McKenna's Pharmacology for Nursing, 2e

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C H A P T E R 1 4  Antineoplastic agents

cells, it is not associated with adverse effects on normal human cells. Gefitinib, lapatinib, nilotinib, sorafenib, sunitinib and temsirolimus work by inhibiting various kinases in the cancer cell. Table 14.6 shows usual indications for all protein tyrosine kinase inhibitors. Gefitinib inhibits tyrosine kinases, including ones associated with epidermal growth factor receptors. It is usually indicated for localised, advanced or metastatic non–small cell lung cancer (NSCLC). Erlotinib is an oral drug that inhibits enzymes asso­ ciated with epidermal growth factor. It is approved for the treatment of non–small cell lung cancer and for first-line treatment of pancreatic cancer when used in combination with gemcitabine. Bortezomib blocks a large protein complex that is necessary for maintaining cell homeostasis, leading to cell death. It must be given IV and is approved for the treatment of mantle cell lymphoma and multiple myeloma. Pharmacokinetics Imatinib is slowly absorbed from the GI tract, reaching peak levels in 2 to 4 hours. It is extensively metabolised in the liver, with a half-life of 18 and then 40 hours. Gefitinib is slowly absorbed from the GI tract, reaching peak levels in 3 to 7 hours. It is metabolised in the liver with a half-life of 48 hours. Lapatinib, given orally, is absorbed from the GI tract, reaching peak levels in 1 to 1.5 hours. Lapatinib is metabolised in the liver, with a half-life of 24 hours. Nilotinib, given orally, reaches peak levels in 3 hours after GI absorption. Most of the drug is excreted unchanged in the stool with a half-life of 17 hours. Sorafenib is well absorbed from the GI tract after oral administration, reaching peak levels in 1 to 2 hours. Most of the drug is excreted unchanged in the stool with a half-life of 24 to 48 hours. Sunitinib, given orally, is slowly absorbed from the GI tract, reaching peak levels in 6 to 12 hours. After metabolism in the liver, it has a half-life of 40 to 60 hours and then 80 to 110 hours for its active metabolite. Temsirolimus, only available for IV use, reaches peak levels at the end of the infusion. It is metabolised in the liver and primarily excreted in the faeces with a half-life of 17 hours and then 55 hours for its active metabolite. Erlotinib is well absorbed orally from the GI tract, reaching peak levels in 4 hours. It is metabolised in the liver with a half-life of 36 hours. Bortezomib, given IV, reaches peak effects at the end of the infusion. It is metabolised in the liver and has a half-life of 40 to 193 hours. Contraindications and cautions All of these drugs are in either pregnancy category C or pregnancy category D (see Chapter 1). Women of childbearing age should be advised to use barrier

contraceptives while taking these drugs. They can enter breast milk, and should be used during breastfeeding only if the benefits to the mother clearly outweigh the risks to the baby. With imatinib, caution should be used in people with known hepatic dysfunction. Nilotinib is contraindicated with individuals who have or are at risk for prolonged QT intervals (hypokalaemia, hypo­ magnesaemia or taking another drug that prolongs the QT interval) because it prolongs the QT interval, and sudden deaths could occur. These drugs should not be given to anyone who has a history of hypersensitivity to any component of the drug being given. Adverse effects The adverse effects associated with imatinib include GI upset, muscle cramps, heart failure, fluid retention and skin rash. The severe bone marrow suppression, alopecia and severe GI effects associated with more traditional antineoplastic therapy do not occur. Gefitinib has been associated with potentially severe interstitial lung disease and various eye symptoms. Nilotinib causes prolonged QT intervals and can impair liver and kidney function. Lapatinib causes diarrhoea and can cause liver impair­ ment and alter heart function. Erlotinib and bortezomib are associated with cardiovascular events and pulmo­ nary toxicity. Bortezomib has also been associated with peripheral neuropathy and liver and kidney impairment. Prototype summary: Imatinib Indications: Treatment of adults with CML who are in blast crisis, accelerated phase, or chronic phase after failure with interferon-alpha therapy. It has since also been approved for use in the treatment of people with CD117-positive unresectable or metastatic GIST. Actions: Tyrosine kinase inhibitor that selectively inhibits the Bcr-Abl tyrosine kinase created by the Philadelphia chromosome abnormality in CML and certain tumour cells present in GIST; blocking this enzyme inhibits proliferation and induces cell division. Pharmacokinetics: Route Onset Peak Oral Slow 2–4 hours T 1/2 : 18 to 40 hours; metabolised in the liver and excreted in the faeces. Adverse effects: Nausea, vomiting, bone marrow suppression, heart failure, headache, dizziness, oedema, rash.