Abstract: the body. For cancer treatment, it

Abstract:The purpose ofthis project is to choose a drug and thoroughly study its properties inaccordance to what was learned in this course.

The drug chosen is Bevacizumab(Avastin). Avastin is used to treat a variety of cancer types and certain eyediseases. Bevacizumab is a type of recombinant humanized monoclonal refinedantibody that can be used to block angiogenesis by inhibiting vascularendothelial growth factor A (VEGF-A).  VEGF-A is a type of a chemical signal thatstimulates angiogenesis (growth of new blood cells and vessels) in a variety ofdiseases, but mainly cancer. The drug is commonly used to treat cancer of thecolon and rectum, which are major health concerns all over the world. Itsadministration on patients depends on the type of the disease and itsprevalence in the body.

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For cancer treatment, it is administered by beinginjected into the veins. In late stages of an eye disease, it is administeredby injection into the eye. The drug has major side-effects, such as rash, nosebleeding and high blood pressure. Severe side effects may include indigestion,blood clotting and risk of serious infections. Nonetheless, Avastin proves tobe an important drug in the fight against cancer.Background:It isimportant to know about Avastin because it is currently a widely used drugagainst many types of cancer.

Bevacizumab is the active element of Avastin andis used to neutralize the vascular endothelial growth factors in order toinhibit angiogenesis tumors, therefore reducing their growth and spread in thebody. Bevacizumab is a type of immunoglobulin G (IgG) antibody consisting oftwo identical light chains with 214 amino acid residues and two heavy chainsconsisting of 543 amino acids, and has a molecular weight of approximately149,000 daltons. 1  Bevacizumab was designedby Ferrara in 1997 and was approved for use by the FDA in medication in 2004. 2 In addition tothe treatment of cancer, the drug has also been proven to be effective in treatmentof eye and retina diseases such as age related macular degeneration (AMD) thatare caused by the abnormal growth of blood vessels in the back of the eye. Currently,the drug is manufactured in San Francisco at the Genentech Vacavillelaboratory. The drug is usually a colourless solution mixed with components ofsodium chloride to dilute it. Although the drug has been approved for useoff-label, its side effects raise concerns over its effectiveness in reducingtumour growths in the body. The aim of this report is to provide an overallpicture about Bevacizumab, its development, what it does, and how it works.

Discovery,Design, and Development:The discovery ofvascular endothelial growth factor (VEGF) facilitated the development ofBevacizumab. VEGF was discovered by Napoleon Ferrara in the Genentechlaboratory in San Francisco. VEGF is a protein in the body that facilitates thegrowth of blood vessels. In his first experimentation of the drug, Napoleonused mice to demonstrate that antibodies used against VEGF can invade thegrowth of tumours. His hypothesis was that by preventing the occurrence ofangiogenesis, the growth of cancer tumours could be controlled and eventuallystopped. Originally, the drug was developed in humanized monoclonal antibodiesderived from mice. The subsequent humanization was then passed through the cellbank system, where standard operation procedures were used to preserve thecells. The cell banks were further examined with viral concomitants andmicrobial substances.

Thereafter, there was the fermentation process of thecell culture in the Bevacizumab. Some raw materials that are applied infermentation are from ruminants. These include extracts of beef and bovinemilk. The drug is then purified in a four-step process. The pharmaceutical developmentof the drug formulation was originally unstable.  The instability of the physical formulationsthat had been used in the first phases of clinical studies. Therefore, the pHof the liquid formulation was increased to 6.

2. This was done so as to changethe chemical compositions and to increase the concentration of polysorbate.During phase II and phase III clinical trials, the liquid formulation stabilizesthe antibody at room temperature, which makes it suitable for handing andshipping the products. For adjusting the osmolality, trehalose dehydrate wasused. 3All Bevacizumab drug products are manufactured by the Genentechinstitute in San Francisco, while packaging and labelling are done inSwitzerland. The drug has been proven to be consistent, and there are noimpurities formed during the manufacturing process. It has been tested forstability and purification and has been approved as an effective cancertreatment mechanism.

Commercially, the drug is available in 16ml and 4ml liquidformulation. 4In 2004,Bevacizumab was approved as Avastin for the effective treatment for colorectalcancer. Two years later, the drug was approved as a suitable treatment forcommon types of lung cancer and was effective in reducing the spread of tumoursin the body.  In the same year, the drugwas approved to be used in concomitant with chemotherapies for lung cancers. In2008, the drug was approved by the FDA to be used in chemotherapy for negativebreast cancers. Over the years, the drug has been approved for many types ofcancer including brain cancer, metastatic cervical cancer, ovarian cancer, andkidney cancer. Pharmacokinetics of the Drug:The pharmacokinetics ofbevacizumab were characterized in patients with various types of solid tumors.The doses tested were 0.

1-10 mg/kg weekly in phase I; 3-20 mg/kg every twoweeks or every three weeks in phase II; 5 mg/kg or 15 mg/kg in phase III. Inall clinical trials, bevacizumab was administered as an IV infusion (100% bioavailability).As observed with other antibodies, the pharmacokinetics of bevacizumab are welldescribed by a two-compartment model. Overall, in all clinical trials,bevacizumab disposition was characterized by a low clearance, a limited volumeof the central compartment (Vc) which is in the range that has been describedfor IgGs and other monoclonal antibodies, and a long elimination half-life ofabout 20 days. This enables target therapeutic bevacizumab plasma levels to bemaintained with a range of administration schedules (such as once every 2 or 3weeks).

5 In the population pharmacokinetics analysisthere was no significant difference in the pharmacokinetics of bevacizumab inrelation to age. Assessment of bevacizumabmetabolism in rabbits after a single IV dose of bevacizumab hinted that itsmetabolic profile was similar to what is expected for a usual IgG moleculewhich does not bind VEGF. The metabolism and elimination of bevacizumab issimilar to endogenous IgG i.e. primarily via proteolytic catabolism throughoutthe body, including endothelial cells, and does not rely primarily onelimination through the kidneys and liver. Binding of the IgG to the FcRnreceptor result in protection from cellular metabolism and the long terminalhalf-life. According to the two-compartmental model of pharmacokinetics, theelimination half-life is about 18 days for females and 20 days for males.

Drug Target and Mechanism of Action:BevacizumabAvastin works in such a way that it inhibits the molecules of VEGF and bindsthem to their soluble receptors in the cells of endothelium. A tumor oftenundergoes what is called an “angiogenic switch”, which is the stimulation ofthe growth of new blood vessels. Tumors can do this by their ability to releaseVEGF (Vascular Endothelial Growth Factor). Studies show about 60% of malignanttumours express VEGF.

A selective antibody designed to inhibit VEGF is theanswer for stopping blood vessel growth, which is Bevacizumab. The drug worksby preventing the isoforms of VEGF and other inhibitors from binding themselvesinto the cell receptors in the endothelium. 6 Whenthe VEGF cell activities are weakened and reduced, the vascular permeabilityand the angiogenesis are inhibited. In the end, the tumors are prevented fromincreasing in size and are eventually destroyed.



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