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General Description:

Tivozanib, identified by CAS number 475108-18-0, is a notable compound with significant therapeutic applications. Renal cell carcinoma (RCC) is responsible for 3% of cancer cases and is one of the 10 most common cancers in adults. The average age of diagnosis is between age 65 to 74. Tivozanib, also known as FOTIVDA, is a kinase inhibitor developed to treat adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) after prior failed systemic therapies. It was approved on March 10, 2021 by the FDA. Marketed by Aveo Oncology, tivozanib is a promising therapy for individuals with RCC who have not been treated successfully with other therapies.

Indications:

This drug is primarily indicated for: Tivozanib is approved in the USA for the treatment of relapsed or refractory renal cell carcinoma in adult patients who have undergone two or more systemic therapies. In the UK and other countries, is indicated as first line therapy of adults with advanced renal cell carcinoma (RCC) and VEGFR and mTOR pathway inhibitor-naïve patients after disease progression following one previous treatment with cytokine therapy for advanced disease. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Tivozanib undergoes metabolic processing primarily in: Tivozanib is primarily metabolized by CYP3A4. After oral ingestion of a radiolabeled 1.34 mg dose of tivozanib in healthy volunteers, unchanged tivozanib accounted for 90% of the radioactive drug detected in serum. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Tivozanib are crucial for its therapeutic efficacy: The median Tmax of tivozanib is 10 hours, however, can range from 3 to 24 hours. A pharmacokinetic study in 8 healthy subjects revealed a Cmax and AUC for radiolabeled tivozanib of 12.1 ± 5.67 ng/mL and 1084 ± 417.0 ng·h/mL, respectively. Steady-state tivozanib concentrations are achieved at concentrations 6-7 times higher the normal dose. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Tivozanib is an important consideration for its dosing schedule: The half-life of tivozanib is about 111 hours according to prescribing information. Information from clinical studies reveals a half-life of 4-5 days. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Tivozanib exhibits a strong affinity for binding with plasma proteins: In vitro, the protein binding of tivozanib is mainly bound to albumin at a rate of ≥ 99%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Tivozanib from the body primarily occurs through: Tivozanib is primarily excreted in the feces. After oral ingestion of a radiolabeled 1.34 mg dose of tivozanib in healthy volunteers, 79% of the administered dose was found in the feces (with 26% unchanged) and 12% was found in the urine solely as metabolites. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Tivozanib is distributed throughout the body with a volume of distribution of: Tivozanib has an apparent volume of distribution (V/F) of 123 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Tivozanib is a critical factor in determining its safe and effective dosage: The apparent clearance (CL/F) of tivozanib is approximately 0.75 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Tivozanib exerts its therapeutic effects through: Tivozanib inhibits growth factor receptors, treating renal cell carcinoma. In mice and rats, tivozanib inhibits tumour angiogenesis, tumour growth, and vascular permeability. Tivozanib was shown to frequently cause hypertension in clinical trials; hypertension must be managed before initiating therapy. Cardiac QT segment prolongation was reported in a tivozanib cardiac safety study, however the reactions were not considered clinically serious. In clinical studies, levels of serum soluble VEGFR2 (sVEGFR2) decreased with time and this effect increased with tivozanib exposure, and sVEGFR2 may serve as a pharmacodynamic marker of VEGFR inhibition. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Tivozanib functions by: The VHL mutation-HIF upregulation-VEGF transcription is the main pathway implicated in the growth of renal cell carcinoma. Vascular endothelial growth factor receptors (VEGFR receptors) are important targets for tyrosine kinase inhibitors, which halt the growth of tumours. Tivozanib is a tyrosine kinase inhibitor that exerts its actions by inhibiting the phosphorylation of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2 and VEGFR-3 and inhibits other kinases such as c-kit and platelet derived growth factor beta (PDGFR β). The above actions inhibit tumour growth and progression, treating renal cell carcinoma. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Tivozanib belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups, classified under the direct parent group Diarylethers. This compound is a part of the Organic compounds, falling under the Organic oxygen compounds superclass, and categorized within the Organooxygen compounds class, specifically within the Ethers subclass.

Categories:

Tivozanib is categorized under the following therapeutic classes: Amides, Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, Benzene Derivatives, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Substrates, Heterocyclic Compounds, Fused-Ring, Kinase Inhibitor, P-glycoprotein substrates, Protein Kinase Inhibitors, Receptors, Vascular Endothelial Growth Factor, antagonists & inhibitors, Tyrosine Kinase Inhibitors, Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Tivozanib include:

• Water Solubility:<1g/mL
• Melting Point: 220-233
• Boiling Point: 550.4 ± 50.0
• logP: 4.31
• caco2 Permeability: 0.5
• pKa: 11.74±0.70