randomized, controlled clinical trials in combination with intravenous 5-fluorouracil-based chemotherapy. The activity of AVASTIN in patients with met

17、astatic colorectal cancer that progressed on or after receiving both irinotecan based- and oxaliplatin based- chemotherapy regimens was evaluated in an open-access trial in combination with intravenous 5-fluorouracil-based chemotherapy.AVASTIN in Combination with Bolus-IFL Study 1 was a randomized,

18、double-blind, active-controlled clinical trial evaluating AVASTIN as first-line treatment of metastatic carcinoma of the colon or rectum. Patients were randomized to bolus-IFL (irinotecan 125 mg/m2 IV, 5-fluorouracil 500 mg/m2 IV, and leucovorin 20 mg/m2 IV given once weekly for 4 weeks every 6 week

19、s) plus placebo (Arm 1), bolus-IFL plus AVASTIN (5 mg/kg every 2 weeks) (Arm 2), or 5-FU/LV plus AVASTIN (5 mg/kg every 2 weeks) (Arm 3). Enrollment in Arm 3 was discontinued, as pre-specified, when the toxicity of AVASTIN in combination with the bolus-IFL regimen was deemed acceptable.Of the 813 pa

20、tients randomized to Arms 1 and 2, the median age was 60, 40% were female, and 79% were Caucasian. Fifty-seven percent had an ECOG performance status of 0. Twenty-one percent had a rectal primary and 28% received prior adjuvant chemotherapy. In the majority of patients, 56%, the dominant site of dis

21、ease was extra-abdominal, while the liver was the dominant site in 38% of patients. Results are presented in Table 1 and Figure 1.Table 1Study 1 Efficacy ResultsIFL + PlaceboIFL + AVASTIN5mg/kg q 2 wksNumber of Patients411402Overall SurvivalaMedian (months)15.620.3Hazard ratio0.66Progression-Free Su

22、rvivalaMedian (months)6.210.6Hazard ratio0.54Overall Response RatebRate (percent)35%45%Duration of ResponseMedian (months)7.110.4a p0.001 by stratified logrank test.b p0.01 by x2 test.Figure 1Duration of Survival in Study 1Error bars represent 95% confidence intervals.The clinical benefit of AVASTIN

23、, as measured by survival in the two principal arms, was seen in the subgroups defined by age (65) and gender.Among the 110 patients enrolled in Arm 3, median overall survival was 18.3 months, median progression-free survival was 8.8 months, overall response rate was 39%, and median duration of resp

24、onse was 8.5 months.AVASTIN in Combination with 5-FU/LV Chemotherapy Study 2 was a randomized, active controlled clinical trial testing AVASTIN in combination with 5-FU/LV as first line treatment of metastatic colorectal cancer. Patients were randomized to receive 5-FU/LV (5 fluorouracil 500 mg/m2,

25、leucovorin 500 mg/m2 weekly for 6 weeks every 8 weeks) or 5-FU/LV plus AVASTIN (5 mg/kg every 2 weeks) or 5-FU/LV plus AVASTIN (10 mg/kg every 2 weeks). The primary endpoints of the trial were objective response rate and progression-free survival. Results are presented in Table 2.Table 2Study 2 Effi

26、cacy Results5-FU/LV5-FU/LV + AVASTIN5mg/kg5-FU/LV + AVASTIN10mg/kgNumber of Patients363533Overall SurvivalMedian (months)13.617.715.2Progression-Free SurvivalMedian (months)5.29.07.2Overall Response RateRate (percent)174024Progression-free survival was significantly longer in patients receiving 5-FU

27、/LV plus AVASTIN at 5 mg/kg when compared to those not receiving AVASTIN. However, overall survival and overall response rate were not significantly different. Outcomes for patients receiving 5-FU/LV plus AVASTIN at 10 mg/kg were not significantly different than for patients who did not receive AVAS

28、TIN.AVASTIN in Combination with 5-FU/LV and Oxaliplatin Chemotherapy Study 3 was an open-label, randomized, 3-arm, active-controlled, multicenter clinical trial evaluating AVASTIN alone, AVASTIN in combination with 5-FU/LV and oxaliplatin (FOLFOX4), and FOLFOX4 alone in the second-line treatment of

29、metastatic carcinoma of the colon or rectum. Patients were previously treated with irinotecan and 5-FU for initial therapy for metastatic disease or as adjuvant therapy. Patients were randomized to FOLFOX4 (Day 1: oxaliplatin 85 mg/m2 and leucovorin 200 mg/m2 concurrently IV, then 5-FU 400 mg/m2 IV

30、bolus followed by 600 mg/m2 continuously IV; Day 2: leucovorin 200 mg/m2 IV, then 5-FU 400 mg/m2 IV bolus followed by 600 mg/m2 continuously IV; repeated every 2 weeks), FOLFOX4 plus AVASTIN, or AVASTIN monotherapy. AVASTIN was administered at a dose of 10 mg/kg every 2 weeks and for patients in the

31、 FOLFOX4 plus AVASTIN arm, prior to the FOLFOX4 chemotherapy on Day 1. Of the 829 patients randomized to the three arms, the median age was 61 years, 40% were female, 87% were Caucasian, and 49% had an ECOG performance status of 0. Twenty-six percent had received prior radiation therapy, 80% receive

32、d prior adjuvant chemotherapy. Ninety-nine percent received prior irinotecan, with or without 5-FU for metastatic colorectal cancer, and 1% received prior irinotecan and 5-FU as adjuvant therapy.The AVASTIN monotherapy arm of Study 3 was closed to accrual after enrollment of 244 of the planned 290 patients following a planned interim analysis by the data monitoring committee (DMC), based on