Iressa

[gefitinib tablets]

Although this metabolite has similar EGFR-TK activity to gefitinib in the isolated enzyme assay, it had only 1/ 14 of the potency of gefitinib in one of the cell- based assays. Gefitinib is cleared primarily by the liver, with total plasma clearance and elimination half-life values of 595 mL/ min and 48 hours, respectively, after intravenous adminis-tration. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.

Special Populations

In population based data analyses, no relationships were identified between predicted steady state trough concentration and patient age, body weight, gender, ethnicity or creatinine clearance.

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Pediatric

There are no pharmacokinetic data in pediatric patients.

Hepatic Impairment

The influence of hepatic metastases with elevation of serum aspartate aminotrans-ferase (AST/ SGOT), alkaline phosphatase, and bilirubin has been evaluated in patients with normal (14 patients), moderately elevated (13 patients) and severely elevated (4 patients) levels of one or more of these biochemical parameters. Patients with moderately and severely elevated biochemical liver abnormalities had gefitinib pharmacokinetics similar to individuals without liver abnormalities (see PRECAU-TIONS section).

Renal Impairment

No clinical studies were conducted with IRESSA in patients with severely compro-mised renal function (see PRECAUTIONS section). Gefitinib and its metabolites are not significantly excreted via the kidney (< 4%).

Drug-Drug Interactions

In human liver microsome studies, gefitinib had no inhibitory effect on CYP1A2, CYP2C9, and CYP3A4 activities at concentrations ranging from 2- 5000 ng/ mL. At the highest concentration studied (5000 ng/ mL), gefitinib inhibited CYP2C19 by 24% and CYP2D6 by 43%. Exposure to metoprolol, a substrate of CYP2D6, was increased by 30% when it was given in combination with gefitinib (500 mg daily for 28 days) in patients with solid tumors.

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