Genetic Polymorphisms Contribute to the Individual Variations of Imatinib Mesylate Plasma Levels and Adverse Reactions in Chinese GIST Patients.

Jing Liu,Weimin Cai,Yingyong Hou,Yuhong Zhou,Hanmei Chen,Hanxing Tong,Junyi He,Zhiyu Chen,Weiqi Lu

doi:10.3390/ijms18030603

Abstract

Imatinib mesylate (IM) has dramatically improved the outcomes of gastrointestinal stromal tumor (GIST) patients. However, the clinical responses of IM may considerably vary among single individuals. This study aimed to investigate the influences of genetic polymorphisms of drug-metabolizing enzyme (CYP3A4), transporters (ABCB1, ABCG2), and nuclear receptor (Pregnane X Receptor (PXR, encoded by NR1I2)) on IM plasma levels and related adverse reactions in Chinese GIST patients. A total of 68 Chinese GIST patients who have received IM 300–600 mg/day were genotyped for six single nucleotide polymorphisms (SNPs) (CYP3A4 rs2242480; ABCB1 rs1045642; ABCG2 rs2231137; NRI12 rs3814055, rs6785049, rs2276706), and the steady-state IM trough plasma concentrations were measured by a validated HPLC method. There were statistically significant variances in the steady-state IM trough plasma concentrations (from 272.22 to 4365.96 ng/mL). Subjects of GG in rs2242480, T allele carriers in rs1045642 and CC in rs3814055 had significantly higher steady-state IM dose-adjusted trough plasma concentrations. Subjects of CC in rs3814055 had significantly higher incidence rate of edema. The genetic polymorphisms of rs2242480, rs1045642, rs3814055 were significantly associated with IM plasma levels, and the genetic variations of rs3814055 were significantly associated with the incidence rate of edema in Chinese GIST patients. The current results may serve as valuable fundamental knowledge for IM therapy in Chinese GIST patients.

Highlights

Gastrointestinal stromal tumors (GISTs) are epidemiologically analyzed to be the most common form of the mesenchymal tumor of the gastrointestinal tract, as the worldwide incidence and prevalence are estimated to be approximately 1 to 1.5 per 100,000 per year and 13 per 100,000, respectively [1]
Inter-individual variations in Imatinib mesylate (IM) pharmacokinetics may, have important clinical consequences. This implicates that timely monitoring of IM plasma concentration is warranted in GIST patients
About 47.06% of patients, whose IM trough plasma concentrations are under the minimal plasma concentration thresholds (1100 ng/mL), this may indicate a high risk of disease progression and treatment failure

Summary

Introduction

Gastrointestinal stromal tumors (GISTs) are epidemiologically analyzed to be the most common form of the mesenchymal tumor of the gastrointestinal tract, as the worldwide incidence and prevalence are estimated to be approximately 1 to 1.5 per 100,000 per year and 13 per 100,000, respectively [1]. There are large individual variations in clinical efficacy and adverse reactions of IM [3,4,5]. Ten to fifteen percent of patients who underwent IM treatment after 3–6 months progressed rapidly to widespread metastatic disease [6], about 30% of patients who developed serious adverse reactions had to stop taking medication [7]. The relationship between IM plasma concentrations and efficacy and toxicity have been described [8,9], minimal plasma concentration thresholds (1100 ng/mL) have been established, under which a substantial increase in treatment failure and drug resistance was observed [10]. Inter-individual variations in IM pharmacokinetics may, have important clinical consequences. This implicates that timely monitoring of IM plasma concentration is warranted in GIST patients

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Conclusion