Sunitinib

Usage

Sunitinib malate is prescribed for the treatment of several types of cancer:

• Gastrointestinal Stromal Tumor (GIST): Specifically for GIST that cannot be surgically removed, has metastasized, or has progressed despite imatinib mesylate treatment.
• Advanced Renal Cell Carcinoma (RCC): For RCC that has spread to other parts of the body.
• Adjuvant Treatment of RCC: Following nephrectomy in patients at high risk of recurrence.
• Pancreatic Neuroendocrine Tumors (pNET): For progressive, well-differentiated pNET that is unresectable, locally advanced, or metastatic.

Pharmacological Classification: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor.

Mechanism of Action: Sunitinib inhibits multiple receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, platelet-derived growth factor receptors (PDGFRs) α and β, stem cell factor receptor (KIT), FMS-like tyrosine kinase 3 (FLT3), colony stimulating factor 1 receptor (CSF-1R), and glial cell line-derived neurotrophic factor receptor (RET). By inhibiting these RTKs, sunitinib blocks signaling pathways involved in tumor angiogenesis (blood vessel formation), tumor growth, and metastasis.

Alternate Names

International Nonproprietary Name (INN): Sunitinib malate

Brand Name: Sutent

How It Works

Pharmacodynamics: Sunitinib exerts its anti-cancer effects primarily by inhibiting tumor angiogenesis and tumor cell proliferation. Inhibition of VEGFRs reduces the formation of new blood vessels that supply the tumor, thereby limiting its growth and spread. Inhibition of PDGFR, KIT, and other RTKs directly targets tumor cell growth and survival.

Pharmacokinetics:

• Absorption: Sunitinib is orally administered and well-absorbed, reaching peak plasma concentrations within 6 to 12 hours. Food may slightly delay absorption, but does not significantly affect overall bioavailability.
• Metabolism: Sunitinib is primarily metabolized by the liver, mainly through CYP3A4 enzyme. A major active metabolite, N-desethyl sunitinib, contributes to the drug’s therapeutic activity.
• Elimination: Sunitinib and its metabolites are primarily eliminated in the feces, with a small portion excreted in urine. The elimination half-life of sunitinib is approximately 40-60 hours, allowing for once-daily dosing.

Mode of Action: Sunitinib competitively binds to the ATP-binding site of its target RTKs, thereby preventing phosphorylation and activation of downstream signaling cascades. This leads to inhibition of cell proliferation, migration, and angiogenesis.

Receptor Binding/Enzyme Inhibition: Sunitinib is an inhibitor of multiple RTKs, as outlined above. It primarily acts by inhibiting receptor autophosphorylation. The main metabolic pathway involves CYP3A4.

Elimination Pathways: Predominantly fecal excretion, with minor renal excretion. Metabolism primarily via CYP3A4.

Dosage

Standard Dosage

Adults:

• GIST and Advanced RCC: 50 mg orally once daily for 4 weeks, followed by a 2-week off period (Schedule 4/2), to complete a 6-week cycle.
• Adjuvant Treatment of RCC: 50 mg orally once daily for 4 weeks, followed by 2 weeks off (Schedule 4/2), for a maximum of 9 cycles (54 weeks).
• pNET: 37.5 mg orally once daily continuously, without a scheduled off-treatment period.

Children: The safety and efficacy of sunitinib in pediatric patients have not been fully established. Limited data suggest a possible starting dose of 20 mg/m² on a 4-weeks-on, 2-weeks-off schedule. Careful monitoring and dose adjustments are crucial in pediatric use.

Special Cases:

• Elderly Patients: No specific starting dose adjustment is required. Close monitoring for toxicity is recommended.
• Patients with Renal Impairment: No starting dose adjustment needed. Monitor and adjust subsequent doses based on individual safety and tolerability.
• Patients with Hepatic Dysfunction:
  • Mild to Moderate Impairment (Child-Pugh Class A and B): No starting dose adjustment needed. Careful monitoring is recommended.
  • Severe Impairment (Child-Pugh Class C): Contraindicated.
• Patients with Comorbid Conditions: Careful monitoring is required in patients with cardiovascular disease, diabetes, thyroid dysfunction, bleeding disorders, and electrolyte imbalances.

Clinical Use Cases

Sunitinib’s clinical use focuses on its approved indications, GIST, RCC, and pNET. Dosing remains consistent with standard recommendations, regardless of the setting (inpatient, outpatient, intensive care). It does not have specific applications for intubation, surgical procedures, or mechanical ventilation. It is not typically used in emergency situations like cardiac arrest or status epilepticus.

Dosage Adjustments

Dose adjustments may be necessary based on individual safety and tolerability. Dose modifications are typically made in 12.5 mg increments. Dose reductions may be necessary for adverse events, while dose increases might be considered in cases of concomitant medications inducing CYP3A4. Renal and hepatic impairment (except severe hepatic impairment) do not require initial dose adjustments, but necessitate careful monitoring and potential subsequent adjustments.

Side Effects

Common Side Effects:

Fatigue, asthenia, diarrhea, nausea, vomiting, stomatitis, dyspepsia, abdominal pain, hand-foot syndrome (palmar-plantar erythrodysesthesia), hypertension, skin discoloration, hair color changes, altered taste, anorexia.

Rare but Serious Side Effects:

Hepatotoxicity (including liver failure), cardiac dysfunction (including heart failure, myocardial infarction, cardiomyopathy), QT interval prolongation, Torsades de pointes, hemorrhagic events, thromboembolic events, reversible posterior leukoencephalopathy syndrome, hypothyroidism, hyperthyroidism, hypoglycemia, osteonecrosis of the jaw, adrenal insufficiency, gastrointestinal perforation.

Long-Term Effects:

Chronic complications from prolonged use may include persistent hypertension, cardiac dysfunction, hypothyroidism, and secondary malignancies.

Adverse Drug Reactions (ADR):

Clinically significant ADRs include severe hepatotoxicity, cardiac events (myocardial infarction, heart failure), QT interval prolongation/Torsades de pointes, severe hemorrhage, thromboembolic events, and osteonecrosis of the jaw. These require immediate medical intervention.

Contraindications

• Hypersensitivity: Sunitinib is contraindicated in patients with a known hypersensitivity to the drug or its excipients.
• Severe Hepatic Impairment (Child-Pugh Class C).

Drug Interactions

• CYP3A4 Inhibitors: Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, erythromycin, clarithromycin, grapefruit juice) can significantly increase sunitinib plasma concentrations. If co-administration is unavoidable, reduce the sunitinib dose and monitor carefully.
• CYP3A4 Inducers: Strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, St. John’s Wort) can decrease sunitinib plasma concentrations. Avoid co-administration if possible or consider dose adjustment.
• Anticoagulants: Sunitinib can increase bleeding risk. Monitor coagulation parameters in patients receiving concomitant anticoagulants.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Category D (FDA); Category D (AU TGA).
• Fetal Risks: Sunitinib can cause fetal harm, including embryolethality, craniofacial and skeletal malformations. It should be avoided during pregnancy. Effective contraception is mandatory.
• Breastfeeding: Sunitinib and its metabolites are excreted in rat milk. It is not known whether they are present in human milk, but due to potential risks to the infant, breastfeeding is contraindicated during sunitinib treatment and for 4 weeks after the last dose.

Drug Profile Summary

• Mechanism of Action: Multi-targeted RTK inhibitor, primarily targeting VEGFRs, PDGFRs, KIT, and other RTKs. Inhibits angiogenesis, tumor growth, and metastasis.
• Side Effects: Common: fatigue, diarrhea, nausea, stomatitis, hypertension. Serious: hepatotoxicity, cardiac events, QT prolongation, hemorrhage, thromboembolic events, hypothyroidism, hypoglycemia, osteonecrosis of the jaw.
• Contraindications: Hypersensitivity, severe hepatic impairment.
• Drug Interactions: CYP3A4 inhibitors/inducers, anticoagulants.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: GIST/Advanced RCC: 50 mg daily (4 weeks on, 2 weeks off). Adjuvant RCC: 50 mg daily (4 weeks on, 2 weeks off) for up to 9 cycles. pNET: 37.5 mg daily continuously.
• Monitoring Parameters: Liver function tests, blood pressure, complete blood count, thyroid function tests, cardiac function (ECG), blood glucose, electrolytes.

Popular Combinations

Sunitinib is generally used as monotherapy. Combination therapies are under investigation but not yet routinely used in standard practice.

Precautions

• General Precautions: Assess cardiac, hepatic, renal, thyroid, and metabolic function before and during treatment. Monitor blood pressure, blood counts, and electrolytes.
• Specific Populations:
  • Pregnant Women: Contraindicated.
  • Breastfeeding Mothers: Contraindicated.
  • Children & Elderly: Careful monitoring for adverse events.
• Lifestyle Considerations: Avoid grapefruit and its juice. Advise against driving or operating machinery if dizziness or fatigue occurs.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Sunitinib?

A: The recommended dose varies based on indication:

• GIST and Advanced RCC: 50 mg orally once daily, 4 weeks on, 2 weeks off.
• Adjuvant Treatment of RCC: 50 mg orally once daily, 4 weeks on, 2 weeks off, for a maximum of 9 cycles.
• pNET: 37.5 mg orally once daily continuously.

Q2: What are the most serious side effects of sunitinib?

A: Serious side effects may include liver failure, heart problems (heart failure, heart attack, cardiomyopathy), severe bleeding, blood clots, and osteonecrosis of the jaw.

Q3: Can sunitinib be used during pregnancy or breastfeeding?

A: No, sunitinib is contraindicated during pregnancy and breastfeeding due to the risk of fetal harm and potential infant exposure.

Q4: How should sunitinib be administered?

A: Sunitinib is administered orally as capsules, once daily. It can be taken with or without food.

Q5: What if a patient misses a dose of sunitinib?

A: If a dose is missed, the patient should not take an extra dose. They should take the next scheduled dose at the regular time.

Q6: Does sunitinib interact with other medications?

A: Yes, sunitinib can interact with certain medications, including some antibiotics, antifungals, and heart medications. It’s important to inform the prescribing physician about all concomitant medications, including over-the-counter drugs and supplements.

Q7: What are the key monitoring parameters for patients on sunitinib?

A: Key parameters include liver function tests, blood pressure monitoring, complete blood counts, thyroid function tests, cardiac monitoring (ECG), blood glucose levels, and electrolyte monitoring.

Q8: Can sunitinib be used in patients with renal impairment?

A: Yes, sunitinib can be used in patients with mild to severe renal impairment, including those on hemodialysis, without an initial dose adjustment. However, close monitoring and subsequent dose adjustments may be needed based on individual safety and tolerability.

Q9: What should be done if a patient develops severe hypertension while on sunitinib?

A: Sunitinib-induced hypertension should be managed aggressively. Dose interruption or reduction may be necessary. Appropriate antihypertensive therapy should be initiated as needed.

Q10: What are the signs and symptoms of sunitinib-induced hepatotoxicity?

A: Signs and symptoms may include jaundice (yellowing of the skin and eyes), dark urine, right upper quadrant pain, and elevated liver enzymes. Liver function tests should be monitored regularly.