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  • Gefitinib


Gefitinib (ZD1839, Iressa™, Astra-Zeneca) is an anilinoquinazoline that has been approved by the U.S. Food and Drug Administration (FDA) as a single-agent therapy for the treatment of patients with locally advanced or meta-static non-small cell lung cancer (NSCLC) who have not responded successfully to chemotherapies with platinum (carboplatin, cisplatin) and doce-taxel (Taxotere®, Aventis), two drugs that are the standard of care for this disease. Gefitinib is the first in a new class of anticancer drugs that inhibit epidermal growth factor receptor/tyrosine kin-ase (EGFR-TK) (Table 1). EGFR is expressed on both normal cells and solid tumor cells, including 40% to 80% of NSCLCs. EGFR-TK is active in many tumor cells; it has a role in tumor growth, metastasis, angiogenesis, and tumor resistance to chemotherapy and radiotherapy, but it is controlled in normal cells.

Lung cancer is the leading cause of cancer deaths in men and women in the U.S. NSCLC, including adenocarci-noma, squamous cell carcinoma, and large cell carcinoma, is the most common type of lung cancer, accounting for almost 80% of all cases. Because most people with early lung cancer do not have any symptoms, only about 15% of lung cancers are found in the early stages. Patients with resectable NSCLC have the greatest chance of survival; however, most people present with unresectable, locally advanced, or metastatic disease (stage IIIB/IV), and their prognosis is poor.
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Table 1  Overview of Gefitinib

FDA-approved indication Gefitinib monotherapy is approved for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after unsuccessful platinum-based and docetaxel chemotherapies.
Mechanism of action Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell-surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EFGR-TK).
Dosage 250 mg/day orally until disease progression occurs. In clinical studies, higher doses did not yield a better response and caused an increase in toxicity.
Pharmacokinetics •        Bioavailability: 60%

•        Peak plasma levels: 3-7 hours

•        Metabolism: hepatic (CYP-3A4)

•        Excretion: fecal (86%)

•        Elimination half-life: 48 hours

Average wholesale pricef $1,950 per bottle of 30 tablets
* Data from Iressa™ package insert. AstraZeneca Pharmaceuticals.1 f Data on file from the manufacturer.


Oral gefitinib exhibits a dose-proportional kinetic profile that is suitable for a once-daily regimen in cancer patients. The drug is absorbed slowly after oral administration and reaches peak plasma levels (maximal concentration [Cmax] ) three to seven hours after administration in healthy volunteers. Steady-state plasma concentrations are reached within 10 days. The mean oral bioavailability of gefitinib is estimated to be 60%.

In a parallel-group, crossover study with healthy volunteers who received 50 mg of gefitinib, food intake decreased the Cmax by 34% and the area-under-the-curve (AUC) concentration by 14%. In another crossover study in healthy volunteers receiving 250 mg of gefitinib, both the Cmaxand the AUC concentration were increased by 34% and 37%, respectively, with food ingestion. However, food does not have a clinically significant effect on bioavailability. cialis professional

The elimination half-life of gefitinib is 48 hours after intravenous (IV) administration. In a phase 1 trial of patients with solid malignant tumors, the mean half-life after a single 50-mg oral dose was 34 hours. After multiple-dose administration, the average mean half-life was 47.6 hours (range, 37-65 hours).

Gefitinib is metabolized primarily by the cytochrome P-450 (CYP-450) hepatic enzyme 3A4. It is cleared predominantly by the liver and is excreted in the feces (86%), with less than 4% of the drug and its metabolites eliminated renally.

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