Effects of the ABCG2 C421A Polymorphism on Plasma Gefitinib Concentration

Abstract

Background In patients with epidermal growth factor (EGFR) exon 21 L858R mutation-positive non-small cell lung cancer (NSCLC) treated with gefitinib, we found that a lower plasma gefitinib concentration was associated with shorter progression-free survival (PFS). ATP-binding castle protein G2 (ABCG2) is considered to inhibit the activities of certain gefitinib transporters, which affects drug pharmacokinetics. The C421A polymorphism affects the function and expression of ABCG2 on cell membrane. Previous studies showed that proton pump inhibitors (PPIs) inhibit gefitinib absorption, as well as the function of ABCG2. We evaluated the plasma concentrations of gefitinib in patients with and without the ABCG2 C421A polymorphism, who were or were not taking PPIs. Methods A total of 61 patients with advanced EGFR-positive NSCLC were enrolled in this study. They were treated with gefitinib at a dose of 250 mg per day. Plasma gefitinib concentration and ABCG2 C421A status were determined after 2 weeks. The patients were divided into CC- and CA/AA genotype groups. We compared the trough and peak gefitinib levels, and the area under the curve (AUC) value for 24-hour gefitinib concentration. We also compared these parameters among four groups distinguished according to the presence/absence of the polymorphism and PPI use. Results The mean trough gefitinib level, and the AUC value for 24-hour gefitinib concentration, were significantly lower in the CA/AA group compared to the CC group (mean trough level: 333.2 ± 188.7 vs. 454.5 ± 206.3 ng/mL, P=0.021; AUC: 9,949.9 ± 5,058.9 vs. 13,085.4 ± 5,075.3 ng・h/mL, P=0.034). Among patients taking PPIs, the mean trough gefitinib level was significantly lower in the CA/AA group than the CC group (220.1 ± 112.6 vs. 340.5 ± 98.3 ng/mL, P=0.033). Conclusions The CA/AA-type of ABCG2 C421A polymorphism may be associated with lower gefitinib plasma concentration.