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Abstract:

The purpose of
this project is to choose a drug and thoroughly study its properties in
accordance 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 eye
diseases. Bevacizumab is a type of recombinant humanized monoclonal refined
antibody that can be used to block angiogenesis by inhibiting vascular
endothelial growth factor A (VEGF-A).  VEGF-A is a type of a chemical signal that
stimulates angiogenesis (growth of new blood cells and vessels) in a variety of
diseases, but mainly cancer. The drug is commonly used to treat cancer of the
colon and rectum, which are major health concerns all over the world. Its
administration on patients depends on the type of the disease and its
prevalence in the body. For cancer treatment, it is administered by being
injected into the veins. In late stages of an eye disease, it is administered
by injection into the eye. The drug has major side-effects, such as rash, nose
bleeding and high blood pressure. Severe side effects may include indigestion,
blood clotting and risk of serious infections. Nonetheless, Avastin proves to
be an important drug in the fight against cancer.

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Background:

It is
important to know about Avastin because it is currently a widely used drug
against many types of cancer. Bevacizumab is the active element of Avastin and
is used to neutralize the vascular endothelial growth factors in order to
inhibit angiogenesis tumors, therefore reducing their growth and spread in the
body. Bevacizumab is a type of immunoglobulin G (IgG) antibody consisting of
two identical light chains with 214 amino acid residues and two heavy chains
consisting of 543 amino acids, and has a molecular weight of approximately
149,000 daltons. 1  Bevacizumab was designed
by Ferrara in 1997 and was approved for use by the FDA in medication in 2004. 2

In addition to
the treatment of cancer, the drug has also been proven to be effective in treatment
of eye and retina diseases such as age related macular degeneration (AMD) that
are 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 Vacaville
laboratory. The drug is usually a colourless solution mixed with components of
sodium chloride to dilute it. Although the drug has been approved for use
off-label, its side effects raise concerns over its effectiveness in reducing
tumour growths in the body. The aim of this report is to provide an overall
picture about Bevacizumab, its development, what it does, and how it works.

Discovery,
Design, and Development:

The discovery of
vascular endothelial growth factor (VEGF) facilitated the development of
Bevacizumab. VEGF was discovered by Napoleon Ferrara in the Genentech
laboratory in San Francisco. VEGF is a protein in the body that facilitates the
growth of blood vessels. In his first experimentation of the drug, Napoleon
used mice to demonstrate that antibodies used against VEGF can invade the
growth of tumours. His hypothesis was that by preventing the occurrence of
angiogenesis, the growth of cancer tumours could be controlled and eventually
stopped. Originally, the drug was developed in humanized monoclonal antibodies
derived from mice. The subsequent humanization was then passed through the cell
bank system, where standard operation procedures were used to preserve the
cells. The cell banks were further examined with viral concomitants and
microbial substances. Thereafter, there was the fermentation process of the
cell culture in the Bevacizumab. Some raw materials that are applied in
fermentation are from ruminants. These include extracts of beef and bovine
milk. The drug is then purified in a four-step process.

The pharmaceutical development
of the drug formulation was originally unstable.  The instability of the physical formulations
that had been used in the first phases of clinical studies. Therefore, the pH
of the liquid formulation was increased to 6.2. This was done so as to change
the chemical compositions and to increase the concentration of polysorbate.

During phase II and phase III clinical trials, the liquid formulation stabilizes
the antibody at room temperature, which makes it suitable for handing and
shipping the products. For adjusting the osmolality, trehalose dehydrate was
used. 3
All Bevacizumab drug products are manufactured by the Genentech
institute in San Francisco, while packaging and labelling are done in
Switzerland. The drug has been proven to be consistent, and there are no
impurities formed during the manufacturing process. It has been tested for
stability and purification and has been approved as an effective cancer
treatment mechanism. Commercially, the drug is available in 16ml and 4ml liquid
formulation. 4

In 2004,
Bevacizumab was approved as Avastin for the effective treatment for colorectal
cancer. Two years later, the drug was approved as a suitable treatment for
common types of lung cancer and was effective in reducing the spread of tumours
in the body.  In the same year, the drug
was approved to be used in concomitant with chemotherapies for lung cancers. In
2008, the drug was approved by the FDA to be used in chemotherapy for negative
breast cancers. Over the years, the drug has been approved for many types of
cancer including brain cancer, metastatic cervical cancer, ovarian cancer, and
kidney cancer.

Pharmacokinetics of the Drug:

The pharmacokinetics of
bevacizumab 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 two
weeks or every three weeks in phase II; 5 mg/kg or 15 mg/kg in phase III. In
all clinical trials, bevacizumab was administered as an IV infusion (100% bioavailability).

As observed with other antibodies, the pharmacokinetics of bevacizumab are well
described by a two-compartment model. Overall, in all clinical trials,
bevacizumab disposition was characterized by a low clearance, a limited volume
of the central compartment (Vc) which is in the range that has been described
for IgGs and other monoclonal antibodies, and a long elimination half-life of
about 20 days. This enables target therapeutic bevacizumab plasma levels to be
maintained with a range of administration schedules (such as once every 2 or 3
weeks). 5 In the population pharmacokinetics analysis
there was no significant difference in the pharmacokinetics of bevacizumab in
relation to age.

Assessment of bevacizumab
metabolism in rabbits after a single IV dose of bevacizumab hinted that its
metabolic profile was similar to what is expected for a usual IgG molecule
which does not bind VEGF. The metabolism and elimination of bevacizumab is
similar to endogenous IgG i.e. primarily via proteolytic catabolism throughout
the body, including endothelial cells, and does not rely primarily on
elimination through the kidneys and liver. Binding of the IgG to the FcRn
receptor result in protection from cellular metabolism and the long terminal
half-life. According to the two-compartmental model of pharmacokinetics, the
elimination half-life is about 18 days for females and 20 days for males.

Drug Target and Mechanism of Action:

Bevacizumab
Avastin works in such a way that it inhibits the molecules of VEGF and binds
them to their soluble receptors in the cells of endothelium. A tumor often
undergoes what is called an “angiogenic switch”, which is the stimulation of
the growth of new blood vessels. Tumors can do this by their ability to release
VEGF (Vascular Endothelial Growth Factor). Studies show about 60% of malignant
tumours express VEGF. A selective antibody designed to inhibit VEGF is the
answer for stopping blood vessel growth, which is Bevacizumab. The drug works
by preventing the isoforms of VEGF and other inhibitors from binding themselves
into the cell receptors in the endothelium. 6 When
the VEGF cell activities are weakened and reduced, the vascular permeability
and the angiogenesis are inhibited. In the end, the tumors are prevented from
increasing in size and are eventually destroyed. 

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