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Sunitinib: Indications, Adverse Effects, Contraindications and Dosage

Mechanism of Action of Sunitinib:

Sunitinib is an oral multikinase inhibitor that suppresses signaling through VEGFR and PDGFR pathways. Additional targets include KIT, FLT3, CSF1R, and RET. The receptor inhibition produces anti-angiogenic and anti-proliferative effects in malignant tumors.

Urologic Indications of Sunitinib:

Sunitinib is a treatment option of metastatic renal cell carcinoma in patients with favorable risk who have contraindications to checkpoint inhibitors (Sternberg et al., 2010). Sunitinib is also used as a second-line therapy after progression on checkpoint inhibitors (e.g. nivolumab or pembrolizumab).

Pharmacokinetics of Sunitinib:

Administration is oral. Hepatic metabolism occurs via CYP3A4 to an active metabolite. Elimination is predominantly biliary and fecal, with a renal component. Effective half-lives are approximately 40–60 hours for the parent drug and 80–110 hours for the active metabolite.

Adverse Effects of Sunitinib:

Gastrointestinal Tract:

Nausea and vomiting, diarrhea, mucositis or stomatitis, and decreased appetite are common. Rare pancreatitis may occur; monitor serum lipase.

Skin:

Impaired wound healing, hand–foot skin reaction (approximately 20%): pressure-bearing areas may develop blisters. Exanthema (approximately 20%) and xeroderma (approximately 16%) may also occur.

Blood:

Thrombocytopenia, anemia, and neutropenia are common to very common.

Other Adverse Effects:

Fatigue (50%), hypertension (25%), heart failure, hypothyroidism (common), bleeding, epistaxis (10%), hypophosphatemia, headache, proteinuria, nephrotic syndrome, peripheral edema, and asthenia. Consider the risk of QT interval prolongation in susceptible patients.

Contraindications of Sunitinib:

• Hypersensitivity to the active substance.
• Do not administer sunitinib in severe hepatic insufficiency; exercise caution with elevated transaminases.
• Persistent grade 3/4 adverse events despite dose reduction.
• Pregnancy and lactation.
• Perioperative period until wound healing is complete.

Drug Interactions of Sunitinib:

Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, Grapefruit) increase exposure; avoid when possible or consider dose reduction of sunitinib. Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin) reduce exposure and may compromise efficacy.

Dosing of Sunitinib:

Administer 50 mg of sunitinib orally once daily on Days 1–28, followed by a two-week treatment break. Reduce the dose to 37.5 mg per day for toxicity, or extend the treatment break in accordance with toxicity management recommendations.

Monitoring During Therapy:

Perform regular monitoring of complete blood count; electrolytes including phosphate; liver function tests; lipase; coagulation parameters as indicated; blood glucose; serum creatinine; urinalysis for proteinuria; and thyroid-stimulating hormone. Conduct focused examinations of the skin and oral cavity and measure blood pressure regularly. Consider baseline and risk-guided electrocardiography and echocardiography in patients with cardiac risk factors.

Supportive Therapy:

Use loperamide for diarrhea. For mucositis, employ regular mouth rinses. To prevent hand–foot skin reaction, reduce mechanical stress and consider keratolytic or corticosteroid-containing topical agents. Treat hypertension in accordance with clinical guidelines. Replace thyroid hormone with levothyroxine for hypothyroidism. If adverse effects remain uncontrolled, reduce the dose or interrupt therapy.

References

Motzer und Bukowski 2006 MOTZER, Robert J. ; BUKOWSKI, Ronald M.: Targeted therapy for metastatic renal cell carcinoma.
In: J Clin Oncol
24 (2006), Dec, Nr. 35, S. 5601–5608. -
URL https://dx.doi.org/10.1200/JCO.2006.08.5415

Motzer u.a. 2007 MOTZER, Robert J. ; HUTSON, Thomas E. ; TOMCZAK, Piotr ; MICHAELSON, M. D. ; BUKOWSKI, Ronald M. ; RIXE, Olivier ; OUDARD, Stéphane ; NEGRIER, Sylvie ; SZCZYLIK, Cezary ; KIM, Sindy T. ; CHEN, Isan ; BYCOTT, Paul W. ; BAUM, Charles M. ; FIGLIN, Robert A.: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
In: N Engl J Med
356 (2007), Jan, Nr. 2, S. 115–124. -
URL https://dx.doi.org/10.1056/NEJMoa065044

  Deutsche Version: Nebenwirkungen, Kontraindikationen und Dosierung von Sunitinib

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