Iressa

[gefitinib tablets]

Clinical Pharmacology
CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of the clinical antitumor action of gefitinib is not fully characterized. 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 (EGFR- TK). EGFR is expressed on the cell surface of many normal cells and cancer cells. No clinical studies have been performed that demonstrate a correlation between EGFR receptor expression and response to gefitinib.

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Pharmacokinetics

Gefitinib is absorbed slowly after oral administration with mean bioavailability of 60%. Elimination is by metabolism (primarily CYP3A4) and excretion in feces. The elimi-nation half-life is about 48 hours. Daily oral administration of gefitinib to cancer patients resulted in a 2- fold accumulation compared to single dose administration. Steady state plasma concentrations are achieved within 10 days. O N N F CI HN N O O

Absorption and Distribution

Gefitinib is slowly absorbed, with peak plasma levels occurring 3-7 hours after dosing and mean oral bioavailability of 60%. Bioavailability is not significantly altered by food. Gefitinib is extensively distributed throughout the body with a mean steady state volume of distribution of 1400 L following intravenous administration. In vitro binding of gefitinib to human plasma proteins (serum albumin and a1- acid glyco-protein) is 90% and is independent of drug concentrations.

Metabolism and Elimination

Gefitinib undergoes extensive hepatic metabolism in humans, predominantly by CYP3A4. Three sites of biotransformation have been identified: metabolism of the N- propoxymorpholino-group, demethylation of the methoxy- substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group. Five metabolites were identified in human plasma. Only O- desmethyl gefitinib has exposure comparable to gefitinib.

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