polatuzumab vedotin

Action and Spectrum

Actions and Spectrum: 

polatuzumab vedotin’s mechanism of action involves two main components: 

• Monoclonal antibody: polatuzumab vedotin contains a monoclonal antibody that targets a protein called CD79b. CD79b is a component of the B-cell receptor complex found on the surface of B cells, including malignant B cells in non-Hodgkin lymphoma. 
• Cytotoxic Payload: A potent cytotoxic drug called vedotin is attached to the monoclonal antibody. The drug is a microtubule-disrupting agent that interferes with the formation and function of microtubules, essential structures for cell division and growth. 

Upon administration, polatuzumab vedotin binds to the CD79b protein on the surface of B cells. This binding triggers the internalization of the polatuzumab vedotin complex into the B cells, resulting in the release of the cytotoxic vedotin drug inside the cells.  

The cytotoxic agent disrupts the microtubules and induces apoptosis (programmed cell death) in the B cells, destroying the cancerous cells. It is primarily indicated for treating diffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin lymphoma. It is specifically used with other drugs, such as rituximab (another monoclonal antibody) and chemotherapy agents, like bendamustine. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Creatinine increased (87%) 

Neutrophil count decreased, grade ≥3 (61%) 

Platelet count decreased (76%) 

Neutropenia (49%) 

Anemia (47%) 

Lymphocyte count decreased (87%) 

Neutrophil count decreased (78%) 

Hemoglobin decreased (78%) 

Thrombocytopenia (49%) 

Upper respiratory tract infection (13%) 

Dizziness (13%) 

Herpes virus infection (12%) 

Lymphopenia (13%) 

Hypoalbuminemia (13%) 

Lower respiratory tract infection (10%) 

Hypocalcemia (11%) 

1-10% 

Calcium decreased, grade ≥3 (9%) 

Lipase increased, grade ≥3 (9%) 

Phosphorus decreased, grade ≥3 (7%) 

Elevated transaminase (7%) 

Arthralgia (7%) 

Hypokalemia, grade ≥3 (9%) 

Hypophosphatemia (9%) 

Potassium decreased, grade ≥3 (7%) 

Pancytopenia (7%) 

Lipase increase (7%) 

Black Box Warning

Black box warning: 

None 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

• Hypersensitivity: It is contraindicated in patients with known hypersensitivity or severe allergic reactions to this medication or its components. 
• Hepatic Impairment: It has not been studied in patients with severe hepatic impairment, and its use is not recommended in this population. 

Caution: 

• Infusion Reactions: Like many monoclonal antibodies, polatuzumab vedotin may cause infusion reactions ranging from mild to severe. These reactions may include fever, chills, rash, itching, difficulty breathing, and changes in blood pressure.  
• Hematologic toxicity: polatuzumab vedotin can cause significant hematologic toxicity, including neutropenia (low levels of neutrophils, a type of white blood cell) and thrombocytopenia (low levels of platelets).  
• Infections: polatuzumab vedotin may increase the risk of bacterial, viral, and fungal infections. Patients should be monitored for signs and symptoms of infection, and appropriate antimicrobial therapy should be initiated as needed. 
• Hepatotoxicity: polatuzumab vedotin has been associated with liver toxicity. Liver function should be monitored regularly during treatment, and the drug should be used cautiously in patients with pre-existing liver disease. 
• Progressive Multifocal Leukoencephalopathy (PML): PML is a rare and potentially fatal viral brain infection reported in patients treated with other monoclonal antibodies.  
• Tumor Lysis Syndrome: polatuzumab vedotin can rapidly break up cancer cells, which may release large amounts of cell contents into the bloodstream. This can cause tumor lysis syndrome, a potentially life-threatening condition characterized by metabolic disturbances.  
• Embryo-Fetal Toxicity: It can harm a developing fetus; effective contraception should be used during treatment and for a certain period after the last dose of polatuzumab vedotin.

Pregnancy / Lactation

Pregnancy consideration: It may cause harm to the developing fetus and is not recommended for use during pregnancy. 

Lactation: Excretion of the drug in human breast milk is unknown 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

• Monoclonal antibody: polatuzumab vedotin contains a monoclonal antibody that targets the CD79b protein, which is present on the surface of B cells, including malignant B cells in non-Hodgkin lymphoma. 
• Antigen Binding: The monoclonal antibody in polatuzumab vedotin specifically binds to the CD79b protein on the surface of B cells. This binding is highly selective for cancerous B cells and allows for targeted cytotoxic drug delivery. 
• Internalization: Once bound to the CD79b protein, polatuzumab vedotin is internalized into the B cells through receptor-mediated endocytosis. 
• Cytotoxic Payload: Attached to the monoclonal antibody is a potent cytotoxic drug called vedotin (also known as MMAE). vedotin is a microtubule-disrupting agent that inhibits microtubule assembly, leading to cell cycle arrest and apoptosis (programmed cell death) in the targeted B cells. 
• Payload Release: Once inside the B cell, the linker connecting the monoclonal antibody to the cytotoxic payload is cleaved, releasing the vedotin drug. 
• Apoptosis Induction: The released vedotin interferes with microtubule function, disrupting cellular structures essential for cell division and growth. This disruption triggers a cascade of events that ultimately leads to apoptosis, causing the targeted B cell to die. 
• Immune Response Enhancement: polatuzumab vedotin activates the immune system, promoting antibody-dependent cellular cytotoxicity (ADCC) and cellular phagocytosis (ADCP). These mechanisms involve activating immune cells, such as natural killer (NK) cells and macrophages, to recognize and destroy the antibody-bound cancer cells. 

Pharmacokinetics: 

Absorption 

Peak plasma concentration of acMMAE (the active form of vedotin): 803 ng/mL 

Peak plasma concentration of unconjugated MMAE: 6.82 ng/mL 

AUC (Area Under the Curve) of acMMAE: 1860 ng·day/mL 

AUC of unconjugated MMAE: 52.3 ng·day/mL 

The peak plasma concentration and AUC values provide insights into the drug’s exposure and concentration in the bloodstream after administration. 

Distribution 

Volume of Distribution (Vd) based on population pharmacokinetic analysis: 3.15 L for acMMAE 

Protein binding (human) for MMAE (the cytotoxic payload): Approximately 71-77% 

The volume of distribution indicates the apparent space in the body where the drug is distributed, and the protein binding percentage reflects the extent to which the cytotoxic MMAE is bound to proteins in the bloodstream. 

Metabolism 

polatuzumab vedotin’s metabolism has not been studied in humans. 

It is expected to undergo catabolism (breakdown) to small peptides, amino acids, unconjugated MMAE, and related catabolites. 

The drug is anticipated to be broken down into smaller molecules through metabolic processes, ultimately eliminating its components. 

MMAE, the cytotoxic payload, is a substrate of the enzyme CYP3A4, which means this enzyme in the liver metabolizes it. 

Elimination and Excretion 

Half-life of acMMAE at Cycle 6: Approximately 12 days 

Half-life of unconjugated MMAE around 4 days after the first infusion 

Clearance: 0.9 L/day 

Adminstartion

Administration: 

The administration of polatuzumab vedotin should follow specific guidelines to ensure patient safety and optimize the efficacy of the treatment.  

Initial Dose Infusion: 

• Infuse the initial dose over 90 minutes. 
• Use a dedicated infusion line to avoid mixing with other medications. 
• During infusion, use a sterile, nonpyrogenic, low-protein binding in-line or add-on 0.2- or 0.22-micron filter. 

Monitoring: 

• During the initial dose infusion, closely monitor the patient for any signs of infusion-related reactions. These may include fever, chills, rash, itching, difficulty breathing, or changes in blood pressure. 
• Continue monitoring for a minimum of 90 minutes after completing the initial infusion. 

Subsequent Dose Infusions: 

• If the patient tolerates the initial infusion rate without significant reactions, subsequent doses may be infused over 30 minutes. 
• Monitor the patient during the subsequent dose infusion and at least 30 minutes after completion. 

Avoid IV Push or Bolus: 

polatuzumab vedotin should not be administered as an IV push or bolus. It should only be given as an intravenous infusion over the specified duration. 

Do Not Mix or Infuse with Other Medications: 

Do not mix or infuse polatuzumab vedotin with other medications in the same infusion line or container to avoid potential interactions or incompatibilities. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: polatuzumab vedotin 

Why do we use polatuzumab vedotin? 

polatuzumab vedotin is used to treat certain types of non-Hodgkin lymphoma, particularly in combination with other drugs. Its primary use is for treating diffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin lymphoma. 

polatuzumab vedotin is typically used in combination with the following medications: 

• rituximab: rituximab is another monoclonal antibody that targets the CD20 protein found in B cells. The combination of polatuzumab vedotin and rituximab enhances the effectiveness of the treatment by targeting different antigens on the surface of B cells. 
• bendamustine: bendamustine is a chemotherapy agent that damages the DNA of cancer cells, leading to cell death. Combining polatuzumab vedotin with bendamustine further enhances the treatment’s cytotoxic effects. 

This combination therapy is used in adult patients with relapsed or refractory DLBCL who are not eligible for a stem cell transplant or have received at least two prior therapies.