بڤاسيزوماب

(تم التحويل من Bevacizumab)
بڤاسيزوماب {{{English}}}?
جسم مضاد علاجي وحيد النسيلة
الاسم النظامي (أيوپاك)
Source zu/o
Target VEGF-A
المعينات Identifiers
رقم CAS 216974-75-3
كود ATC L01XC07
PubChem ?
بنك العقاقير BTD00087
بيانات كيميائية
الصيغة C6638H10160N1720O2108S44 
كتلة جزيئية approx. 149 kDa
بيانات الحركية الدوائية Pharmacokinetic
التوافر الحيوي 100% (IV only)
الأيض ?
عمر النصف 20 days (range: 11–50 days)
اخراج ?
اعتبارات علاجية
بيانات الترخيص

EU US

فئة السلامة أثناء الحمل

C(الولايات المتحدة)

الوضع القانوني

Prescription only

المسارات Intravenous

دواء بڤاسيزوماب Bevacizumab واسمه التجاري أفستين Avastin Genentech شركة هوفمان لا روش وهو ضد وحيد النسيلة مماثل للبشري يتعرف ويعطل العامل أ لنمو بطانة الأوعية vascular endothelial growth factor A (VEGF-A) .[1] و VEGF-A منبه كيميائي نمو أوعية دموية جديدة is a chemical signal that stimulates the growth of new blood vessels (angiogenesis), especially in cancer, retinal proliferation of diabetes in the eye, and other diseases. Bevacizumab was the first clinically available angiogenesis inhibitor in the United States.[بحاجة لمصدر]

Bevacizumab is currently approved by the U.S. Food and Drug Administration (FDA) for cancers that are metastatic (have spread to other parts of the body). It received its first approval in 2004 for combination use with standard chemotherapy for metastatic colon cancer and non-small cell lung cancer.[2] In 2008, it was approved by the FDA for use in metastatic breast cancer, a decision that generated some controversy as it went against the recommendation of its advisory panel,[3] who objected because it only slowed tumor growth but failed to extend survival. In the US, Members of a Food and Drug Administration panel have now said they do not see enough of a benefit from Avastin in advanced breast cancer to justify its serious risks, although the drug is still approved for use in Australia.[4]

It is used without FDA approval, but on the basis of clinical studies, for treatment of macular degeneration, an eye disease also characterized by proliferation of blood vessels in the retina.

Clinical studies are underway in non-metastatic breast cancer, renal cell carcinoma, glioblastoma multiforme, ovarian cancer, castrate-resistant (formally called hormone refractory) prostate cancer, non-metastatic unresectable liver cancer and metastatic or unresectable locally advanced pancreatic cancer. A study released in April 2009 found that bevacizumab is not effective at preventing recurrences of non-metastatic colon cancer following surgery.[5] In May 2009, it received FDA approval for treatment of recurring glioblastoma multiforme, while treatment for initial growth is still in phase III clinical trial.[6]

‎==‎الخلفية‎==

‏‎الاسم التجاري أفاستين

بيفاسيزوماب هو عبارة عن اجسام مضادة وحيدة النسلية معدل ليلائم الطبيعة البشرية وقد كان اول مثبط لتولد الاوعية متوفر تجاريا وهويوقف نمو الورم من خلال منع تشكل اوعية دموية جديدة من خلال استهداف وتثبيط وظيفة بروتين طبيعي يدعى عامل النمو البطاني الوعائي (VEGF)‎‏ وهو إشارة كيميائية تحفز يشكل اوعية دموية جديدة, خصوصاً في السرطان, والتولد الشبكي لداء البول السكري في العين, وأمراض أخرى. هذا الدواء طور اول مرة كنسخة معدلة لتصميم وراثي لاجسام مضادة للفأر والتي تحتوي مركبات كل من الفأر والانسان. ‏Genentech‏ قادرة على انتاج اجسام مضادة في كميات على نطاق الانتاج Genentech is able to produce the antibody in production-scale quantities.

بفاسيزوماب أول مانع تولد أوعية سريري متوافر في الولايات المتحدة, وحالياً مصدق عليه من فبل منظمة الدواء والغذاء الأميركية(FDA), من أجل سرطانات النقيلية (التي تنتشر إلى أجزاء أخرى من الجسم).

حصل على أول تصديق في العام 2004 لاستخدام مركب مع المعالجة المعيارية بالمواد الكيميائية لسرطان القولون النقيلي. في العام 2008 تم الموافقة عليه من قبل FDA لاستخدامه في سرطان الثدي النقيلي, القرار الذي أثار بعض الجدل ضد توصية جدول محلفيه الاستشاري, والذي اعترض لأنه فقط يبطء نمو الورم ولكنه فشل في إطالة مدة البقاء على قيد الحياة.

في الولايات المتحدة قال أعضاء من محلفي منظمة الغذاء والدواء أنهم لا يرون فائدة كافية من الأفاستين في سرطان الثدي المتقدم ليبرروا أخطاره الجدية, وعلى الرغم من ذلك فما زال الدواء مصدقاً عليه للاستخدام في استراليا.

إنه مستخدم دون مصادقة من منظمة الغذاء والدواء عليه, ولكن فقط في فقه الدراسات السريرية لمعالجة الانحلال البقعي, (مرض في العين مميز أيضاً بتوالد الأوعية الدموية في الشبكية).

الدراسات السريرية تسير الآن في سرطان الثدي غير النقيلي, وسرطان خلايا الكلية, والورم الأرومي الدِبْقي متعدد الأشكال, وسرطان المبيض, ومقاوم التخصي (المدعو رسمياً الهرمون العنيد الذي لا ينصهر) سرطان البروستات, وسرطان الكبد غير النقيلي وغير القطوع, وسرطان البنكرياس المتقدم محلياً غير النقيلي وغير القطوع.

وجدت دراسة أطلقت في نيسان من العام 2009 أن البفاسيزوماب ليس فعالاً في منع عودة سرطان القولون غير النقيلي بعد الجراحة. في أيار من العام 2009 حصل على تصديق منظمة الغذاء والدواء لمعالجة عودة الورم الأرومي الدِبْقي متعدد الأشكال, بينما معالجة النموّ الأوّلي مازال في طور المرض السريري التجريبي.

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Indications

Bevacizumab was approved by the FDA in February 2004 for use in metastatic colorectal cancer when used with standard chemotherapy treatment (as first-line treatment) and with 5-fluorouracil-based therapy for second-line metastatic colorectal cancer. This recommendation was based on E3200 trial - addition of bevacizumab to oxaliplatin/5-FU/leucovorin (FOLFOX4) therapy. It was approved by the EMEA in January 2005 for use in colorectal cancer.

In 2006, the FDA approved bevacizumab for use in lung cancer in combination with standard first-line chemotherapy. A study conducted by the Eastern Cooperative Oncology Group (ECOG) demonstrated a 2-month improvement in overall survival in patients with Stage IIIb/IV non-small cell lung cancer (NSCLC). Due to the observance of severe pulmonary hemorrhage in patients with NSCLC with squamous histology in an earlier study, patients with such histology were excluded from the pivotal ECOG trial.

In 2008, the FDA approved Bevacizumab for use in breast cancer. A panel of outside advisers voted 5 to 4 against approval, but their recommendations were overruled. The panel expressed concern that data from the clinical trial did not show any increase in quality of life or prolonging of life for patients - two important benchmarks for late-stage cancer treatments. The clinical trial did show that bevacizumab reduced tumor volumes and showed an increase in progression free survival time. It was based on this data that the FDA chose to overrule the recommendation of the panel of advisers. This decision was lauded by patient advocacy groups and some oncologists. Other oncologists felt that granting approval for late-stage cancer therapies that did not prolong or increase the quality of life for patients would give license to pharmaceutical companies to ignore these important benchmarks when developing new late-stage cancer therapies.[3] On March 28, 2007, the European Commission approved bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer.[7]

Bevacizumab is usually given intravenously through the arm every 14 days. In colon cancer, it is given in combination with the chemotherapy drug 5-FU (5-fluorouracil), leucovorin, and oxaliplatin or irinotecan.

In 2009, the FDA approved Bevacizumab for use in metastatic renal cell cancer (a form of kidney cancer) which is the drug's sixth indication[8] [9], following earlier reports of activity[10] and EU approval in 2007. Also in 2009, an FDA advisory committee unanimously recommended Bevacizumab for treatment of glioblastoma multiforme, a type of brain cancer.[11]

In the September 2009 issue of the Journal of Clinical Oncology, UCLA researchers reported that Avastin improves response and survival in patients with recurrent glioblastoma in comparison to historical controls.[12] Avastin may also be useful in the treatment of radiation necrosis, since it reduces edema and mass effect and diminishes blood-brain-barrier leakage.

Bevacizumab did not meet its primary endpoint of extending overall survival (OS) in a recent phase III trial in unresectable gastric cancer (in combination with paclitaxel / Taxol), but it did demonstrate a positive result in treatment of ovarian cancer.

Investigational

Bevacizumab has also demonstrated activity in ovarian cancer[13][14], and glioblastoma multiforme[15], a type of brain tumour, when used as a single agent. The FDA granted accelerated approval of Avastin for the treatment of recurrent glioblastoma multiforme in May 2009.[16]

Bevacizumab has been investigated as a possible treatment of pancreatic cancer, as an addition to chemotherapy, but studies have shown no improvement in survival.[17][18][19] It may also cause higher rates of high blood pressure, bleeding in the stomach and intestine, and intestinal perforations.

The drug is also undergoing initial trials as an addition to established chemotherapy protocols and surgery in the treatment of pediatric osteosarcoma.[20]

Uses in eye disease

Many diseases of the eye, such as age-related macular degeneration (AMD) and diabetic retinopathy, damage the retina and cause blindness when blood vessels around the retina grow abnormally and leak fluid, causing the layers of the retina to separate. This abnormal growth is caused by VEGF, so bevacizumab has been successfully used to inhibit VEGF and slow this growth.

Bevacizumab has recently been used by ophthalmologists as an intravitreal agent in the treatment of proliferative (neovascular) eye diseases, particularly for choroidal neovascular membrane (CNV) in AMD. Although not currently approved by the FDA for such use[بحاجة لمصدر], the injection of 1.25-2.5 mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity[بحاجة لمصدر] Many retina specialists have noted impressive results in the setting of CNV, proliferative diabetic retinopathy, neovascular glaucoma, diabetic macular edema, retinopathy of prematurity[21] and macular edema secondary to retinal vein occlusions.

Ranibizumab, a Fab fragment derived from the same parent molecule as bevacizumab, has been developed by Genentech (by the same scientist Napoleone Ferrara) for intraocular use. This drug, under the trade name Lucentis, now has FDA approval. It has undergone extensive clinical trials. Reports indicate substantially better outcomes in patients treated with intravitreal Lucentis than conventional treatments in people with choroidal neovascularization (wet age related macular degeneration). Most patients with choroidal neovascularization lose vision or at best maintain vision despite treatment with laser, photodynamic therapy or Macugen. A much larger proportion (up to 70%) gained vision with Lucentis.

Some investigators believe that bevacizumab at a cost of $42 a dose is as effective as ranibizumab at a cost of over $1,593 a dose.[22][23]

As Genentech has developed both drugs it has little interest in seeing Bevacizumab use in the eye and it is likely to remain off label. Off-label use of this medication has created significant controversy in medical retina and vitreo-retinal surgery. On October 11, 2007, Genentech issued a letter to Physicians that they would no longer sell bevacizumab to compounding pharmacies. This will effectively stop its use for macular degeneration patients who have no insurance coverage for Ranibizumab (Lucentis) and for any patient who has other vision threatening conditions where Bevacizumab has been shown to work.

However, the ophthalmic community, led by the American Academy of Ophthalmology (AAO) and the American Society of Retinal Specialists (ASRS), fought back and managed to get Genentech to agree to continue providing bevacizumab to retinal surgeons, who in turn could get compounding pharmacies to "cut" the dosage to the appropriate ophthalmic dosage for continued use.

The National Eye Institute (NEI) of the National Institutes of Health (NIH) announced in October 2006 that it would fund a comparative study trial [1] of ranibizumab (Lucentis) and bevacizumab (Avastin) to assess the relative safety and effectiveness in treating AMD. This study, called the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT Study), will enroll about 1,200 patients with newly diagnosed wet AMD, randomly assigning the patients to one of four treatment groups:

(Group1) Lucentis with four-week dosing, and after one year, re-randomization to Lucentis every four weeks or variable dosing as required based on diagnostic findings;

(Group 2) Bevacizumab with four-week dosing, and after one year, re-randomization to bevacizumab every four weeks or variable dosing as required based on diagnostic findings;

(Group 3) Lucentis on a variable dosing schedule for 2 years; after initial treatment, with monthly evaluation and re-treatment based on signs of lesion activity; and

(Group 4) Bevacizumab on a variable dosing schedule for 2 years; after initial treatment, with monthly evaluation and re-treatment based on signs of lesion activity.

The CATT Study will be conducted at 47 clinical sites throughout the United States, which will follow the patients for two years and is expected to take four years to complete. Enrollment began on February 22, 2008, with fifteen sites beginning recruiting. One-year follow-up data will be reported in 2009.

The primary goals of the study are to better understand the safety and efficacy of intravitreal bevacizumab and to develop better dosing and re-treatment guidelines for both bevacizumab and Lucentis.

As of July 2010, Avastin is being used successfully in a case study of Familial Exudative Vitreoretinopathy in Buffalo, New York.[بحاجة لمصدر]


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Concerns

Side effects

Bevacizumab inhibits the growth of blood vessels, which is part of the body's normal healing and maintenance. The body grows new blood vessels in wound healing, and as collateral circulation around blocked or atherosclerotic blood vessels. One concern is that bevacizumab will interfere with these normal processes, and worsen conditions like coronary artery disease or peripheral artery disease.[24]

The main side effects are hypertension and heightened risk of bleeding. Bowel perforation has been reported. In advanced lung cancer, less than half of patients qualify for treatment.[25] Posterior reversible encephalopathy syndrome,[26]nasal septum perforation, and renal thrombotic microangiopathy have been reported.[27]

These effects are largely avoided in ophthalmological use since the drug is introduced directly into the eye thus minimizing any effects on the rest of the body.

Costs

Bevacizumab is one of the most expensive drugs widely marketed. Doctors and editorials have criticized the high cost, for a drug that doesn't cure cancer but only prolongs life. In the U.S., insurance companies have refused to pay for all or part of the costs of bevacizumab, and in countries with national health care systems, such as the UK and Canada, the health care systems have restricted its use because of the low ratio of benefits to cost. Genentech argues that the benefit is worth the cost, and the high cost pays for the expensive and risky research needed to develop new drugs. Genentech has adjusted the price for patients in certain circumstances. In 2008, sales of Avastin were nearly $2.7 billion.[28]

For colorectal cancer, Meyer wrote in the New England Journal of Medicine that bevacizumab extended life by 4.7 months (20.3 months vs. 15.6 months) in the initial study, at a cost of $42,800 to $55,000[29] and the Health company National Institute for Health and Clinical Excellence criticised that the drug should be removed because the cost. It costs about £21,000 per patient.[30]

The addition of bevacizumab to standard treatment can prolong the lives of breast and lung cancer patients by several months, at a cost of $100,000 a year in the United States. [31] Costs in other countries vary; in Canada it is reported to cost $40,000 CAD per year. [32] ==انظر أيضا=-

المصادر

  1. ^ Los M, Roodhart JM, Voest EE (2007). "Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer". The Oncologist. 12 (4): 443–50. doi:10.1634/theoncologist.12-4-443. PMID 17470687. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
  2. ^ Avastin Prescribing Information, Genentech Inc., October 2006, www.clinicaltrials.gov
  3. ^ أ ب "F.D.A. Approves Drug's Use for Breast Cancer". The New York Times. February 22, 2008.
  4. ^ "Breast cancer drug 'still safe' for Aussie women". July 22, 2010. Unknown parameter |word= ignored (help)
  5. ^ Reed, Katie. "Roche drug Avastin fails cancer study, shares fall". Reuters 22 Apr 2009. Accessed 22 Apr 2009
  6. ^ Genentech, Inc. "FDA Grants Accelerated Approval of Avastin for Brain Cancer (Glioblastoma) That Has Progressed Following Prior Therapy". Market Watch 5 May 2009.
  7. ^ Jasek, W, ed. (2007). Austria-Codex (in German) (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. ISBN  3-85200-181-4 Check |isbn= value: checksum (help).CS1 maint: Unrecognized language (link)
  8. ^ FDA clears Genentech drug for kidney cancer San Francisco Chronicle, August 2, 2009
  9. ^ http://www.genengnews.com/news/bnitem.aspx?name=59562374 "FDA Gives Roche's Avastin the Go-Ahead for Metastatic Renal Carcinoma "
  10. ^ Rini BI (2007). "Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: current status and future directions". Clin Cancer Res. 13 (4): 1098–106. doi:10.1158/1078-0432.CCR-06-1989. PMID 17317817. Unknown parameter |month= ignored (help)
  11. ^ Pollack, Andrew (2009-03-31). "F.D.A. Panel Supports Avastin to Treat Brain Tumor". New York Times. Retrieved 2009-08-13.
  12. ^ OncoGenetics.Org (2009). "Avastin dramatically improves response, survival in deadly recurrrent glioblastomas". OncoGenetics.Org. Retrieved 2009-09-02. Unknown parameter |month= ignored (help)
  13. ^ Konner JA et al. Proc ASCO 2007 (2008). "A phase II study of intravenous (IV) and intraperitoneal (IP) paclitaxel (Tax), IP cisplatin (Cis), and IV bevacizumab (Bev) as first-line chemotherapy for optimal stage II or III ovarian, primary peritoneal, and fallopian tube cancer". http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=31096. Unknown parameter |month= ignored (help)
  14. ^ Burger RA et al. J Clin Oncol 28:7s, 2010 (2010). "Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study". http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=52788. Unknown parameter |month= ignored (help)
  15. ^ T. F. Cloughesy, M. D. Prados, P. Y. Wen, T. Mikkelsen, L. E. Abrey, D. Schiff, W. K. Yung, Z. Maoxia, I. Dimery, and H. S. Friedman. A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM). J Clin Oncol (Meeting Abstracts) 2008 26: 2010b. [Abstract].
  16. ^ Richard Pazdur, M.D. (2009). "FDA Approval for Bevacizumab". National Cancer Insitute. Retrieved 2010-05-11. Unknown parameter |month= ignored (help)
  17. ^ Saif MW (2008). "New developments in the treatment of pancreatic cancer. Highlights from the "44th ASCO Annual Meeting". Chicago, IL, USA. May 30 - June 3, 2008". JOP. 9 (4): 391–7. PMID 18648128.
  18. ^ Rocha-Lima CM (2008). "New directions in the management of advanced pancreatic cancer: a review". Anticancer Drugs. 19 (5): 435–46. doi:10.1097/CAD.0b013e3282fc9d11. PMID 18418211. Unknown parameter |month= ignored (help)
  19. ^ Riess H (2008). "Antiangiogenic strategies in pancreatic cancer". Recent Results Cancer Res. 177: 123–9. doi:10.1007/978-3-540-71279-4_14. PMID 18084954.
  20. ^ Md. Girl,11, First To Try New Cancer Treatment.
  21. ^ Azad R, Chandra P (2007). "Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity". Indian journal of ophthalmology. 55 (4): 319. doi:10.4103/0301-4738.33057. PMID 17595491.
  22. ^ Medicare Eye Study Finds Untapped Savings, Wall Street Journal, June 17, 2010
  23. ^ Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study, Adnan Tufail, et al., for the ABC Trial Investigators, BMJ 2010;340:c2459, doi: 10.1136/bmj.c2459 (10 June 2010)
  24. ^ New England Journal of Medicine, 8 May 2008, 358(19):2066, Clinical Implications of Basic Research: A New Weapon for Attacking Tumor Blood Vessels, Gregg L. Semenza.
  25. ^ Vamsidhar Velcheti, Avinash Viswanathan, Ramaswamy Govindan (2006). "The Proportion of Patients with Metastatic Non-small Cell Lung Cancer Potentially Eligible for Treatment with Bevacizumab: A Single Institutional Survey". Journal of Thoracic Oncology. 1 (5): 501. doi:10.1097/01243894-200606000-00023. PMID 17409907.CS1 maint: Multiple names: authors list (link) Full text
  26. ^ Reversible posterior leukoencephalopathy syndrome in cancer. Vaughn C, Zhang L, Schiff D. Curr Oncol Rep. 2008 Jan;10(1):86-91. Review. PMID: 18366965
  27. ^ Vera Eremina, J.Ashley Jefferson; et al. (2008). "VEGF Inhibition and Renal Thrombotic Microangiopathy". The New England Journal of Medicine. 358 (11): 1129. doi:10.1056/NEJMoa0707330. PMID 18337603. Explicit use of et al. in: |author= (help) Full text
  28. ^ Genentech 2008 10-K Report,
  29. ^ Two Steps Forward in the Treatment of Colorectal Cancer, Robert J. Mayer, N Engl J Med, 350:2406-2408 June 3, 2004
  30. ^ Critics condemn bowel cancer drug rejection written by Helen Briggs, Health reporter of BBC News, Retrieved 24 August 2010
  31. ^ A Cancer Drug Shows Promise, at a Price That Many Can't Pay, By ALEX BERENSON, New York Times, February 15, 2006
  32. ^ P.E.I. sole holdout on cancer drug CBC News, November 26, 2009

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