1. FILGRASTIM C845H1343N223O243S9 18.8 kDa ID DB00099 GROUP
Immunosuppressive Agents /Antineutropenic Agents/Hematopoietic Agents

2. DESCRIPTION
Filgrastim is a recombinant, non-pegylated human granulocyte colony stimulating factor (G-CSF) analogue manufactured by recombinant DNA technology using a strain of E. coli. It is marketed as the brand name Neupogen by Amgen. Chemically, it consists of 175 amino acid residues. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis, except for the addition of an N-terminal methionine necessary for expression in E coli. Tbo-filgrastim, which is marketed by Sicor Biotech and FDA approved on August 29, 2012, contains the same active ingredient as Neupogen and is biologically similar, but it is formulated to be short-acting.
INDICATION
Filgrastim is used in patients with acute myeloid leukemia receiving induction or consolidation chemotherapy. It is also used in cancer patients receiving bone marrow transplant. In general, filgrastim increases neutrophil counts in order to decrease the risk of infection or duration of neutropenia in the aforementioned patient populations. Infection and neutropenia are adverse events associated with chemotherapy. Furthermore, filgrastim is also indicated for patients with severe chronic neutropenia. It mobilizes hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis to allow for a more rapid engraftment. Tbo-filgrastim has a narrower indication profile than Neupogen - it is a leukocyte growth factor indicated for the reduction in the duration of severe neutropenia in patients with non-myeloid malignancies.

3. PHARMACODYNAMICS
Used in the treatment of chemotherapy-induced neutropenia by enhancing the production of neutrophils. Filgrastim acts on hematopoietic cells by binding to specific cell surface receptors thereby stimulating proliferation, differentiation, commitment, and end cell functional activation. When tbo-filgrastim is administered to cancer patients, it took 3-5 days to reach maximum absolute neutrophil count (ANC). Levels of neutrophils returned to baseline by 21 days following completion of chemotherapy. In the healthy volunteer trials, doubling the tbo-filgrastim subcutaneous dose from 5 to 10 mcg/kg resulted in a 16-19% increase in the ANCmax and a 33-36% increase in the area under the effect curve for ANC.
MECHANISM OF ACTION
Filgrastim binds to the G-CSF receptor and stimulates the production of neutrophils in the bone marrow. As a G-CSF analog, it controls proliferation of committed progenitor cells and influences their maturation into mature neutrophils. Filgrastim also stimulates the release of neutrophils from bone marrow storage pools and reduces their maturation time. Filgrastim acts to increase the phagocytic activity of mature neutrophils. In patients receiving cytotoxic chemotherapy, Filgrastim can accelerate neutrophil recovery, leading to a reduction in duration of the neutropenic phase

4. ABSORPTION
Absorption and clearance of Neupogen follows first-order pharmacokinetic modeling without apparent concentration dependence. When 3.45 mcg/kg and 11.5 mcg/kg of Neupogen is subcutaneously administered, the maximum serum concentration is 4 and 49 ng/mL‚ respectively‚ within 2 to 8 hours. Neupogen does not accumulate. It is estimated that when filgrastim is subcutaneously administered, the absolute bioavailability is approximately 62% and 71% for 375 mcg and 750 mcg doses respectively. When 5 mcg/kg tbo-filgrastim is subcutaneously administered, the absolute bioavailability is 33%. It takes 4-6 hours for tho-filgrastim to reach maximum concentration. Like Neupogen, accumulation was not observed.
HALF-LIFE
Elimination half-life, healthy subjects and cancer patients, Neopogen = 3.5 hours; Elimination half-life, cancer patients, tbo-filgrastim = hours
ROUTE OF ELIMINATION
Filgrastim is primarily eliminated by the kidney and neutrophils/neutrophil precursors; the latter presumably involves binding of the growth factor to the G-CSF receptor on the cell surface, internalization of the growth factor-receptor complexes via endocytosis, and subsequent degradation inside the cells.
VOLUME OF DISTRIBUTION = 150 mL/kg
CLEARANCE = mL/minute/kg (SC administration of 3.45 mcg/kg and 11.5 mcg/kg in both normal subjects and cancer patients, Neupogen)

5. SIDE EFFECTS
redness, swelling, bruising, itching or a lump at site of injection
bone, joint, or muscle pain
headache
nosebleeds
pain in the left upper part of the stomach or the tip of the left shoulder
fever
shortness of breath
trouble breathing
fast breathing
wheezing
dizziness
sweating
hives
rash
itching
swelling around the mouth or eyes
unusual bruising or purple markings under the skin

6. SEQUENCE
MTPLGPASSLPQSFLLKCLEQVRKIQGDGAALQEKLCATYKLCHPEELVLLGHSLGIPWAPLSSCPSQALQLAGCLSQLHSGLFLYQGLLQALEGISPELGPTLDTLQLDVADFATTIWQQMEELGMAPALQPTQGAMPAFASAFQRRAGGVLVASHLQSFLEVSYRVLRHLAQP
TARGETS
Granulocyte colony-stimulating factor receptor,Neutrophil elastase

7. NEUPOGEN
DESCRIPTION
NEUPOGEN® is a 175 amino acid protein manufactured by recombinant DNA technology.1 NEUPOGEN® is produced by Escherichia coli (E coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene. NEUPOGEN® has a molecular weight of 18‚800 daltons. The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis‚ except for the addition of an N-terminal methionine necessary for expression in E coli. Because NEUPOGEN® is produced in E coli‚ the product is nonglycosylated and thus differs from G-CSF isolated from a human cell.
INDICATION
NEUPOGEN® (filgrastim) is a prescription medication used to reduce the risk of infection in patients with some tumors, who are receiving strong chemotherapy that may cause severe neutropenia with fever. Your doctor will do blood tests to monitor your blood cell counts before and during your treatment with NEUPOGEN®.

8. DOSAGE
Continuous 24-hour IV infusions of 20 mcg/kg over an 11- to 20-day period produced steady-state serum concentrations of NEUPOGEN® with no evidence of drug accumulation over the time period investigated. Pharmacokinetic data in geriatric patients ( ≥ 65 years) are not available.
VARIATION
methionylated and non-glycosylated
HALF LIFE 3.5 h
FORMULATION
The single use vials contain either 300 mcg or 480 mcg Filgrastim at a fill volume of 1.0 mL or 1.6 mL, respectively. The single use prefilled syringes contain either 300 mcg or 480 mcg Filgrastim at a fill volume of 0.5 mL or 0.8 mL, respectively.

9. WARNING
Do not take NEUPOGEN® if you are allergic to NEUPOGEN® or any of its ingredients. Do not take NEUPOGEN® if you are allergic to other medicines made using the bacteria E coli. Ask your doctor if you are not sure.
NEUPOGEN® may reduce your chance of getting an infection, but it does not prevent all infections. An infection can happen anytime you or your child’s neutrophil counts are low. Look for signs of infection, such as fever, chills, rash, sore throat, diarrhea, or redness, swelling, or pain around a cut or sore. If you or your child have any of these signs, contact your healthcare professional immediately.
NEUPOGEN® can cause serious allergic reactions. These reactions can cause a rash over the whole body, shortness of breath, wheezing, dizziness, swelling around the mouth or eyes, fast pulse, and sweating. If you start to have any of these symptoms, stop using NEUPOGEN® and call your doctor or seek emergency care right away. If you have an allergic reaction during the injection of NEUPOGEN®, stop the injection right away.

10. Your spleen may become enlarged and can rupture while taking NEUPOGEN®
Your spleen may become enlarged and can rupture while taking NEUPOGEN®. A ruptured spleen can cause death. The spleen is located in the upper left section of your stomach area. Call your doctor right away if you have pain in the left upper stomach area or left shoulder tip area. This pain could mean your spleen is enlarged or ruptured.
A serious lung problem called acute respiratory distress syndrome (ARDS) has been reported with NEUPOGEN® use. Call your doctor or seek emergency care right away if you have shortness of breath, trouble breathing, or a fast rate of breathing.
If you have a sickle cell disorder, make sure that you tell your doctor before you start taking NEUPOGEN®. If you have a sickle cell crisis after getting NEUPOGEN®, tell your doctor right away.
Talk to your doctor if you experience unusual bleeding or bruising while taking NEUPOGEN®, as this could mean a decrease of platelets which reduces the ability of blood to clot.
The most common side effect you may experience is aching in the bones and muscles. This aching can usually be relieved by taking a non-aspirin pain reliever such as acetaminophen.
Some people experience redness, swelling, or itching at the site of injection. This may be an allergy to the ingredients in NEUPOGEN®, or it may be a local reaction. If you notice any signs of a local reaction, call your doctor.

11. PATENTS
NUMBER COUNTRY APPROVED EXPIRES
Canada
Canada
REFERENCES