Tivozanib

Tivozanib is a highly selective oral inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases. Its high selectivity for VEGFR-1, VEGFR-2, and VEGFR-3 — with additional inhibitory activity against c-KIT and PDGFRβ — distinguishes it from less selective TKIs and reduces off-target effects.

Mechanism of Action

The VHL mutation–HIF upregulation–VEGF transcription axis is the principal pathway driving renal cell carcinoma. Tivozanib inhibits phosphorylation of VEGFR-1, VEGFR-2, and VEGFR-3, blocking VEGF-mediated tumor angiogenesis and vascular permeability. It also inhibits c-KIT and PDGFRβ, which contribute to tumor stromal signaling.

Key pharmacodynamic effects:

• Inhibits tumor angiogenesis, tumor growth, and vascular permeability in preclinical models.
• Reduces serum soluble VEGFR2 (sVEGFR2) in a concentration-dependent manner — sVEGFR2 serves as a pharmacodynamic marker of VEGFR inhibition in clinical studies.
• Frequently causes hypertension (a class effect of VEGFR inhibitors), which must be controlled before and during therapy.
• Associated with modest, non-clinically serious QT prolongation in cardiac safety studies.

Pharmacokinetics

• Tmax: median 10 hours (range 3–24 hours) after oral administration.
• Volume of distribution: apparent Vd (V/F) ~123 L.
• Protein binding: ≥99% bound to albumin in vitro.
• Metabolism: primarily CYP3A4; unchanged tivozanib accounts for ~90% of radioactive drug in serum after a radiolabeled oral dose — indicating limited first-pass metabolism.
• Half-life: ~111 hours (~4.5 days) per prescribing information; 4–5 days per clinical study data.
• Clearance: apparent CL/F ~0.75 L/h.
• Excretion: primarily fecal — 79% of dose recovered in feces (26% as unchanged drug), 12% in urine (as metabolites only).
• Steady state: reached at concentrations approximately 6–7 times the single-dose level with repeated dosing.

• TIVO-1 (first-line RCC): progression-free survival 11.9 vs 9.4 months (placebo); overall response rate 33% vs 6%.
• TIVO-3 (refractory RCC): non-inferior PFS to sorafenib (11.7 vs 10.5 months) with a more favorable tolerability profile.

• Advanced renal cell carcinoma as first-line treatment, or after progression on prior systemic therapies.

• Hypersensitivity to tivozanib or any of the excipients.
• Uncontrolled hypertension.
• Pregnancy and breastfeeding.

Very Common (>10%): hypertension (up to 84%), fatigue, diarrhea, nausea, decreased appetite, vomiting, dysphonia (voice hoarseness), abdominal pain, constipation, rash.

Common (1–10%): hair color changes, hair loss, weight loss, headache, mucositis, hand-foot skin reaction, anemia, thrombocytopenia, asthenia.

Serious (less common):

• Hypertensive crisis (requires immediate treatment).
• Arterial thromboembolic events (stroke, MI).
• Hemorrhage.
• Proteinuria; nephrotic syndrome.
• Thyroid dysfunction.
• Hepatotoxicity.

• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) — increase tivozanib exposure; avoid or use with caution.
• Strong CYP3A4 inducers (e.g., rifampin, phenytoin) — decrease tivozanib exposure; avoid.
• Grapefruit juice: avoid — increases drug levels.

Standard Dose

1.34 mg orally once daily for 21 days, followed by 7 days off (3-weeks-on / 1-week-off cycle). Continue cycles until disease progression or unacceptable toxicity. May be taken with or without food. Capsules should be swallowed whole.

Dose Modifications

• Grade 2 hypertension: optimize antihypertensive management; continue tivozanib.
• Grade 3+ hypertension: hold until controlled to Grade ≤1, then resume at 1.34 mg or reduced to 0.89 mg.
• Other toxicities: hold or reduce dose to 0.89 mg per cycle based on severity.

Blood Pressure Monitoring (Critical)

Assess blood pressure at baseline and monitor regularly during treatment. Control hypertension aggressively, including with antihypertensive medications. Treat hypertensive emergencies immediately.

Thromboembolic Risk

Monitor for signs and symptoms of arterial events (stroke, MI, TIA). Risk is higher in patients with prior arterial disease.

Hand-Foot Skin Reaction

Keep skin clean and dry; moisturize frequently; wear comfortable, breathable footwear. Consider dose reduction if severe.

Hair and Voice Changes

Hair depigmentation (whitening) and dysphonia (hoarseness) are usually reversible after discontinuation; rarely require treatment changes.

Pregnancy

Tivozanib is teratogenic. Effective contraception is required during treatment and for at least 1 month after the last dose. Breastfeeding is contraindicated.

Store below 30°C in the original packaging. Do not remove the desiccant from the bottle. Keep out of reach of children.

3 years. Do not use after the expiry date.

Prescription required. Typically prescribed in oncology settings for advanced renal cell carcinoma; requires regular blood pressure monitoring during treatment.