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General Description:

Enfortumab vedotin, identified by CAS number 1346452-25-2, is a notable compound with significant therapeutic applications. Enfortumab vedotin is an antibody-drug conjugate used in the treatment of patients with advanced, treatment-resistant urothelial cancers. It is comprised of a fully human monoclonal antibody targeted against Nectin-4 and a microtubule-disrupting chemotherapeutic agent, monomethyl auristatin E (MMAE), joined by a protease-cleavable link. It is similar to , another antibody conjugated with MMAE that targets CD-30 instead of Nectin-4. The clinical development of enfortumab vedotin was the result of a collaboration between Astellas Pharma and Seattle Genetics and it was first approved for use in the United States in December 2019 under the brand name Padcev^TM. Enfortumab vedotin was later approved by the European Commission on April 13, 2022.

Indications:

This drug is primarily indicated for: Enfortumab vedotin is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Enfortumab vedotin undergoes metabolic processing primarily in: The catabolism of enfortumab vedotin has not been studied in humans. Given its structure, it is expected to be catabolized to smaller peptides, amino acids, unconjugated MMAE, and MMAE metabolites. MMAE is released from enfortumab vedotin via proteolytic cleavage by intracellular proteases and is metabolized primarily by CYP3A4 _in vitro_. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Enfortumab vedotin are crucial for its therapeutic efficacy: Following the first treatment cycle, C_max and AUC_0-28d for enfortumab vedotin were 28 µg/mL and 111 µg.d/mL, respectively. The C_max and AUC_0-28d of unconjugated MMAE following the same cycle were 4.8 ng/mL and 69 ng.d/mL, respectively. The T_max of MMAE is 1-3 days following the end of the infusion. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Enfortumab vedotin is an important consideration for its dosing schedule: The elimination half-lives of enfortumab vedotin and MMAE are 3.4 days and 2.4 days, respectively. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Enfortumab vedotin exhibits a strong affinity for binding with plasma proteins: MMAE was found to be 68-82% protein-bound _in vitro_. The specific proteins to which MMAE is bound have not been elucidated. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Enfortumab vedotin from the body primarily occurs through: Excretion kinetics have not been fully characterized, but may be extrapolated from data available from another MMAE-containing antibody-drug conjugate - kinetic studies of this drug demonstrated that 17% of the total MMAE administered was recovered in feces, and 6% was recovered in urine, primarily as unchanged drug, over a 1-week period. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Enfortumab vedotin is distributed throughout the body with a volume of distribution of: The estimated steady-state volume of distribution is 11 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Enfortumab vedotin is a critical factor in determining its safe and effective dosage: The mean clearance of enfortumab vedotin and free MMAE was 0.10 L/h and 2.7 L/h, respectively. The clearance of MMAE appears to be limited by its rate of release from enfortumab vedotin. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Enfortumab vedotin exerts its therapeutic effects through: Enfortumab vedotin is an anti-cancer agent that destroys tumor cells by inhibiting their ability to replicate. Patients with moderate to severe hepatic impairment should not use enfortumab vedotin - although it has not been studied in this population, other MMAE-containing antibody-drug conjugates have demonstrated increased rates of adverse effects in patients with moderate-severe hepatic impairment. Enfortumab vedotin may also cause significant hyperglycemia leading, in some cases, to diabetic ketoacidosis, and should not be administered to patients with a blood glucose level >250 mg/dl. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Enfortumab vedotin functions by: Enfortumab vedotin is an antibody-drug conjugate comprised of multiple components. It contains a fully human monoclonal antibody directed against Nectin-4, an extracellular adhesion protein which is highly expressed in urothelial cancers, attached to a chemotherapeutic microtubule-disrupting agent, monomethyl auristatin E (MMAE). These two components are joined via a protease-cleavable linker. Enfortumab vedotin binds to cells expressing Nectin-4 and the resulting enfortumab-Nectin-4 complex is internalized into the cell. Once inside the cell, MMAE is released from enfortumab vedotin via proteolytic cleavage and goes on to disrupt the microtubule network within the cell, arresting the cell cycle and ultimately inducing apoptosis. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Enfortumab 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:

Enfortumab 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, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Globulins, Immunoglobulins, Immunoproteins, Immunotherapy, Microtubule Inhibitors, MONOCLONAL ANTIBODIES AND ANTIBODY DRUG CONJUGATES, Nectin-4-directed Antibodies, P-glycoprotein substrates, Proteins, Serum Globulins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Enfortumab vedotin include:

• Molecular Weight: 152000.0