Tivozanib

Uses

Tivozanib is a kinase inhibitor to treat adult patients with renal cell carcinoma (RCC) who have failed prior systemic therapies or experienced relapsed disease.

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.

Tivozanib is also used to associated treatment for these conditions: Advanced Renal Cell Carcinoma, Renal Cell Adenocarcinoma

How Tivozanib works

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.

Toxicity

LD50 information for tivozanib is not readily available in the literature, however the European Medicines Agency (EMA) assessment report indicates the oral maximum tolerated dose (MTD) in mice was 524 mg/kg; doses ≥ 750 mg/kg led to severe and lethal effects. In rats, the oral MTD was to 276 mg/kg; at doses ≥ 369 mg/kg, severe effects and death occurred.

In tivozanib monotherapy studies, two patients received overdoses of tivozanib. One volunteer with a prior history of hypertension experienced aggravated uncontrolled hypertension that resulted in death after taking 3 doses of 1340 microgram tivozanib in one day (total of 4020 micrograms). A second patient patient ingested two doses of 1340 microgram tivozanib in one day (total of 2680 micrograms), and experienced no adverse effects. Carefully control blood pressure before starting tivozanib; regularly monitor blood pressure during treatment. In the case of a confirmed or suspected overdose, discontinue tivozanib, monitor the patient closely, and provide supportive treatment as necessary. No antidote exists for an overdose with tivozanib.

Food Interaction

• Take with or without food.

Tivozanib Hypertension interaction

[Moderate] Hypertension has been observed in patients treated with naxitamab.

Most hypertensive events occurred on the day of the infusion and may occur up to 9 days after the infusion.

Do not administer this drug to patients with uncontrolled hypertension.

Interrupt therapy and resume at a reduced rate or permanently discontinue based on severity.

It is recommended to monitor blood pressure during the infusion, an at least daily on Days 1 to 8 of each cycle.

[Moderate] Tivozanib has not been studied in patients with systolic blood pressure greater than 150 mmHg or diastolic blood pressure greater than 100 mmHg.

Control blood pressure prior to initiating therapy.

Monitor blood pressure after 2 weeks and at least monthly thereafter.

Treat patients with antihypertensives when hypertension occurs.

Withhold therapy for severe hypertension despite optimal antihypertensive therapy.

For persistent hypertension (despite use of antihypertensive medications), reduce the dose.

Discontinue if hypertension is severe and persistent despite antihypertensive therapy and dose reduction or in patients who experience hypertensive crisis.

Tivozanib Drug Interaction

Unknown: cabozantinib, hydrocortisone, influenza virus vaccine, inactivated, atropine / diphenoxylate, acetaminophen / hydrocodone, zoster vaccine, inactivated, sunitinib, levothyroxine, acetaminophen, febuxostat, cyanocobalamin, cholecalciferol

Tivozanib Disease Interaction

Moderate: hypertension, cardiac ischemia/arterial thromboembolic events, heart failure, hemorrhagic events, hepatic dysfunction, hypertension, renal dysfunction, thyroid disorders, venous thrombolic events

Volume of Distribution

Tivozanib has an apparent volume of distribution (V/F) of 123 L.

Elimination Route

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.

Half Life

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.

Clearance

The apparent clearance (CL/F) of tivozanib is approximately 0.75 L/h.

Elimination Route

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.

Innovators Monograph

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