Axitinib

Usage

• Axitinib is prescribed for the treatment of advanced renal cell carcinoma (RCC), a type of kidney cancer. It is used in patients who have received prior systemic therapy and in combination with avelumab or pembrolizumab as a first-line treatment for advanced RCC.
• Pharmacological Classification: Axitinib is classified as a tyrosine kinase inhibitor (TKI), specifically a vascular endothelial growth factor receptor (VEGFR) inhibitor.
• Mechanism of Action: Axitinib works by inhibiting VEGFR-1, VEGFR-2, and VEGFR-3. These receptors play a crucial role in angiogenesis (the formation of new blood vessels), which is essential for tumor growth and metastasis. By blocking these receptors, Axitinib reduces the blood supply to the tumor, thereby inhibiting its growth and spread.

Alternate Names

• INN: axitinib
• Brand Name: Inlyta

How It Works

• Pharmacodynamics: Axitinib exerts its antitumor effect by inhibiting angiogenesis. It selectively targets VEGFRs, which are key mediators of tumor vascularization. This leads to reduced tumor blood supply, hindering tumor growth and progression.

• Pharmacokinetics:

  • Absorption: Axitinib is administered orally and reaches peak plasma concentrations within 4 hours. Food can affect absorption; a high-fat meal increases absorption, while a moderate-fat meal slightly reduces absorption.
  • Metabolism: Axitinib is primarily metabolized in the liver by CYP3A4/5 enzymes.
  • Elimination: It is mainly eliminated through feces, with a smaller portion excreted in urine.

• Mode of Action: Axitinib competitively binds to the intracellular ATP-binding site of VEGFRs, blocking the signaling cascade that promotes angiogenesis. This inhibits the growth of new blood vessels needed by the tumor to survive.

• Receptor Binding/Enzyme Inhibition: Axitinib specifically inhibits VEGFR 1, 2, and 3.

• Elimination Pathways: Primarily hepatic metabolism via CYP3A4/5, followed by fecal excretion.

Dosage

Standard Dosage

Adults:

• Initial dose: 5 mg orally twice daily, approximately 12 hours apart.
• The dose may be increased to 7 mg twice daily, then to a maximum of 10 mg twice daily, based on individual tolerability and safety, provided the patient is normotensive or not requiring antihypertensive medication, and has no adverse reactions > Grade 2 for two consecutive weeks.

Children:

• The safety and efficacy of Axitinib in children and adolescents (<18 years) have not been established. It is not recommended for pediatric use.

Special Cases:

• Elderly Patients (≥65 years): No dose adjustment is required.
• Patients with Renal Impairment: No dose adjustment is required, but use with caution in patients with creatinine clearance <15 mL/min.
• Patients with Hepatic Dysfunction:
  • Mild impairment (Child-Pugh class A): No dose adjustment required.
  • Moderate impairment (Child-Pugh class B): Reduce the starting dose by approximately 50%. Further adjustments may be needed based on individual tolerability and safety.
  • Severe impairment (Child-Pugh class C): Axitinib is contraindicated.
• Patients with Comorbid Conditions: Caution should be exercised in patients with hypertension, cardiac disease, a history of or risk for thromboembolism. Close monitoring and appropriate management are necessary.

Clinical Use Cases

Axitinib’s primary use is in the treatment of advanced RCC in specific settings as described above; the use of axitinib in clinical scenarios such as Intubation, Surgical Procedures, Mechanical Ventilation, Intensive Care Unit (ICU) Use and other Emergency Situations is not applicable.

Dosage Adjustments

• Dose adjustments may be necessary based on individual safety and tolerability. Dose reduction may be required for managing adverse reactions. When reducing the dose, decrease to 3 mg twice daily, then to 2 mg twice daily if further reduction is needed.
• In patients taking strong CYP3A4/5 inhibitors, reduce the initial dose by approximately 50%.

Side Effects

Common Side Effects:

Diarrhea, hypertension, fatigue, decreased appetite, nausea, vomiting, constipation, dysphonia (hoarseness), palmar-plantar erythrodysesthesia (hand-foot syndrome), and increased risk of bleeding.

Rare but Serious Side Effects:

Cardiac failure, arterial and venous thromboembolic events (including myocardial infarction, transient ischemic attack, stroke, deep vein thrombosis, pulmonary embolism), posterior reversible encephalopathy syndrome, gastrointestinal perforation, hepatotoxicity, proteinuria, thyroid dysfunction, impaired wound healing, severe hypertension including hypertensive crisis.

Long-Term Effects:

Chronic complications may include cardiovascular issues related to hypertension and thromboembolic events. Long-term effects on fertility are also possible.

Adverse Drug Reactions (ADR):

Clinically significant ADRs include hypertensive crisis, severe bleeding, thromboembolic events, cardiac failure, and gastrointestinal perforation. These require immediate medical attention.

Contraindications

• Hypersensitivity to axitinib.
• Severe hepatic impairment (Child-Pugh Class C).
• Recent active gastrointestinal bleeding.
• Untreated brain metastases.

Drug Interactions

• Strong CYP3A4/5 inhibitors: Co-administration can significantly increase axitinib plasma concentrations. Avoid co-administration or use an alternative medication with no or minimal CYP3A4/5 inhibition. If co-administration is unavoidable, reduce the axitinib dose.
• Strong CYP3A4/5 inducers: Co-administration may decrease axitinib plasma levels, potentially reducing its effectiveness. Examples include rifampin, phenytoin, carbamazepine, St. John’s Wort.
• Numerous other drug interactions exist, consult a comprehensive drug interaction resource for details.
• Food and lifestyle factors: Grapefruit, starfruit, and Seville oranges should be avoided as they can increase axitinib levels.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Axitinib can cause fetal harm and should not be used during pregnancy. Women of childbearing potential must use effective contraception during treatment and for 1 week after the last dose. Men should also use contraception during treatment and for 1 week after the last dose.
• Breastfeeding: Axitinib is likely present in breast milk and has the potential for serious adverse reactions in breastfed infants. Breastfeeding should be discontinued during treatment and for 2 weeks after the last dose.

Drug Profile Summary

• Mechanism of Action: TKI, inhibits VEGFR 1, 2, and 3, reducing angiogenesis.
• Side Effects: Diarrhea, hypertension, fatigue, nausea, vomiting, dysphonia, hand-foot syndrome. Serious side effects: cardiac failure, thromboembolic events, hypertensive crisis, GI perforation.
• Contraindications: Hypersensitivity, severe hepatic impairment, recent GI bleeding, untreated brain metastases.
• Drug Interactions: Strong CYP3A4/5 inhibitors and inducers, numerous other drug interactions.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy, breastfeeding should be discontinued.
• Dosage: Adults: 5 mg BID initially, can be increased to 7 mg BID, then up to 10 mg BID based on tolerability. Special adjustments for moderate hepatic impairment.
• Monitoring Parameters: Blood pressure, complete blood count, liver function tests, thyroid function tests, signs and symptoms of bleeding, cardiac function.

Popular Combinations

• Axitinib + Avelumab: For first-line treatment of advanced RCC.
• Axitinib + Pembrolizumab: For first-line treatment of advanced RCC.

Precautions

• General Precautions: Monitor blood pressure, cardiac function, and signs and symptoms of bleeding. Assess liver and kidney function, thyroid function, and complete blood count. Screen for allergies.
• Specific Populations: Caution in patients with pre-existing cardiovascular disease, history of thromboembolism, hepatic or renal impairment.
• Pregnant Women: Contraindicated.
• Breastfeeding Mothers: Contraindicated.
• Children & Elderly: Not recommended for children. No dose adjustment needed for the elderly.
• Lifestyle Considerations: Avoid grapefruit, starfruit, and Seville oranges. Caution when driving or operating machinery due to potential fatigue and dizziness.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Axitinib?

A: The initial dose is 5 mg orally twice daily. This can be increased to 7 mg and then up to 10 mg twice daily based on the patient’s individual tolerability and safety provided they are normotensive and have no adverse reactions > Grade 2. Dose reduction to 3 mg, and then 2 mg twice daily, may be necessary for managing adverse reactions.

Q2: How does Axitinib work against kidney cancer?

A: It inhibits VEGFRs, which are essential for angiogenesis. By blocking these receptors, it reduces blood supply to the tumor, inhibiting its growth and spread.

Q3: What are the most common side effects of Axitinib?

A: Common side effects include diarrhea, hypertension, fatigue, decreased appetite, nausea, vomiting, dysphonia, and hand-foot syndrome.

Q4: What are the serious side effects that require immediate medical attention?

A: Serious side effects include cardiac failure, severe hypertension (including hypertensive crisis), arterial and venous thromboembolic events (e.g., stroke, myocardial infarction, pulmonary embolism), gastrointestinal perforation, and severe bleeding.

Q5: Can Axitinib be used during pregnancy or breastfeeding?

A: No, Axitinib is contraindicated during pregnancy and breastfeeding due to the risk of fetal harm and potential adverse reactions in breastfed infants.

Q6: Are there any specific drug interactions I should be aware of with Axitinib?

A: Yes, strong CYP3A4/5 inhibitors and inducers can significantly alter Axitinib levels. Avoid concurrent use or adjust dosage accordingly. Consult a comprehensive drug interaction resource for a complete list.

Q7: What should I monitor in patients taking Axitinib?

A: Monitor blood pressure, complete blood count, liver function, thyroid function, and closely observe for signs of bleeding or cardiac issues.

Q8: What are the contraindications to using Axitinib?

A: Axitinib is contraindicated in patients with severe hepatic impairment, hypersensitivity to the drug, recent active gastrointestinal bleeding, and untreated brain metastases.

Q9: How should dose adjustments be made for patients with moderate hepatic impairment?

A: The starting dose should be reduced by approximately 50%. Subsequent doses can be adjusted based on the individual’s safety and tolerability.

Q10: Are there any dietary restrictions while taking Axitinib?

A: Yes, patients should avoid grapefruit, starfruit, and Seville oranges as these can increase axitinib levels.