Pazopanib

Usage

• Pazopanib is prescribed for the treatment of advanced renal cell carcinoma (RCC) and advanced soft tissue sarcoma (STS) in patients who have received prior chemotherapy. Its efficacy has not been demonstrated in patients with adipocytic soft tissue sarcoma or gastrointestinal stromal tumors.
• Pharmacological Classification: Pazopanib is a tyrosine kinase inhibitor (TKI). More specifically, it is a multi-target receptor tyrosine kinase inhibitor.
• Mechanism of Action: Pazopanib inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, platelet-derived growth factor receptors (PDGFR)-α and -β, and c-kit, thereby blocking tumor growth and progression by inhibiting angiogenesis and tumor cell proliferation.

Alternate Names

• International Nonproprietary Name (INN): Pazopanib
• Brand Name: Votrient

How It Works

• Pharmacodynamics: Pazopanib exerts its anti-cancer effects by primarily inhibiting multiple tyrosine kinases involved in angiogenesis and tumor growth. This leads to a reduction in tumor vascularization and a decrease in tumor cell proliferation.
• Pharmacokinetics: Pazopanib is administered orally and exhibits variable absorption, influenced by food intake. It is extensively metabolized in the liver, primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Elimination occurs mainly through feces, with a small portion excreted in urine. The elimination half-life is approximately 31 hours, suggesting potential drug accumulation.
• Mode of Action: Pazopanib competitively binds to the ATP-binding pockets of target tyrosine kinases, preventing phosphorylation and activation of downstream signaling pathways involved in angiogenesis, cell growth, and proliferation.
• Receptor Binding/Enzyme Inhibition: Pazopanib inhibits VEGFR-1, -2, -3, PDGFR-α, PDGFR-β, and c-kit. It also inhibits FGFR-1 and -3, and KIT.
• Elimination Pathways: Pazopanib is mainly eliminated through hepatic metabolism (primarily via CYP3A4) and biliary/fecal excretion, with minimal renal excretion.

Dosage

Standard Dosage

Adults:

• The recommended dose is 800 mg orally once daily, taken without food (at least 1 hour before or 2 hours after a meal). The tablets should be swallowed whole and not crushed or broken.
• The maximum dose is 800 mg daily.

Children:

• Pazopanib is not recommended for children younger than 2 years old due to potential effects on organ development and maturation. For older children, the dosage must be determined by a physician and will be based on the patient’s body surface area and other factors. Safety and efficacy have not been fully established in pediatric patients.

Special Cases:

• Elderly Patients: No specific dose adjustment is recommended for elderly patients, but they should be closely monitored for adverse effects. A meta-analysis suggests patients over 60 years of age may be at higher risk for elevated alanine aminotransferase (ALT).
• Patients with Renal Impairment: No dose adjustment is necessary for patients with creatinine clearance above 30 mL/min. Caution is advised for patients with creatinine clearance below 30 mL/min due to limited experience in this population.
• Patients with Hepatic Dysfunction: For patients with mild hepatic impairment (normal bilirubin and elevated ALT, or bilirubin up to 1.5 times the upper limit of normal [ULN] irrespective of ALT), the recommended dose is 800 mg once daily. For moderate hepatic impairment (bilirubin >1.5 to 3 x ULN irrespective of ALT), the recommended dose is reduced to 200 mg once daily. Pazopanib is contraindicated in patients with severe hepatic impairment (bilirubin >3 x ULN irrespective of ALT).
• Patients with Comorbid Conditions: Close monitoring and dose adjustments may be necessary for patients with pre-existing cardiovascular disease, hypertension, QT prolongation, hypothyroidism, liver disease, bleeding disorders, or gastrointestinal conditions.

Clinical Use Cases

Pazopanib’s use is specifically indicated for advanced RCC and certain types of advanced STS. It is not indicated for use in the clinical scenarios listed (Intubation, Surgical Procedures, Mechanical Ventilation, ICU Use, Emergency Situations).

Dosage Adjustments

• Dose reductions (in 200 mg decrements) may be necessary based on individual tolerability and the management of adverse reactions.

Side Effects

Common Side Effects:

• Diarrhea, nausea, vomiting, loss of appetite, changes in hair color, hair loss, fatigue, weakness, high blood pressure, skin rash, dry skin, itching.

Rare but Serious Side Effects:

• Hepatotoxicity (liver damage), including liver failure, QT prolongation, Torsades de pointes, severe bleeding, heart problems (including decreased left ventricular ejection fraction, myocardial ischemia, and cardiac failure), tumor lysis syndrome, pneumothorax, gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome (RPLS).

Long-Term Effects:

• Chronic complications can include persistent hypertension, hypothyroidism, cardiac dysfunction, renal impairment, and secondary malignancies.

Adverse Drug Reactions (ADR):

• Hepatotoxicity, QT prolongation/Torsades de pointes, severe bleeding, heart failure, tumor lysis syndrome, RPLS, angioedema, anaphylaxis.

Contraindications

• Hypersensitivity to pazopanib or any component of the formulation.
• Severe hepatic impairment.
• Coadministration with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) without dose adjustment.
• Coadministration with strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine) or P-glycoprotein inhibitors.

Drug Interactions

• CYP450 Interactions: Pazopanib is primarily metabolized by CYP3A4, and coadministration with CYP3A4 inhibitors or inducers can significantly alter its plasma concentration.
• Other Interactions: Pazopanib can interact with numerous medications, including:
  • Strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir): Increase pazopanib levels.
  • Strong CYP3A4 inducers (e.g., rifampin, phenytoin): Decrease pazopanib levels.
  • P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitors: Increase pazopanib levels.
  • Drugs that prolong the QT interval (e.g., amiodarone, quinidine): Increase the risk of Torsades de pointes.
  • Gastric acid-reducing agents (e.g., proton pump inhibitors, H2 blockers): Decrease pazopanib absorption.
  • Simvastatin: Increases the risk of liver enzyme elevations.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D (Australia); Not assigned (US FDA)
• Pazopanib can cause fetal harm. Animal studies showed teratogenicity and embryolethality at clinically relevant doses. It is contraindicated during pregnancy unless the benefits outweigh the risks. Effective contraception should be used during treatment and for at least 2 weeks after the last dose.
• Breastfeeding: Pazopanib may be excreted in breast milk and can potentially cause serious adverse reactions in nursing infants. Breastfeeding is contraindicated during treatment and for 2 weeks after the last dose.

Drug Profile Summary

• Mechanism of Action: Multi-target tyrosine kinase inhibitor, primarily targeting VEGFR, PDGFR, and c-kit.
• Side Effects: Diarrhea, nausea, vomiting, fatigue, hypertension, hair loss, skin changes, hepatotoxicity, QT prolongation.
• Contraindications: Hypersensitivity, severe hepatic impairment, coadministration with strong CYP3A4 inhibitors/inducers or P-gp inhibitors without dose adjustment.
• Drug Interactions: Numerous drug interactions, notably with CYP3A4 inhibitors/inducers, P-gp inhibitors, and drugs that prolong the QT interval.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: 800 mg orally once daily (adjustments needed for hepatic impairment and drug interactions).
• Monitoring Parameters: Liver function tests, blood pressure, complete blood count, electrocardiogram (ECG) (especially for patients at risk for QT prolongation), renal function, thyroid function.

Popular Combinations

While there are no firmly established “popular” combinations, pazopanib is sometimes used in combination with other targeted therapies or chemotherapy agents in clinical trials for various cancers. The specific combinations and their rationale depend on the tumor type and ongoing research.

Precautions

• General Precautions: Monitor for hepatotoxicity, QT prolongation, hypertension, bleeding, and gastrointestinal perforation. Pre-screening for these conditions is essential.
• Specific Populations:
  • Pregnant Women: Contraindicated due to risk of fetal harm.
  • Breastfeeding Mothers: Contraindicated due to potential adverse effects on infants.
  • Children & Elderly: Use with caution, consider age-related physiological changes.
  • Menstruating Individuals: Specific considerations not applicable.
• Lifestyle Considerations: Alcohol consumption should be limited due to potential liver-related side effects. Smoking may interact with pazopanib metabolism. Avoid grapefruit and grapefruit juice. Patients should be advised about potential fatigue and its impact on activities like driving.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Pazopanib?

A: The standard recommended dosage for adults is 800 mg orally once daily, taken without food. Adjustments are needed for patients with moderate to severe hepatic impairment and when co-administered with interacting medications. Pazopanib is not recommended for children under 2 years old.

Q2: What are the most common side effects of Pazopanib?

A: The most common side effects include diarrhea, nausea, vomiting, hair loss/changes in hair color, fatigue, high blood pressure, and skin rash.

Q3: How does Pazopanib work?

A: Pazopanib is a multi-targeted tyrosine kinase inhibitor that primarily inhibits VEGFR, PDGFR, and c-kit, thereby blocking tumor angiogenesis and cell proliferation.

Q4: What are the serious side effects to watch out for with Pazopanib?

A: Serious side effects can include hepatotoxicity, QT prolongation/Torsades de pointes, severe bleeding, heart problems (including decreased LVEF), tumor lysis syndrome, pneumothorax, and gastrointestinal perforation.

Q5: Can Pazopanib be used during pregnancy or breastfeeding?

A: Pazopanib is contraindicated during pregnancy and breastfeeding due to potential risks to the fetus/infant.

Q6: What are the key drug interactions with Pazopanib?

A: Pazopanib interacts with strong CYP3A4 inhibitors and inducers, P-gp inhibitors, drugs that prolong the QT interval, and gastric acid-reducing agents.

Q7: How should Pazopanib be taken?

A: Pazopanib should be taken orally once daily without food (at least 1 hour before or 2 hours after a meal). The tablets should be swallowed whole and not crushed or broken.

Q8: How should I monitor patients on Pazopanib?

A: Closely monitor liver function tests, blood pressure, ECG, complete blood count, and renal function. Thyroid function tests should also be performed.

Q9: Is there a specific antidote for Pazopanib overdose?

A: There is no specific antidote for pazopanib overdose. Treatment is supportive and focuses on managing symptoms.

Q10: What should I do if a patient misses a dose of Pazopanib?

A: If a dose is missed, the patient should not take the missed dose if it is less than 12 hours until the next scheduled dose. They should take the next dose at their regular scheduled time.