Introduction
Sutent (sunitinib malate) is an oral multi-targeted tyrosine kinase inhibitor developed by Pfizer. It was first approved by the FDA in 2006 and represents a significant advancement in the treatment of several advanced malignancies. As a small molecule inhibitor, Sutent targets multiple receptor tyrosine kinases involved in tumor proliferation, angiogenesis, and metastasis.
Mechanism of Action
Sunitinib functions as a multi-targeted receptor tyrosine kinase inhibitor with potent activity against:
- Vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3)
- Platelet-derived growth factor receptors (PDGFR-α and PDGFR-β)
- Stem cell factor receptor (KIT)
- Fms-like tyrosine kinase-3 (FLT3)
- Colony stimulating factor receptor Type 1 (CSF-1R)
- RET proto-oncogene
By inhibiting these pathways, sunitinib simultaneously targets tumor cell proliferation and angiogenesis while promoting apoptosis. The drug's multi-targeted approach disrupts both tumor growth and blood supply to malignancies.
Indications
Sutent is FDA-approved for: 1. Gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate 2. Advanced renal cell carcinoma (RCC) 3. Progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease 4. Adjuvant treatment of adults at high risk of recurrent RCC following nephrectomy
Dosage and Administration
Standard dosing: 50 mg orally once daily for 4 weeks, followed by 2 weeks off (Schedule 4/2) Alternative schedule: 37.5 mg orally once daily continuously (after consultation with oncology specialist) Administration:- Take with or without food
- Swallow whole; do not crush or break capsules
- If vomiting occurs after dose, do not take additional dose
- Based on tolerability and adverse effects
- Recommended starting dose reduction: 37.5 mg daily
- Subsequent reduction: 25 mg daily
- Renal impairment: No initial dose adjustment necessary
- Hepatic impairment: Use caution in severe impairment
- Elderly: No specific dose adjustment required
- Pediatrics: Safety and efficacy not established
Pharmacokinetics
Absorption: Peak plasma concentrations reached within 6-12 hours; bioavailability unaffected by food Distribution: Volume of distribution: 2230 L; extensively binds to plasma proteins (95% primarily to albumin) Metabolism: Primarily hepatic via CYP3A4 to active metabolite SU12662 Elimination: Half-life: 40-60 hours (sunitinib) and 80-110 hours (active metabolite); primarily fecal elimination (61%) with renal excretion accounting for 16% Steady-state: Achieved within 10-14 days; accumulation of both sunitinib and its active metabolite occursContraindications
1. Hypersensitivity to sunitinib or any component of the formulation 2. Concurrent use with strong CYP3A4 inducers (unless medical necessity outweighs risk)
Warnings and Precautions
Cardiovascular:- Left ventricular dysfunction and congestive heart failure
- QT interval prolongation and torsades de pointes
- Hypertension (monitor blood pressure regularly)
- Hemorrhagic events including tumor-related hemorrhage
- Severe hepatic impairment may increase toxicity
- Monitor liver function tests regularly
- Severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis
- Hand-foot syndrome (palmar-plantar erythrodysesthesia)
- Thyroid dysfunction (monitor thyroid function)
- Adrenal function impairment
- Renal toxicity including proteinuria and nephrotic syndrome
- Osteonecrosis of the jaw
- Wound healing complications
- Thrombotic microangiopathy
Drug Interactions
Major interactions:- Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin): Increase sunitinib exposure → reduce sunitinib dose
- Strong CYP3A4 inducers (rifampin, carbamazepine, St. John's wort): Decrease sunitinib exposure → avoid concomitant use or increase sunitinib dose
- CYP3A4 substrates with narrow therapeutic index: Sunitinib may affect their metabolism
- Drugs that prolong QT interval: Additive effect
- Anticoagulants: Increased bleeding risk
Adverse Effects
Very common (>10%):- Fatigue (74%)
- Diarrhea (60%)
- Nausea (58%)
- Anorexia (48%)
- Vomiting (40%)
- Hypertension (30%)
- Mucosal inflammation (29%)
- Dysgeusia (28%)
- Rash (27%)
- Hand-foot syndrome (26%)
- Bleeding events (26%)
- Neutropenia (19%)
- Thrombocytopenia (18%)
- Congestive heart failure (2%)
- Left ventricular dysfunction (2%)
- QT prolongation (1%)
- Hemorrhagic events (3%)
- Thrombotic microangiopathy (<1%)
- Hepatotoxicity (1%)
- Pancreatitis (<1%)
- Tumor lysis syndrome (<1%)
Monitoring Parameters
Baseline assessment:- Complete blood count with differential
- Comprehensive metabolic panel including liver and renal function
- Thyroid function tests
- ECG (especially if cardiac risk factors present)
- Left ventricular ejection fraction assessment
- Blood pressure
- Urinalysis for proteinuria
- CBC weekly for first cycle, then each cycle
- Blood pressure weekly initially, then regularly
- Thyroid function monthly
- Liver function tests each cycle
- ECG as clinically indicated
- LVEF assessment as clinically indicated
- Signs/symptoms of congestive heart failure
- Signs of bleeding or hemorrhage
- Skin examination for hand-foot syndrome
- Dental examination for osteonecrosis of the jaw risk
Patient Education
Key points for patients:- Take exactly as prescribed; do not adjust dose without medical supervision
- Report any chest pain, shortness of breath, or swelling immediately
- Monitor blood pressure regularly as advised by healthcare provider
- Report signs of infection (fever, chills) or unusual bleeding/bruising
- Be aware of potential hand-foot skin reactions and report redness, pain, or blistering
- Maintain good oral hygiene and inform dentist about Sutent therapy
- Use effective contraception during treatment and for several months after completion
- Avoid grapefruit and grapefruit juice during therapy
- Report severe diarrhea, vomiting, or dehydration symptoms
- Be aware of potential fatigue and plan activities accordingly
- Keep all scheduled appointments for monitoring and laboratory tests
- Inform all healthcare providers about Sutent therapy, including before any surgical procedures
References
1. FDA Prescribing Information: Sutent (sunitinib malate). 2021 2. Motzer RJ, et al. Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma. N Engl J Med. 2007;356:115-124 3. Demetri GD, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329-1338 4. Raymond E, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501-513 5. Goodman VL, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007;13:1367-1373 6. Rini BI, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:2271-2281 7. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2021 8. Micromedex Solutions [Internet]. Greenwood Village (CO): Truven Health Analytics; 2021