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Gefitinib
General information
Gefitinib is an anilinoquinazoline derivative, the first agent to have been introduced as a potent inhibitor of EGFR tyrosine kinase for the treatment of advanced non-small-cell lung cancer refractory or resistant to cytotoxic chemotherapy. Case series have shown significant radiographic regression and improvement of symptoms. A history of never smoking cigarettes and bronchoalveolar histology are significant predictors of a radiographic response to gefitinib. In addition, there are higher response rates in Japanese versus non-Japanese subjects, in those of performance status 0–1, in women, and in those with adenocarcinoma histology and prior immunotherapy or hormonal therapy. If several of these characteristics are present simultaneously, higher response rates and a longer median survival time with gefitinib, or the structurally related erlotinib, can be expected [ R ].
The recommended dose of gefitinib is 250 mg/day, and 500 mg/day causes increased toxicity without additional efficacy.
Pharmacokinetics
The mean absolute systemic availability after oral administration averages 60% [ ]. Gefitinib probably crosses the blood–brain barrier, which is favorable in patients with metastatic disease [ ]. Its half-life is about 48 hours, and steady-state concentrations are achieved within 10 days. Hepatic metabolism via CYP3A4 and biliary excretion are the major routes of elimination, and renal excretion is of minor importance.
Organs and systems
Respiratory
The most serious adverse reaction to gefitinib is lung toxicity, including rapidly progressive dyspnea with a risk of severe hypoxemia and bilateral ground-glass attenuation on chest CT.
Of 110 patients with non-small-cell lung cancer who took gefitinib over 3 months, 12 developed significant lung toxicity and five died from progressive complications, including chronic pulmonary fibrosis. The mechanism may involve impairment of healing of epithelium, since EGF is needed to regenerate damaged alveolar epithelial cells. Thus, any underlying lung damage (for example pre-existing pulmonary fibrosis) may predispose to lung toxicity [ , ].
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A 70-year-old woman with a long history of smoking developed a non-small-cell lung cancer, stage IV [ ]. She was given radiotherapy and chemotherapy consisting of cisplatin and gemcitabine. However, she developed hemolytic–uremic syndrome, with raised LDH activity, hypoalbuminemia, reticulocytosis, and a high blood urea nitrogen concentration. When the disease progressed she was given gefitinib 250 mg/day, which resulted in improvement in tumor-related bone pain after several days. However, she developed a characteristic drug-related acneoid reaction and after 2 months developed progressive dyspnea and a dry cough, which gradually worsened. She had interstitial infiltrates in both lungs. Despite high-dose glucocorticoids, her condition worsened and she needed mechanical ventilation. She then developed hemodynamic instability and died.
Gastrointestinal
During treatment with gefitinib 250 mg/day about 40% of patients develop grade 2 diarrhea, which can be successfully controlled in most cases by symptomatic treatment with loperamide. Patients are advised to take loperamide 4 mg immediately, followed by 2 mg after every loose bowel movement (up to a maximum of 10 mg/day). If the is response inadequate, withdrawal of gefitinib may be warranted [7 R ].
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