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General Description:

Polatuzumab vedotin, identified by CAS number 1313206-42-6, is a notable compound with significant therapeutic applications. Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that delivers monomethyl auristatin E (MMAE), an anti-mitotic agent, to cancer cells. The drug consists of three components - a humanized immunoglobulin G1 (IgG1) monoclonal antibody specific for human CD79b (polatuzumab), MMAE, and protease-cleavable linker called maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PAB) that covalently attaches MMAE to polatuzumab. Polatuzumab vedotin was granted accelerated FDA approval on June 10, 2019 and was approved by Health Canada on July 9, 2020.

Indications:

This drug is primarily indicated for: In the US, polatuzumab vedotin is used in combination with and to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, after at least two prior therapies. In Canada, this indication is approved for patients who are not eligible for autologous stem cell transplant and have received at least one prior therapy. In Canada, polatuzumab vedotin is also used in combination with , , , and (R-CHP) to treat adult patients with previously untreated large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), high grade B-cell lymphoma, Epstein-Barr viruspositive (EBV+) DLBCL NOS, and T-cell/histiocyte rich LBCL. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Polatuzumab vedotin undergoes metabolic processing primarily in: Polatuzumab vedotin is expected to undergo catabolism into small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. MMAE is metabolized by CYP3A4/5. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Polatuzumab vedotin are crucial for its therapeutic efficacy: After the first polatuzumab vedotin dose of 1.8 mg/kg, the mean (± SD) C_max of antibody-conjugated MMAE and unconjugated MMAE were 803 (± 233) ng/mL and 6.82 (± 4.73) ng/mL, respectively. The mean AUC_inf of antibody-conjugated MMAE and unconjugated MMAE were 1860 (± 966) day x ng/mL and 52.3 (± 18.0) day x ng/mL, respectively. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Polatuzumab vedotin is an important consideration for its dosing schedule: The terminal half-life of polatuzumab vedotin is approximately 12 days (95% CI: 8.1 to 19.5 days) at Cycle 6. The terminal half-life of unconjugated MMAE is approximately four days after the first dose of polatuzumab vedotin. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Polatuzumab vedotin exhibits a strong affinity for binding with plasma proteins: MMAE is 71% to 77% bound to plasma proteins. Its blood-to-plasma ratio is 0.79 to 0.98, _in vitro_. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Polatuzumab vedotin from the body primarily occurs through: Polatuzumab vedotin is predominantly excreted in feces, as well as in urine to some extent. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Polatuzumab vedotin is distributed throughout the body with a volume of distribution of: The estimated central volume of distribution of polatuzumab vedotin based on population PK analysis is 3.15 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Polatuzumab vedotin is a critical factor in determining its safe and effective dosage: The predicted clearance of polatuzumab vedotin is 0.9 L/day. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Polatuzumab vedotin exerts its therapeutic effects through: Polatuzumab vedotin is an anti-cancer agent that works to cause apoptosis in malignant B cells. _In vitro_, it exerted cytotoxic effects on most diffuse large B-cell lymphoma (DLBCL) cell lines: this effect was consistent across cell lines, regardless of the cell-of-origin subtypes and whether they harboured mutations in the _CD79B_ gene or not. In mouse xenograft models, polatuzumab vedotin caused apoptosis and reduced proliferation of mature CD79b+ B-cell NHL cell lines. Polatuzumab vedotin can cause immunosuppression, including neutropenia and thrombocytopenia. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Polatuzumab vedotin functions by: Polatuzumab vedotin is an antibody-drug conjugate consisting of a CD79b-directed antibody, a microtubule-disrupting agent called monomethyl auristatin E (MMAE), and a cleavable linker that holds the components together. CD79 is a heterodimer composed of CD79a and CD79b. Responsible for signal transduction, CD79 forms a complex with the B cell receptor (BCR) and is almost exclusively expressed on B cells, including malignant B cells. Most importantly, CD79b gained increasing attention as a promising therapeutic target as it plays an essential role in BCR expression, transport, and functions such as B cell proliferation and differentiation. Once the antibody component binds to CD79b, polatuzumab vedotin is internalized, and lysosomal proteases cleave the linker to release MMAE in the cell. MMAE is a microtubule-disrupting anti-mitotic agent that exerts cytotoxic effects against malignant B cells. It binds to microtubules, inhibits mitosis by interfering with tubulin and tubulin polymerization, and induces apoptosis in dividing B cells. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Polatuzumab vedotin belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Polatuzumab vedotin is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antibody-drug Conjugates, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, Blood Proteins, Cancer immunotherapy, CD79b-directed Antibody–Drug Conjugates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 Substrates, Globulins, Immunoglobulins, Immunologic Factors, Immunoproteins, Immunotherapy, MONOCLONAL ANTIBODIES AND ANTIBODY DRUG CONJUGATES, Noxae, P-glycoprotein substrates, Proteins, Serum Globulins, Toxic Actions. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Polatuzumab vedotin include:

• Molecular Weight: 150000.0
• Molecular Formula: C6670H10317N1745O2087S40