Action and Spectrum

Actions and Spectrum:

tivozanib is a tyrosine kinase inhibitor (TKI) that works by selectively blocking the activity of vascular endothelial growth factor (VEGF) receptors, which are proteins required in growth and survival of cancer cells. By inhibiting these receptors, tivozanib can slow down or stop the growth of tumors.

Specifically, tivozanib selectively targets and inhibits the VEGF receptors 1, 2, and 3, which are overexpressed in many types of cancer, including renal cell carcinoma (RCC). This inhibition reduces the blood supply to the tumor, which can slow down its growth and potentially lead to its regression.

tivozanib has a relatively narrow spectrum of activity compared to other TKIs, meaning it mainly targets VEGF receptors and has little effect on other tyrosine kinases. This selectivity is thought to contribute to its efficacy and safety profile. It has been shown to have a higher binding affinity for VEGF receptors compared to other TKIs, which may explain its improved clinical outcomes in patients with advanced RCC.

Drug Interaction

Adverse Reaction

Frequency defined

>10%

• Back pain (19%)
• Dysphonia (27%)
• Hypothyroidism (24%)
• Vomiting (18%)
• Hemoglobin increased (19%)
• Stomatitis (21%)
• Nausea (30%)
• Sodium decreased (36%)
• Hemoglobin decreased (16%)
• Alkaline phosphatase increased (30%)
• Potassium increased (26%)
• Lymphocytes decreased (25%)
• AST increased (28%)
• Palmoplantar erythrodysesthesia syndrome (16%)
• Weight decreased (17%)
• Arterial thromboembolism (<15%)
• Lipase increased (32%)
• Delirium (<15%)
• Bleeding (17%)
• Phosphate decreased (38%)
• Creatinine increased (50%)
• Rash (18%)
• Hyperthyroidism (<15%)
• Proteinuria (<15%)
• Glucose increased (50%)
• Calcium increased (15%)
• Bilirubin increased (11%)
• Diarrhea (43%)
• Cough (22%)
• Venous thromboembolism (<15%)
• Hypertension (44%)
• Magnesium decreased (26%)
• Osteonecrosis (<15%)
• Decreased appetite (39%)
• aPTT prolonged (26%)
• Cardiac failure (<15%)
• Hepatobiliary disorders (<15%)

1-10%

• Sodium decreased (9%)
• Lipase increased (9%)
• Phosphate decreased (5%)
• Dyspnea (3%)
• Decreased appetite (5%)
• Vomiting (1%)
• Alkaline phosphatase increased (4%)
• Hemoglobin decreased (1%)
• Calcium increased (2%)
• Bleeding (3%)
• AST increased (1%)
• Glucose increased (3%)
• Rash (1%)
• Back pain (2%)
• Bilirubin increased (3%)
• Dysphonia (1%)
• AST increased (1%)
• Decreased weight (3%)
• Potassium increased (3%)
• Lymphocytes decreased (5%)
• Diarrhea (2%)
• Amylase increased (2%)
• Stomatitis (2%)
• aPTT prolonged (1%)
• Hypothyroidism (1%)
• Palmoplantar erythrodysesthesia syndrome (1%)
• ALT increased (4%)

Black Box Warning

Black Box Warning:

• Risk of potentially fatal and severe liver damage, known as hepatotoxicity.
• The warning states that tivozanib can cause serious and potentially fatal liver injury, including liver failure, and for the patients should have to be monitored closely for signs of liver dysfunction.
• Patients should have their liver function tests monitored before starting treatment with tivozanib and periodically during treatment.

Contraindication / Caution

Contraindication/Caution:

Contraindication

• tivozanib should not be used in patients who have a prior history of severe hypersensitivity reactions to tivozanib or any of its components and in patients with untreated brain metastases (a condition in which the cancer has outspread to the brain)
• Patients who are taking strong CYP3A4 inhibitors (medications that affect the metabolism of tivozanib) should also avoid taking tivozanib, as this can increase the risk of side effects.

Caution

• Caution in patients with a history of liver disease or with pre-existing liver dysfunction, as Tivozanib can cause severe liver toxicity.
• Caution in patients with a history of hypertension or those who are taking antihypertensive medications, as tivozanib can increase blood pressure.

Pregnancy / Lactation

Pregnancy consideration:

US FDA pregnancy category: Not assigned

Lactation:  

Excreted into human milk is Not known.

Pregnancy category:

• Category A: well-controlled and Satisfactory studies do not show risk to the fetus in the first/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 available 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:

• tivozanib is a tyrosine kinase inhibitor (TKI) that specifically targets vascular endothelial growth factor receptors (VEGFRs). VEGFRs are involved in the regulation of angiogenesis, the process by which new blood vessels are formed, and they play a key role in the growth and spread of cancer.
• In clinical trials, tivozanib has demonstrated significant efficacy in the treatment of advanced renal cell carcinoma (RCC), with longer progression-free survival compared to other TKIs.
• Overall, tivozanib represents an important advance in the treatment of RCC and other cancers, providing a highly targeted and effective approach to inhibiting tumor growth and improving patient outcomes.

Pharmacodynamics:

• Inhibition of VEGFRs: tivozanib selectively inhibits the activity of VEGFR-1, VEGFR-2, and VEGFR-3, which are receptors for a vascular endothelial growth factor (VEGF). By blocking the activity of these receptors, tivozanib reduces the formation of new blood vessels within tumors, leading to decreased tumor growth.
• Anti-angiogenic effects: tivozanib has anti-angiogenic effects, which means that it prevents the growth of new blood vessels in tumors.
• Prolonged inhibition: tivozanib has a long half-life, which means that it stays in the body for a relatively long time.
• Low off-target effects: tivozanib has a high degree of selectivity for VEGFRs, which means that it has fewer off-target effects than other drugs that inhibit VEGFRs. 

Pharmacokinetics:

Absorption

The maximum plasma concentration reached for this substance is 86.9 ng/mL 10 hours after administration, and the area under the concentration-time curve (AUC) is 1510 ng⋅hr/mL. 

Distribution

The protein binding of this substance is equal to or greater than 99%, with a volume of distribution of 123 liters, and the mean ratios of blood-to-plasma concentrations range from 0.495 to 0.615 in healthy individuals.

Metabolism

CYP3A4 is the primary enzyme responsible for metabolizing it.

Elimination and Excretion

The half-life of this substance is 111 hours, and its clearance rate is 0.75 L/hr.

When a single 1.34-mg dose is administered, approximately 79% of the substance is excreted through faeces (with 26% being unchanged), while approximately 12% is excreted through urine (with no unchanged substance being detected).

Adminstartion

Administration:

Oral Administration

• tivozanib should be taken with or without food, as directed.
• In case a dose is missed, it should be skipped and the following dose should be taken at the scheduled time. It is important not to take two doses at the same time

Patient Information Leaflet

Patient information leaflet

Generic Name:  tivozanib

Pronounced: tivozanib [ tye-VOE-zan-ib ]

Why do we use tivozanib?

tivozanib is a medication used for the treatment of advanced renal cell carcinoma (RCC), which is a type of kidney cancer. It works by inhibiting the growth of new blood vessels that supply tumors, which can help to slow or stop the progression of cancer cells.

tivozanib is classified as a tyrosine kinase inhibitor and is specifically designed to target vascular endothelial growth factor (VEGF) receptors, which are inculpated in generation of new blood vessels in tumors.