Tisotumab vedotin API Manufacturers

General Description:

Tisotumab vedotin, identified by CAS number 1418731-10-8, is a notable compound with significant therapeutic applications. Tisotumab vedotin is a tissue factor-directed antibody-drug conjugate (ADC) comprised of an anti-tissue factor (TF) human IgG1-kappa antibody conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent, via a protease-cleavable valine-citrulline linker. Each monoclonal antibody molecule carries an average of four MMAE molecules. Tisotumab vedotin is the first TF-directed ADC that works by binding to TFs expressed on solid tumours. TF is a primary initiator of the extrinsic blood coagulation cascade and plays a key role in tumor-associated angiogenesis, progression, and metastasis for tumor survival. TF is a novel target for cancers, as it is often overexpressed on solid tumours, including cervical cancer, and it is associated with poor clinical outcomes. Tisotumab vedotin targets TF-expressing cells to deliver MMAE to induce direct cytotoxicity and bystander killing of neighboring cells. On September 20, 2021, the FDA granted accelerated approval to tisotumab vedotin-tftv for the treatment of recurrent or metastatic cervical cancer in adults in whom the disease progressed during or after chemotherapy. This is the first and only approved antibody-drug conjugate for this therapeutic indication. The approval was based on tumour response and the durability of the response as demonstrated in InnovaTV 204 (NCT03438396): in this trial, the objective response rate was 24% and the median response duration was 8.3 months. Tisotumab vedotin-tftv is marketed under the trade name Tivdak as an intravenous injection. Tisotumab vedotin is currently under investigation as a treatment for other solid tumors, including ovarian, lung, colorectal, pancreatic, and head and neck cancers. It is also being investigated for the combination use with other chemotherapeutic agents for recurrent or metastatic cervical cancer.

Indications:

This drug is primarily indicated for: Tisotumab vedotin is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Tisotumab vedotin undergoes metabolic processing primarily in: Tisotumab vedotin-tftv most likely undergoes catabolism to form small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Via proteolytic cleavage, tisotumab vedotin-tftv releases unconjugated MMAE, which is primarily metabolized 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 Tisotumab vedotin are crucial for its therapeutic efficacy: Following administration of one 3-week cycle of tisotumab vedotin-tftv 2 mg/kg, the peak concentrations reached near the end of the infusion, while unconjugated MMAE concentrations peaked approximately two to three days after tisotumab vedotin-tftv dosing. The mean (± SD) C_max of tisotumab vedotin-tftv was 40.8 (8.12) μg/mL and the mean (± SD) AUC was 57.5 (13.4) day x μg/mL. The mean (± SD) C_max of unconjugated MMAE was 5.91 (4.2) ng/mL and the mean (± SD) AUC was 50 (35.8) day x ng/mL. The C_max of tisotumab vedotin-tftv increased proportionally and there was no drug accumulation. Steady-state concentrations of tisotumab vedotin-tftv and unconjugated MMAE were reached after one treatment cycle. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Tisotumab vedotin is an important consideration for its dosing schedule: The median terminal half-life of tisotumab vedotin-tftv and unconjugated MMAE is 4.04 (range: 2.26-7.25) days and 2.56 (range: 1.81-4.10) days, respectively. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Tisotumab vedotin exhibits a strong affinity for binding with plasma proteins: Plasma protein binding of MMAE ranged from 68% to 82% _in vitro_. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Tisotumab vedotin from the body primarily occurs through: The excretion of tisotumab vedotin-tftv is not fully characterized. Following a single-dose of another antibody-drug conjugate that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after tisotumab vedotin-tftv administration. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Tisotumab vedotin is distributed throughout the body with a volume of distribution of: The tisotumab vedotin-tftv steady-state volume of distribution is 7.83 (%CV: 19.1) L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Tisotumab vedotin is a critical factor in determining its safe and effective dosage: The linear clearance of tisotumab vedotin-tftv and unconjugated MMAE was 1.54 (%CV: 28.8) L/day and 45.9 (%CV: 61.1) L/day, respectively. Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin-tftv. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Tisotumab vedotin exerts its therapeutic effects through: Tisotumab vedotin is an anticancer antibody-drug conjugate that is made up of an antibody and monomethyl auristatin E (MMAE), a cytotoxic component of the drug. It works by binding to tissue factors expressed on cervical tumours and releasing MMAE upon cell entry to mediate its cytotoxic activity. Apart from directly killing tumour cells, tisotumab vedotin may exert a bystander effect by killing neighbouring cells and promote immunogenic cell death pathways, including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Tisotumab vedotin functions by: Tisotumab vedotin is a tissue factor (TF)-directed antibody-drug conjugate (ADC) anti-TF IgG1-kappa antibody conjugated to the microtubule-disrupting agent MMAE via a protease-cleavable vc (valine-citrulline) linker. It may exhibit multiple mechanisms of action; however, it primarily works by inducing cytotoxic effects on TF-expressing tumours. Tisotumab vedotin binds to TFs expressed on cervical tumours, which leads to the internalization of the antibody-drug conjugate-TF complex. Once internalized, MMAE from the drug-target complex is released via proteolytic cleavage. MMAE is a microtubule-disrupting agent that disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. Tisotumab vedotin may also promote bystander killing of neighbouring cells. According to _in vitro_ studies, tisotumab vedotin induces immunogenic cell death and promotes tumour cell death through Fcγ receptor-mediated effector functions, such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Tisotumab vedotin may inhibit TF-activated factor VII (FVIIa)–dependent intracellular signalling, with negligent effects on procoagulant activity. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Tisotumab 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:

Tisotumab vedotin is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, Antibodies, Antibodies, Monoclonal, Antineoplastic Agents, Antineoplastic Agents, Immunological, Blood Proteins, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Globulins, Immunoglobulins, Immunoproteins, P-glycoprotein substrates, Peptides, 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 Tisotumab vedotin include:

• Molecular Weight: 153000.0