Effects of Histamine 2-receptor Antagonists and Proton Pump Inhibitors on the Pharmacokinetics of Gefitinib in Patients With Non–small-cell Lung Cancer

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Abstract

Introduction

In this study, we investigated the degree of drug interactions between gefitinib and gastric acid suppressants (ie, histamine 2-receptor antagonists [H2RAs] or proton pump inhibitors [PPIs]) with a clinical standard dose in Japanese patients with non–small-cell lung cancer.

Methods

Retrospectively, 47 patients were divided into 3 groups: gefitinib therapy with a PPI (15 patients) or an H2RA (8 patients) or gefitinib therapy alone (24 patients). On day 15 after beginning gefitinib therapy (administration at 08:00) with or without H2RA (administration twice daily at 08:00 and 18:30) or PPI (administration once daily at 08:00 or 18:30), whole blood samples were collected just prior to and at 1, 2, 4, 6, 8, 12, and 24 hours after administration.

Results

The total area under the observed plasma concentration-time curve (AUC0-24) and the maximum and trough plasma concentrations of gefitinib with the PPI were significantly lower than those without the PPI. The AUC0-24 of gefitinib with PPI administration in either the morning or evening were significantly lower than those without PPI administration (P = .015 and .049, respectively); however, there were no significant differences in gefitinib AUC0-24 between patients taking PPI in the morning and evening. No significant differences were observed in gefitinib exposure among the 3 CYP2C19 genotypes. The AUC0-24 of gefitinib with H2RA tended to be lower than that without H2RA.

Conclusion

If the plasma concentrations of gefitinib cannot be monitored, the combination of gefitinib and PPI should be avoided, and an H2RA should also be used carefully.

Micro-Abstract

We investigated the drug interactions between gefitinib and gastric acid suppressants. Plasma concentrations of gefitinib with proton pump inhibitors (PPIs) after either the morning or evening administration were significantly lower than those without PPIs, and in clinically applicable doses of histamine 2-receptor antagonists, gefitinib exposure was slightly affected. If gefitinib concentrations cannot be monitored, the combination of gefitinib and PPIs should be avoided.

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