Pegfilgrastim

Pegfilgrastim is a biotechnologically produced protein from the bacterium Escherichia coli and is used in the context of cancer in patients who are being treated with chemotherapy. However, in the course of this therapy option, which now helps patients to achieve good survival rates, not only the rapidly dividing tumor cells are attacked, but also healthy cells in the tissue, such as the blood cells. As a result, many patients experience blood count changes and develop neutropenia, a deficiency of neutrophil blood cells that serve as part of the innate immune defense system to eliminate pathogens such as bacteria and viruses, in the course of chemotherapy. The risk of infections is significantly increased by such a deficiency. A possible consequence is then the occurrence of neutropenic fever, which can be fatal.

Pegfilgrastim is derived from filgrastim, which is also a biotechnologically produced protein, forming its pegylated form with a lower molecular mass. Both mimic G-CSF, the body's granulocyte colony-stimulating factors. These are endogenous peptide hormones that are secreted, for example, during inflammation to stimulate the formation of white blood cells for defense. As cytokines, they stimulate the maturation and differentiation of neutrophil granulocytes and their release from the bone marrow into the blood, and also improve their function.

Applications and indications

Pegfilgrastim is administered as a solution for injection(Neulasta®) as a substitute for G-CSF in the body, as these are very sensitive in the context of chemotherapy and are quickly eliminated. In this context, pegfilgrastim as an active ingredient supports the formation of new neutrophil granulocytes in the bone marrow.

Neulasta® can be injected either by medical personnel or by oneself, but prior consultation with the physician and following his instructions is essential. It is administered once subcutaneously (under the skin) no earlier than 24 hours after the last dose of chemotherapy. The usual dose is 6mg in a pre-filled syringe.

This application is for adults who are at least 18 years old.

Pegfilgrastim is also available under the trade names Pelmeg®, Pelgraz®, and Ziextenzo® as a 6mg solution for injection in a prefilled syringe.

History

The active ingredient pegfilgrastim is an analogue of the previously approved filgrastim and was manufactured to represent a longer-acting variant. Filgrastim is shorter acting with a short half-life, which resulted in more frequent administration of the drug. Thus, a longer-acting form was developed by covalently bonding a PEG (polyethylene glycol) moiety to the N-terminus of filgrastim. Hence, the name pegfilgrastim is composed of PEG and filgrastim. Pegfilgrastim has the same pharmacological effect as filgrastim and differs only in its longer half-life and slower elimination rate, which makes it longer-acting.

The active ingredient was approved by the FDA in 2002.

Pharmacodynamics/mechanism of action

Filgrastim acts as G-CSF by binding to the associated G-CSF receptor. Subsequently, a conformational change of the receptor takes place, initiating intracellular signal transductions that cause processes such as proliferation and maturation of cells. These are located, among others, on the granulocytes, which include the neutrophil granulocytes. In this way, it is possible to react to pathogens within a short period of time.

After binding of pegfilgrastim to the GCR receptor, a significant increase in the number of neutrophil granulocytes in the blood is recorded within 24 hours, whereby the function of the immune system is maintained despite chemotherapy.

Pharmacokinetics

Due to the additional PEG group in pegfilgrastim, compared to filgrastim, the drug is not degraded and renally eliminated after approximately 6-8 hours, but once it has bound to the G-CSF receptor on the target cells, the neutrophils, it is degraded by endocytosis (uptake into the cell) within the cell. This mechanism extends the plasma half-life to up to 80 hours. Thus, a prophylaxis against a possible neutropenia is achieved with only one administration of the drug. Compared to this, filgrastim had to be administered daily until the desired levels of neutrophils in the blood were reached. This could take a period of up to 14 days.

Pegfilgrastim thus eliminates the need for daily injections and blood counts.

Interactions

Concomitant use of Neulasta® with pegfilgrastim as the active ingredient and 5-fluorouracil (5-FU), a cytostatic drug, and other antimetabolites may result in increased myelosuppression (failure of blood formation in the bone marrow).

Otherwise, clinical studies did not reveal any indications of possible interactions with other drugs, as these were not specifically investigated in clinical trials.

Contraindications & precautions

The drug must not be taken in case of hypersensitivity to the active ingredients pegfilgrastim/ filgrastim or to the remaining ingredients of the drug!

In patients with sickle cell disease, administration of pegfilgrastim has been shown to cause sickle cell crisis. Therefore, monitoring of laboratory values and appropriate clinical parameters is required during use.

Side effects

Symptoms that may develop very rapidly and are due to the so-called "capillary leak syndrome":

• Swelling/swelling up
• Difficulty breathing
• Swelling in the area of the abdomen and feeling of fullness
• General fatigue

The side effects of Neulasta® with pegfilgrastim as the active component can be fairly well classified according to frequency and are listed below.

Very common side effects that may occur include bone pain, nausea, and headache.

Common side effects that may occur include:

• Skin rash in the form of itchy, reddish, raised pustules.
• pain at the injection site
• Redness, bleeding, bruising, pain, and discomfort at the injection site
• Joint and muscle pain
• Blood count changes

Occasional side effects that may occur include:

• Symptoms of an allergic reaction such as skin redness, rash, itchy skin areas
• severe allergic reactions including anaphylaxis (weakness, drop in blood pressure, difficulty breathing, swelling of the face)
• spleen enlargement, rupture of spleen
• Respiratory problems
• Sweet syndrome, in which there may be plum-colored, swollen, painful lesions on the limbs and sometimes on the face/neck accompanied by fever
• Coughing up blood (hemoptysis).

Rare side effects that may occur are:

• Inflammation of the aorta (main artery)
• bleeding in the lungs (pulmonary hemorrhage)
• Stevens-Johnson syndrome, in which reddish, target-like or circular patches may appear on the trunk with blisters located in the center, as well as peeling of the skin, ulcers on the mouth/throat/nose/genitals/eyes
  Flu-like symptoms such as fever may also accompany it.

Pregnancy and lactation

There is currently no or very limited experience with the use of pegfilgrastim in pregnant women. Therefore, it is recommended to refrain from taking medicines containing pegfilgrastim during pregnancy.

The same applies to nursing mothers, as it has not been proven whether pegfilgrastim/metabolites can pass into breast milk and thus pose a risk to the child.