Iressa - Clinical Pharmacology

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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.

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.

Rifampicin, an inducer of CYP3A4, reduced mean AUC of gefitinib by 85% in healthy male volunteers (see PRECAUTIONS-Drug Interactions and DOSAGE AND ADMINISTRATION-Dosage Adjustment sections). Concomitant administration of itraconazole (200 mg QD for 12 days), an inhibitor of CYP3A4, with gefitinib (250 mg single dose) to healthy male volunteers, increased mean gefitinib AUC by 88% (see PRECAUTIONS-Drug Interactions section). Co- administration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above pH 5.0) reduced mean gefitinib AUC by 44% (see PRECAU-TIONS- Drug Interactions section).