Axitinib

Approved Indications:

• Advanced Renal Cell Carcinoma (RCC):
• Indicated for the treatment of advanced renal cell carcinoma in adults after failure of one prior systemic therapy (e.g., cytokine therapy, tyrosine kinase inhibitors like sunitinib).
• Also used in treatment-naïve patients when appropriate based on clinical guidelines.

Clinically Accepted Off-Label Uses:

• Thyroid Cancer (Refractory):
• Investigational use in advanced or refractory differentiated thyroid carcinoma, particularly in patients unresponsive to radioactive iodine therapy.
• Hepatocellular Carcinoma (HCC):
• Studied in combination with other agents such as immune checkpoint inhibitors.
• Other Solid Tumors:
• Under clinical evaluation in various advanced malignancies like non-small cell lung cancer (NSCLC), and colorectal cancer in combination regimens.

Adults (Renal Cell Carcinoma):

• Initial Dose: 5 mg orally twice daily (approximately 12 hours apart) with or without food.
• Dose Adjustments:
• Dose can be increased to 7 mg and then 10 mg twice daily based on individual tolerability.
• Reduce to 3 mg or 2 mg twice daily for toxicity or drug interactions.
• Administration Route: Oral; tablets should be swallowed whole with water.

Renal Impairment:

• No dose adjustment required in mild to moderate renal impairment.
• Use with caution in severe renal impairment.

Hepatic Impairment:

• Child-Pugh Class A: No adjustment needed.
• Child-Pugh Class B: Reduce initial dose to 2 mg twice daily.
• Child-Pugh Class C: Not recommended due to limited data.

Pediatrics:

• Safety and efficacy in patients <18 years of age have not been established.

Geriatrics:

• No specific dosage adjustment required, but monitor closely for toxicity.

Axitinib is a potent and selective second-generation tyrosine kinase inhibitor (TKI) that specifically targets vascular endothelial growth factor receptors VEGFR-1, VEGFR-2, and VEGFR-3, which are critical regulators of angiogenesis. By inhibiting these receptors, axitinib suppresses the proliferation and survival of endothelial cells, reduces neovascularization in tumors, and impairs tumor growth and metastasis. This anti-angiogenic effect leads to reduced tumor vascularization, thereby starving the tumor of nutrients and oxygen.

• Absorption: Rapidly absorbed with peak plasma concentrations within 2–6 hours post-dose.
• Bioavailability: Approximately 58%.
• Distribution: High plasma protein binding (>99%), mainly to albumin.
• Metabolism: Extensively metabolized in the liver, primarily via CYP3A4, with minor contributions from CYP1A2, CYP2C19, and UGT1A1.
• Half-life: Terminal elimination half-life is about 2.5 to 6.1 hours.
• Excretion: Elimination occurs mainly via feces (~41%) and urine (~23%), primarily as metabolites.

• Pregnancy Risk: Based on animal studies and its mechanism of action, axitinib may cause fetal harm. It is classified under Pregnancy Category D (risk to the fetus exists).
• Lactation: It is not known whether axitinib is excreted in human milk. Due to potential serious adverse reactions in nursing infants, breastfeeding is not recommended during and for at least 2 weeks after the last dose.
• Fertility Warning: Axitinib may impair fertility in both males and females based on preclinical data.

• Primary Class: Antineoplastic Agent
• Subclass: Tyrosine Kinase Inhibitor (VEGFR Inhibitor)

• Known hypersensitivity to axitinib or any of its excipients.
• Pregnancy (due to potential fetal harm).
• Severe hepatic impairment (Child-Pugh Class C).
• Concurrent use with strong CYP3A4 inducers (unless benefit outweighs risk).

• Hypertension: Common and may be severe; blood pressure must be well controlled before initiating therapy. Monitor regularly during treatment.
• Thromboembolic Events: Risk of arterial and venous thrombotic events including stroke, myocardial infarction, and pulmonary embolism.
• Hemorrhage: Gastrointestinal bleeding and hematuria have been reported.
• Gastrointestinal Perforation/Fistula: Rare but serious risk—discontinue immediately if suspected.
• Proteinuria: Monitor urine protein periodically; withhold treatment for severe proteinuria.
• Hypothyroidism: May develop during treatment; monitor thyroid function tests.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue if neurological symptoms occur.
• Hepatic Toxicity: Monitor liver function tests.
• Wound Healing Complications: Discontinue therapy for at least 2 days before surgery and resume based on clinical judgment.

Common Adverse Effects:

• Cardiovascular: Hypertension, increased blood pressure
• Gastrointestinal: Diarrhea, decreased appetite, nausea, vomiting, stomatitis
• General: Fatigue, weight loss, asthenia
• Dermatologic: Hand-foot syndrome, rash
• Endocrine: Hypothyroidism

Serious and Rare Adverse Effects:

• Arterial thromboembolic events (e.g., MI, stroke)
• GI perforation or fistula
• Hemorrhage (gastrointestinal or CNS)
• Hepatotoxicity
• Posterior reversible encephalopathy syndrome (PRES/RPLS)
• Severe hypertension crisis
• Proteinuria leading to nephrotic syndrome

Onset & Severity:

• Most side effects appear within the first few weeks of treatment and may be dose-dependent.

Major Drug-Drug Interactions:

• CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole): May increase axitinib plasma levels → increase toxicity risk.
• CYP3A4 Inducers (e.g., rifampin, phenytoin, carbamazepine, St. John's Wort): May reduce axitinib efficacy by decreasing systemic exposure.
• Antihypertensives: Additive hypotensive or hypertensive effects may require dose modification.

Food & Alcohol:

• Can be taken with or without food.
• Alcohol may exacerbate hepatic side effects; caution is advised.

Enzymes Involved:

• Primarily CYP3A4, with lesser involvement from CYP1A2 and CYP2C19.

• Combination Therapy in RCC: Ongoing studies and updated guidelines support axitinib in combination with immune checkpoint inhibitors (e.g., pembrolizumab or avelumab) as first-line therapy for advanced RCC.
• EMA/FDA Update: New safety updates include monitoring for thyroid function and stricter recommendations on hypertension control.
• NCCN Guidelines (Recent): Axitinib-based combinations are considered Category 1 preferred regimens for metastatic clear cell RCC.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C.
• Humidity & Light: Protect from excessive moisture and light.
• Handling: Store in original container; do not crush or split tablets.
• Disposal: Unused tablets should be disposed of in accordance with local regulations for cytotoxic agents.