Plerixafor Injection - Indications, Dosage, Side Effects, Drug Warnings, and Precautions

Overview

Plerixafor belongs to the class of hematopoietic stem cell (blood-forming cells) mobilizers. It is administered before performing stem cell transplantation. It enhances the movement of the stem cells (mobilization) from the bone marrow into peripheral blood circulation. It was approved by the FDA (the United States Food and Drug Administration) on December 15th, 2008, for mobilizing patients’ own stem cells followed by its collection before stem cell transplantation in patients diagnosed with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). CXCR4 chemokine receptor is a protein that holds white blood cells in the blood marrow. Plerixafor is a potent CXCR4 chemokine receptor blocker and is used along with the granulocyte colony-stimulating factor (a protein that helps to produce white blood cells) to increase the release of hematopoietic stem cells from the bone marrow.

Plerixafor is a bicyclam derivative and an azamacrocycle (nitrogen-containing) compound constituting two cyclam rings that are connected by a 1,4-phenylene-bis (methylene) linking bond. It also acts as an immunological adjuvant (modulates immune response) and an antineoplastic agent. It blocks C-X-C chemokine receptor type 4 (a protein involved in viral replication) and exhibits anti-HIV activity. Structurally, it is a tertiary amino compound and belongs to the family of benzenes. Plerixafor is evidently well tolerated and does not cause liver injury.

What Are the Uses of Plerixafor Injection?

Plerixafor is used for releasing hematopoietic stem cells into peripheral blood circulation. Some of its indications are as follows -

• It is used in combination with granulocyte-colony stimulating factor (G-CSF).

• To collect hematopoietic (blood-forming) stem cells that are needed for autologous (own stem cells) transplantation in cancer patients.

• It is indicated in patients having cancers such as multiple myeloma and non-Hodgkin's lymphoma.

• Indicated for patients who require hematopoietic stem cell transplantation for treating certain types of blood cancers (hematological malignancies).

Contraindications

No significant contraindications are present with the use of Plerixafor. In some conditions, it is avoided due to potential risk possibilities. These contraindications are as follows -

• Known history of developing hypersensitivity to Plerixafor.

• In pregnant women due to fetal harm.

Available Dosage Forms and Strengths

• Plerixafor injection is a preservative-free, clear (colorless to pale yellow), sterile, isotonic solution containing 20 mg (milligram) of Plerixafor in each 1 mL (milliliter) of the solution.

• Plerixafor is available in liquid (injectable) form as a single-use vial that contains 1.2 mL of a solution.

• 20 mg of Plerixafor is present per mL solution (20 mg/mL).

Storage and Handling

• Plerixafor is delivered as single-use vials containing 24 mg (1.2 mL of 20 mg/mL) of Plerixafor.

• It is stored at a controlled room temperature of 25° Celsius (77° Fahrenheit) with permitted variations between 15° to 30°C (59° to 86°F).

• Each vial is strictly intended for only single use.

• Any remaining unused drug after injection is discarded.

Dosage and Administration

• Route of Administration - Subcutaneous injection.

• Recommended Dose - 0.24 mg/kg (milligram/kilogram) body weight for subcutaneous (SC) injection.

The actual body weight of the patient is estimated to calculate the volume of Plerixafor solution to be injected subcutaneously.

• Calculation - 0.012 X actual body weight of the patient (kg) = volume of Plerixafor to be administered (mL).

The maximum dose of Plerixafor should not exceed more than 40 mg per day.

• The Recommended Dose of Concomitantly Administered Drug - 10 micrograms/kg of granulocyte colony-stimulating factor (G-CSF) is given as the morning dose prior to the evening dose of Plerixafor for four days and also on every single day before the apheresis procedure.

Plerixafor is administered subcutaneously by injection nearly 11 hours before initiation of apheresis.

• In Case of Renal Impairment - Plerixafor is adjusted according to creatinine clearance value. If creatinine clearance is less than 50 mL/min, the Plerixafor dose is lowered by one-third up to 0.1 6 mg/kg.

The daily dose should not exceed 27 mg when calculated according to the patient’s body weight in renal impairment.

If creatinine clearance is more than 50 mL/min, Plerixafor is reduced to 0.24 mg/kg once daily, not exceeding 40 mg/day when calculated to the body weight of the patient.

What Are the Warnings and Precautions for Plerixafor?

Generally, Plerixafor subcutaneous injection is well tolerated, however, it contains certain warnings and precautions to be followed with special clinical consideration.

• Risk of mobilizing tumor cells in patients with leukemia as the use of leukemic cells is contraindicated in hematopoietic stem cell (HSC) transplant.

• Risk of hematologic abnormalities resulting in Increased circulating white blood cells (leukocytes) and reduced platelet counts.

• A potential risk for the occurrence of splenic rupture.

• Use of Plerixafor in pregnancy could lead to harmful effects on the fetus.

For Patients

What Is Hematopoietic Stem Cell Transplantation?

Hematopoietic stem cell transplant (HSCT), commonly known as stem cell transplant, is a therapeutic procedure where healthy hematopoietic (blood-forming tissue) stem cells from the donor’s bone marrow are transplanted into the recipient’s bone marrow that has abnormal or decreased activity. This helps to improve the bone marrow function in the recipient and leads to the regeneration of functional hematopoietic cells.

Hematopoietic cell transplantation is broadly classified into two types, namely autologous transplant and allogeneic transplant. In an autologous stem cell transplant, the patient's own bone marrow stem cells are used as donor tissue, and in an allogeneic stem cell transplant, the donor's bone marrow stem cells belong to another healthy donor.

Autologous stem cell transplants are advantageous since the patient’s own cells are used, which reduces the risk of tissue or graft rejection. The initial steps in autologous stem cell transplants involve the harvesting of the patient’s own stem cells. The stem cells are removed from the bone marrow or peripheral blood and stored by freezing it until further use following chemotherapy or radiation therapy.

Autologous stem cell transplants are primarily effective in treating certain types of leukemia and lymphomas, as well as multiple myeloma. These transplants are recommended for the treatment of cancers such as testicular cancer, neuroblastoma, and common cancers that occur in children. The use of autologous transplants is also recommended in autoimmune disorders like multiple sclerosis (MS), systemic lupus erythematosus (lupus), and systemic sclerosis.

How Is Plerixafor Effective in Autologous Stem Cell Transplants?

Autologous hematopoietic stem cell (HSC) transplants are effective treatment interventions for non-Hodgkin's lymphoma and multiple myeloma patients. The major source for these stem cells is the peripheral circulating blood, which needs to be mobilized from the bone marrow. Plerixafor enhances the effective mobilization of these hematopoietic stem cells in the following ways -

• Cytokines (special proteins that control the activity of immune cells and also blood cells) like G-CSF and chemotherapy are recent regimens for mobilizing stem cells.

• However, these agents are unable to increase the HSC mobilization due to the activity of chemokine receptor CXCR4 (C-X-C Chemokine Receptor 4) with its ligand CXCL (chemokine C-X-C motif ligand) 12.

• These receptors favor the retention of hematopoietic stem cells in the bone marrow tissue.

• Plerixafor a target-specific selective inhibitor of CXCR4, which increases the mobilization of stem cells needed for autologous transplantation.

• It rapidly moves the stem cells from the bone marrow to the blood circulation peripherally within a few hours.

• These mobilized cells are collected by apheresis (the process of separating cellular components present in the blood) and used for autologous hematopoietic stem cell transplantation.

What Are the Adverse Side Effects of Plerixafor?

The majority of the adverse reactions are reported during the use of Plerixafor along with G-CSF and also during an overdose of Plerixafor. Some of the commonly occurring adverse side effects are as follows -

• Diarrhea.

• Nausea.

• Fatigue

• Injection site reactions (irritation and pain).

• Headache.

• Arthralgia (pain in the shoulder joints).

• Dizziness.

• Vomiting.

• Abdominal pain.

• Insomnia.

• Erythema (skin reaction causing redness).

• Hematoma (swelling due to collection of blood clots).

• Hemorrhage (excessive bleeding).

• Induration (hardening of skin tissues) and inflammation (immune response causing swelling and pain).

• Paresthesia (change in sensations like pricking or burning especially in hands and feet).

• Pruritus (itching and irritation in the skin).

• Rash and urticaria (rashes causing itchiness with swelling).

• Swelling.

What Are the Precautions to Be Followed During Administration of Plerixafor Injection?

Plerixafor injection is a therapeutic intervention, and adequate precautions should be followed for the safety and efficacy of the therapy. Some of the important precautionary measures are as follows -

• Vials of Plerixafor should be clear and particle free. They should be visually inspected for the presence of any particulate matter or discoloration before administration and discarded if there is any particulate matter present or noticeable discoloration.

• Patients should be given prior counseling regarding the safety, expected outcome, and also potential side effects of the injection.

• Women who are of reproductive potential should be informed about the potentially harmful effects of Plerixafor on the fetus and to avoid pregnancy during the treatment duration.

• Patients should be informed about the signs and symptoms of injection reactions and other side effects like gastrointestinal disturbances and should be advised to report to the doctor immediately if adverse reactions occur.

For Doctors

Clinical Pharmacology of Plerixafor

Pharmacodynamics

Plerixafor is an immunostimulant that acts as a CXCR4 antagonist. Hematopoietic stem cells show a unique expression of the CD34 marker. Plerixafor elevates blood levels of CD34+ (cluster of differentiation) cells in patients with non-Hodgkin’s lymphoma and multiple myeloma, along with the combined effects of G-CSF in the peripheral blood. The peak mobilization of CD34+ cells was observed between six to nine hours after Plerixafor administration. In healthy volunteers, Plerixafor causes a sustained elevation of the CD34+ count in the peripheral blood after 4 to 18 hours of administration and a peak CD34+ count ranging from 10 to 14 hours.

Mechanism of Action

• Plerixafor blocks the CXCR4 chemokine receptor activity binding to its cognate ligands such as stromal cell-derived factor (SDF-1a) and CXCR4.

• CXCR4 is essential for controlling the trafficking and recruiting of human hematopoietic stem cells (HSCs) to remain inside the bone marrow compartment.

• Once inside the marrow, CXCR4 on the stem cells anchors them to the bone marrow matrix through SDF-1a factors.

• Administering Plerixafor results in leukocytosis and prevents the binding of stem cells to the matrix, resulting in the release of stem cells into the blood circulation.

• Elevated levels of HSCs in circulating blood occur due to the inhibitory effects of Plerixafor on the chemokine CXCR4 receptor.

Pharmacokinetics:

The pharmacokinetic profile of Plerixafor follows a two-compartment distribution model associated with first-order absorption. This means that the distribution of Plerixafor is not uniform in all the tissues and body fluids. Its distribution is compartmentalized and specific to the target tissues.

Absorption:

• Peak plasma concentrations of Plerixafor occur within 30 to 60 minutes following subcutaneous administration.

• The central volume of distribution depends on the body weight of the individual.

• Its half-life is nearly 0.3 hours with the terminal population half-life of 5.3 hours in individuals with normal renal functioning.

Distribution

• 58 % of Plerixafor binds with human plasma proteins.

• The volume of distribution is estimated to be 0.3 L/kg and is predominantly distributed in the extravascular fluid space.

Metabolism

• Plerixafor is not metabolized in the liver and does not affect the activity of cytochrome P450 enzymes.

• Thus Plerixafor does not cause potential cytochrome P450-dependent drug interactions.

Elimination

• The primary route of elimination is by kidneys through urine.

• Nearly 70 percent of the dose, in the form of the parent drug, is excreted during the first 24 hours of administration.

• In renal impairment, its elimination is reduced and hence requires dose reduction in such cases.

Clearance

• Total plasma clearance for Plerixafor is 4.38 L/h and renal clearance is found to be 3.15 L/h.

Toxicities

Plerixafor is a well-tolerated immunostimulant that is associated with minimal toxicities. Excessive mobilization of stem cells or overdosage of Plerixafor would induce certain toxic side effects. Some of the reported toxicities of Plerixafor are as follows -

• Anaphylactic shock.

• Hypersensitivity reactions.

• Mobilization of tumor cells particularly in leukemia patients.

• Leukocytosis (increased count of white blood cells).

• Thrombocytopenia (decreased platelet count).

• Splenomegaly (enlargement of the spleen).

• Splenic rupture.

• Abnormal sleep disturbances.

• Fetal risk if used during pregnancy.

• Vasovagal reactions.

• Orthostatic hypotension.

• Syncope.

• Oral hypoesthesia.

• Constipation.

• Dyspepsia.

• Musculoskeletal pain.

• Urticaria.

• Periorbital swelling.

• Dyspnea.

• Hypoxia.

Drug-Drug Interactions

Plerixafor is not a substrate molecule and thereby does not inhibit or induce liver cytochrome

P450 isozymes. Hence, drug-drug interactions involving cytochrome P450s do not occur in Plerixafor injection. Some of the drug interactions with concomitantly used drugs are as follows -

• In concomitant use along with Filgrastim, tumor cells are released from the bone marrow and get collected as leukapheresis products. This leads to potential tumor cell reinfusion.

• Plerixafor when used concomitantly with G-CSF increases the risk of hyperleukocytosis.

• Medications that are used in lowering renal function (vasopressin) and actively competing for tubular secretion (Acetaminophen) lead to elevated plasma concentrations of Plerixafor.

Conclusion:

Autologous stem cell transplantation is a promising therapeutic intervention for treating non-Hodgkin's lymphoma, multiple myeloma, and patients with other types of malignancies. Mobilization of hematopoietic stem cells is crucial for transplants. The use and efficacy of Plerixafor have provided added advantages in autologous stem cell transplantation.