Small Molecule Multitargeted TKI Therapy

Publication
Article
Oncology Nurse EditionONCOLOGY Nurse Edition Vol 22 No 11
Volume 22
Issue 11

Sorafenib is indicated for the treatment of patients with advanced renal cell cancer, and patients with unresectable hepatocellular cancer. Sunitinib is indicated for the treatment of patients with advanced renal cell cancer, and patients with gastrointestinal stromal tumor (GIST) after disease progression on imatinib mesylate (Gleevec).

Indications

Sorafenib is indicated for the treatment of patients with advanced renal cell cancer, and patients with unresectable hepatocellular cancer. Sunitinib is indicated for the treatment of patients with advanced renal cell cancer, and patients with gastrointestinal stromal tumor (GIST) after disease progression on imatinib mesylate (Gleevec).

Mechanism of Action

Sorafenib inhibits a number of tyrosine kinases, including Raf kinase, an enzyme in the RAS pathway, as well as the vascular endothelial growth factor receptor (VEGFR)-2 and platelet-derived growth factor receptor (PDGFR)-β pathways, so not only does it block angiogenesis, but it also blocks cell proliferation via the RAS pathway. Similarly, sunitinib also has antitumor and antiangiogenesis activity through blockade of multiple targets. It inhibits PDGFR-α and β, VEGFR-1,-2, and -3, stem cell factor receptor (KIT), fms-like tyrosine kinase-3 (FLT-3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET).

Metabolism

Sorafenib reaches peak plasma levels in 3 hours after oral dosing. Mean elimination half-life is 25–48 hours. Steady state is reached in 7 days with daily dosing. If drug is given with a high-fat meal, bioavailability is significantly reduced. Drug is highly protein bound, and metabolized by liver cytochrome P450 enzyme CYP3A4, and glucuronidation is mediated by the UGT1A9 pathway. Drug is primarily excreted in feces, and to a lesser degree, urine. Japanese patients may have a 45% lower systemic exposure.

Sunitinib reaches peak plasma levels within 6–12 hours after oral dosing, and the metabolites are highly protein bound. Absorption is not affected by food intake. Drug is metabolized by the liver cytochrome P450 enzyme CYP3A4. Terminal half-life of sunitinib and its primary metabolite are 40–60 hours and 80–110 hours, respectively. Drug is excreted primarily in the feces.

Drug Administration

Sorafenib: 400 mg PO twice daily taken 1 hour before or 2 hours after a meal. Available in 200 mg tablets; if dose reduction needed, reduce to 400 mg daily, and if needed again, reduce dose to 400 mg every other day.

Sunitinib: 50 mg PO daily (with or without food) for 4 weeks, followed by 2 weeks off, in a 6-week cycle. Dose escalation is in 12.5-mg increments, if needed. Available in 12.5 mg and 25 mg tablets.

Patient Education

Teach patient: Purpose of the drug, and how to take it.

• Sorafenib, twice daily 1 hour before or 2 hours after food. Sunitinib once daily with or without food. Possible drug interactions and medicines to avoid, such as St. John’s Wort. If taking sunitinib, avoid grapefruit or grapefruit juice. Avoid aspirin and NSAIDs, and talk to a nurse or doctor prior to taking any over-the-counter medications.

• Lower thyroid gland function tests.

• Effect of drug on blood tests (monitored regularly): Drug may increase serum lipase and amylase, and lower serum phosphate levels. If taking sunitinib, drug may increase LFTs and decrease thyroid gland function.

• Potential side effects, self-care measures, and signs/symptoms to report right away (such as bleeding that does not  stop, shortness of breath, dizziness that does not go away).

– Hypertension may occur, and blood pressure will be monitored regularly.

– Patient should go to hospital ED if severe abdominal pain, nausea, vomiting, or constipation develops, as this may herald a rare gastrointestinal perforation.

– Effective birth-control practices should be used, and women should not breastfeed while receiving the drug.

– Hand-foot syndrome and rash may occur; patient should talk with his nurse or doctor about how to manage this.

– Drug may rarely affect pumping function of the heart. If taking sunitinib, heart test will be done prior to patient starting the drug, and periodically during treatment if needed. Patient should tell provider right away if s/he develops pressure in the chest, has chest pain or difficulty catching her breath, or develops swelling of the feet.

– Sorafenib should be interrupted prior to undergoing major surgery, and resumed after wound has healed.

– Sunitinib may cause adrenal insufficiency, so if patient experiences a stressful event (such as trauma, surgery, infection), he/she will need to be monitored very closely.

Interactions

• Sorafenib: CYP2C9 substrates (eg, warfarin): monitor INR closely. CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, dexamethasone, St. John’s Wort): will increase metabolism of sorafenib and lower its serum concentrations. Doxorubicin, irinotecan, docetaxel, fluorouracil (5-FU): increase antineoplastic serum concentrations so avoid concurrent administration or dose-reduce; 5-FU: drug may also cause a lower area under the curve of 5-FU. CYP2B6 and CYP2C8 substrates: avoid if possible, or dose-reduce substrate drug.

• Sunitinib: CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir [Reyataz], indinavir, nefazodone, nelfinavir, ritonavir [Norvir], saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) increase sunitinib serum levels; avoid concurrent use or decrease sunitinib dose. CYP3A4 inducers (as above) decrease sunitinib serum level; avoid concurrent use or increase sunitinib dose.

Special Considerations

• Sorafenib: Assess baseline CBC; platelets; and serum chemistries, including amylase, lipase, phosphate, LFTs, and thyroid function tests, and repeat periodically during treatment.

• Sunitinib: CBC, platelet count, blood chemistries should be assessed prior to each treatment cycle; thyroid function tests should be assessed at baseline and then as needed; baseline EKG with QT measurement, as well as serum magnesium and potassium should be assessed, and repeated periodically during treatment; baseline serum lipase, amylase, phosphate, LFTs should be assessed.

Contraindications/Precautions

• Known hypersensitivity to the drug or its components.

• Sunitinib: use drug cautiously in patients with QT prolongation, on antiarrhythmia agents, or with pre-existing cardiac disease, bradycardia, or electrolyte disturbances. 

Adverse Reactions by System for both drugs; differences are specified

(most common are in boldface type)

CNS: Depression, paresthesias; sunitinib: rare seizures, reversible posterior leukoencephalopathy syndrome (RPLS).
CV: Hypertension, hemorrhage; sorafenib: rare transient ischemic attack, arrhythmia, thromboembolism, myocardial infarction, angina; sunitinib: swelling, including pedal edema, QTc prolongation (dose-dependent).
GI: Diarrhea, constipation, nausea, vomiting, anorexia, stomatitis, hypoalbuminemia; sunitinib: taste changes, dyspepsia.
GU: sorafenib: rare acute renal failure.
Hematologic: Bleeding, anemia, neutropenia, thrombocytopenia, lymphopenia.
Metabolic: Elevated lipase, amylase, transient increases in AST, ALT; ↓ serum phosphate; sunitinib: ↑ AST/ALT, alkaline phosphatase, total bilirubin, indirect bilirubin, creatinine, uric acid, changes in potassium and sodium, decreased thyroid function, weight loss.
Musculoskeletal: arthralgia, myalgia.
Respiratory: sorafenib: hoarseness.
Reproductive: sorafenib: erectile dysfunction.
Skin: Hand-foot syndrome, rash; sunitinib: skin discoloration, depigmentation of hair strands, hair loss, delayed wound healing.
Other: Fatigue, abdominal pain, weakness, asthenia.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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