Relationship Among Gefitinib Exposure, Polymorphisms of Its Metabolizing Enzymes and Transporters, and Side Effects in Japanese Patients With Non-Small-Cell Lung Cancer.

INTRODUCTION: The present study investigated the effects of patients' genetic variations in the pharmacokinetics of gefitinib at steady-state. We analyzed 31 Japanese patients with non-small-cell lung cancer (NSCLC) who had been treated with gefitinib. We focused on common polymorphisms within important gefitinib exposure genes, including cytochromes P450 (CYPs) CYP3A4*1G, CYP3A5 (*3), and CYP2D6 (*5 and *10) and ATP-binding cassette (ABC) ABCG2 (421C>A) and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T).

MATERIALS AND METHODS: Fourteen days after beginning 250 mg of gefitinib therapy, when the patients were in steady-state, blood samples were collected just before and 1, 2, 4, 6, 8, 12, and 24 hours after oral gefitinib administration. The plasma concentrations of gefitinib were measured using high-performance liquid chromatography.

RESULTS: The median area under the concentration-time curve from 0 to 24 hours (AUC0-24) and trough plasma concentration (C0) of gefitinib was 10,086 ng · h/mL (range, 3247-24,726 ng · h/mL) and 334 ng/mL (range, 77.9-813 ng/mL), respectively. No significant differences were found in the AUC0-24 or C0 for gefitinib or in the frequency of diarrhea, skin rash or hepatotoxicity among the CYP3A4, CYP3A5, CYP2D6, ABCG2 (421C>A), and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T) genotype groups. However, the AUC0-24 and C0 levels of gefitinib in the patients with diarrhea or hepatotoxicity were significantly greater than in those without (diarrhea: AUC0-24, 14,246 vs. 8918 ng · h/mL, P = .006; C0: 421 vs. 261 ng/mL, P = .002; hepatotoxicity: AUC0-24, 12,967 vs. 8473 ng · h/mL, P = .024; C0: 420 vs. 248 ng/mL, P = .002).

CONCLUSION: The side effects from gefitinib were related to exposure but not genetic polymorphism. Therefore, therapeutic drug monitoring after beginning gefitinib therapy rather than the analysis of polymorphism before initiating therapy might be beneficial.