Indications
Gefitinib is indicated for the ongoing treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have experienced disease progression following treatment with either platinum-based or docetaxel chemotherapies. This therapeutic option is particularly relevant for individuals whose cancer has not responded adequately to these conventional treatments, providing an alternative pathway for disease management.
Pharmacodynamics
Gefitinib functions by inhibiting the intracellular phosphorylation of various tyrosine kinases linked to transmembrane cell surface receptors, notably those associated with the epidermal growth factor receptor (EGFR-TK). The EGFR is present on the surface of numerous normal and malignant cells, and its inhibition by gefitinib can interrupt cellular processes that are critical to tumor growth and survival, making it an effective treatment for certain types of cancer that over-express this receptor.
Absorption
Upon oral administration, gefitinib is absorbed slowly, achieving a mean bioavailability of approximately 60%. The time to reach peak plasma concentrations typically ranges from 3 to 7 hours post-dose. Notably, the bioavailability of gefitinib is not influenced by food intake, allowing for flexibility in administration with regard to meals.
Metabolism
Gefitinib is primarily metabolized in the liver via the cytochrome P450 enzyme CYP3A4. Its metabolic pathways include modification of the N-propoxymorpholino group, demethylation of the methoxy substituent on the quinazoline moiety, and oxidative defluorination of the halogenated phenyl group. Understanding these metabolic processes is essential for anticipating drug interactions and tailoring treatment to individual patient needs.
Mechanism of Action
Gefitinib functions as a selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase by targeting its adenosine triphosphate (ATP)-binding site. EGFR is frequently overexpressed in various human carcinomas, including lung and breast cancers. This overexpression amplifies the activation of anti-apoptotic Ras signal transduction pathways, leading to enhanced cancer cell survival and unchecked cell proliferation. By inhibiting EGFR tyrosine kinase, gefitinib effectively disrupts these downstream signaling pathways, thereby curtailing malignant cell growth and proliferation. As the first selective inhibitor of EGFR tyrosine kinase, also known as Her1 or ErbB-1, gefitinib offers a targeted therapeutic approach to managing cancers characterized by EGFR overexpression.
