Influence of genetic variants of imatinib on pharmacokinetics and recurrence-free survival in postoperative patients with gastrointestinal stromal tumor.
Luning Sun, Mingqing Xu, Qiang Zhang, Yi Liu, Qiongye Huang, Jianghao Xu, Fengyuan Li, Hao Xu, Yongqing Wang
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引用次数: 0
Abstract
Purpose: Imatinib is the first-line therapy for gastrointestinal stromal tumor (GIST), significantly enhancing patient prognosis. However, its clinical efficacy and safety are highly dependent on plasma concentration, which exhibits considerable interindividual variability. The purpose of this study is to determine the optimal monitoring time for imatinib concentration in postoperative patients with GIST, analyze single nucleotide polymorphisms affecting plasma concentration, and investigate their correlation with efficacy and adverse drug reactions (ADRs), offering valuable insights for personalized therapy.
Methods: This study was conducted on 116 postoperative patients with GIST treated with imatinib in China between 2014 and 2018. Imatinib peak and trough concentrations (Cmax and Cmin) were measured in 608 samples using liquid chromatography-tandem mass spectrometry to determine the optimal monitoring time for steady-state concentration. DNA was extracted from 60 patients' peripheral blood to Genotype 22 single nucleotide polymorphisms in genes such as CYP3A4, CYP3A5, ABCB1, SLC22A1, and SLC22A5 (OCTN2). Therapeutic efficacy was evaluated based on recurrence-free survival (RFS), and ADRs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Statistical analyses were performed using SPSS 26.0, with p < 0.05 considered statistically significant.
Results: The Cmax and Cmin of imatinib and its metabolite N-desmethyl imatinib reached their highest levels within the first month of treatment, and were stabilized by the third month. Genetic polymorphisms in ABCG2 (rs2231137), SLC22A1 (rs628031, rs3605065), and SLC22A5 (OCTN2) (rs2631372) were significantly associated with variations in imatinib Cmin. Genetic polymorphisms in CYP3A5 (rs776746), ABCG2 (rs2231137), and SLC22A1 (rs755828176) influenced imatinib Cmax. Patients carrying the CG and CC genotypes of SLC22A5 (OCTN2) (rs2631372) exhibited longer RFS and lower disease progression risk compared to those with the GG genotype (p < 0.05). Additionally, there was no significant correlation between the occurrence of ADRs and the studied genetic polymorphisms.
Conclusions: Imatinib plasma concentration was stabilized by the third month in postoperative patients with GIST. Genetic polymorphisms in ABCG2, SLC22A1, and SLC22A5 (OCTN2) were associated with imatinib plasma concentration, while SLC22A5 (OCTN2) also influenced recurrence rates. These results provide a reference for personalized therapy and concentration monitoring.
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The European Journal of Clinical Pharmacology publishes original papers on all aspects of clinical pharmacology and drug therapy in humans. Manuscripts are welcomed on the following topics: therapeutic trials, pharmacokinetics/pharmacodynamics, pharmacogenetics, drug metabolism, adverse drug reactions, drug interactions, all aspects of drug development, development relating to teaching in clinical pharmacology, pharmacoepidemiology, and matters relating to the rational prescribing and safe use of drugs. Methodological contributions relevant to these topics are also welcomed.
Data from animal experiments are accepted only in the context of original data in man reported in the same paper. EJCP will only consider manuscripts describing the frequency of allelic variants in different populations if this information is linked to functional data or new interesting variants. Highly relevant differences in frequency with a major impact in drug therapy for the respective population may be submitted as a letter to the editor.
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