Impacts of SNPs on adverse events and trough concentration of imatinib in patients with gastrointestinal stromal tumors

Abstract

Although imatinib has dramatically improved the outcomes of patients with gastrointestinal stromal tumor (GIST), marked inter-individual differences in its efficacy and toxicity have been observed. Extensive pharmacogenetic studies in Caucasian and Asian populations have demonstrated that several genetic polymorphisms are involved in these differences; however, no studies have focused on Japanese patients with GIST. This study aimed to evaluate the impacts of genetic polymorphisms of drug metabolizing enzymes and transporters on the incidence of adverse events and trough plasma concentrations (C_troughs) of imatinib in Japanese patients with GIST. Of 35 candidate SNPs genotyped from 65 patients, ABCG2 421C>A was significantly associated with increased incidence rates of grade 2 or higher rash. When relationships between the genotypes and C_troughs were examined in a subgroup of 38 patients from whom plasma was available, 5 SNPs were associated with significant trends toward increased or decreased dose-adjusted C_troughs. Of them, SLCO1B3 334T>G and SLCO1A2 -1032G>A made significant contributions to the individual variability of C_trough by multivariate regression analysis. Genetic variations in ABCG2, SLCO1B3, and SLCO1A2 may play important roles in the safety and pharmacokinetics of imatinib in Japanese patients with GIST, although a replication study is necessary for validation.

Keywords: Adverse drug reaction; Gastrointestinal stromal tumors; Genetic polymorphism; Imatinib; Transporter.