伊马替尼血药浓度监测在胃肠间质瘤患者全程化管理中的应用探索  

Application of imatinib plasma concentration monitoring in the whole process management of gastrointestinal stromal tumor patients

作　　者：杨琳希 汪明[1] 徐润灏 屠霖[1] 庄淳[1] 赵文毅[1] 马欣俐 李敏[2] 张洁[2] 曹晖[1] Yang Linxi;Wang Ming;Xu Runhao;Tu Lin;Zhuang Chun;Zhao Wenyi;Ma Xinli;Li Min;Zhang Jie;Cao Hui(Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China;Department of Laboratory, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China)

机构地区：[1]上海交通大学医学院附属仁济医院胃肠外科,200127 [2]上海交通大学医学院附属仁济医院检验科,200127

出　　处：《中华胃肠外科杂志》2019年第9期841-847,共7页Chinese Journal of Gastrointestinal Surgery

基　　金：2017年上海市领军人才项目;申康促进市级医院临床技能与临床创新能力三年行动项目(16CR3001A).

摘　　要：目的探讨甲磺酸伊马替尼(IM)血药浓度监测在胃肠间质瘤(GIST)患者服药后的意义。方法采用回顾性病例系列研究方法。病例入组标准:(1)经术后病理或穿刺病理证实GIST并接受IM维持治疗者;(2)已连续相同方式服用相同剂量IM至少4周(达到稳态血药浓度)。排除服用IM仿制药者、合并严重脏器功能不全者以及服用IM同时服用已知显著影响IM药代动力学相关药物者。2018年8月至2019年5月期间就诊于上海交通大学医学院附属仁济医院GIST诊疗中心的185例患者纳入研究,男性114例,女性71例;中位年龄60(30~89)岁;晚期患者63例。术前治疗或术后辅助治疗患者均一次口服IM400mg/d,KIT外显子9突变的患者及IM400mg/d治疗期间疾病进展者一次口服IM600mg/d;如患者服药期间患者出现骨髓抑制等不良反应,则减量或分两次服用。采集外周静脉血(采集时间为:一次服药者为末次服药后22~24h,两次服药者为每天第一次服药前2h内),运用高效液相色谱-串联质谱法(HPLC-MS/MS)检测患者的IM血药浓度。IM血药浓度监测结果与临床数据相关性分析使用直线回归分析。结果185例患者共采集241份稳态IM药物谷浓度血样。分析结果显示,服药剂量为300mg/d和400mg/d的患者,IM血药浓度分别为(942.4±433.5)μg/L和(1340.0±500.1)μg/L(t=6.317,P<0.001);服药剂量为600mg/d的患者,IM血药浓度为(2188.0±875.5)μg/L,高于剂量为400mg者(t=3.557,P=0.004);差异均具有统计学意义。在服药剂量为300mg/d的患者中,GIST晚期患者的IM血药浓度显著低于非晚期患者[(795.6±225.8)μg/L和(992.2±484.4)μg/L,t=2.088,P=0.042]。在服药剂量为400mg/d的患者中,年龄>60岁者的IM药物浓度高于年龄≤60岁者[(1461.0±595.3)μg/L比(1240.0±380.9)μg/L,t=2.528,P=0.013];且伴有腹泻的患者其IM药物浓度显著低于无腹泻者[(745.8±249.6)μg/L比(1382.0±486.9)μg/L,t=6.794,P<0.001];差异也均具有统计学意义。无论服药�Objective To investigate the significance of monitoring imatinib mesylate (IM) plasma concentrations in patients with gastrointestinal stromal tumor (GIST). Methods A retrospective descriptive study was carried out. Inclusion criteria:(1) patients with GIST confirmed by postoperative pathology or puncture pathology receiving maintenance therapy of IM;(2) administration of same dose of IM for at least 4 weeks (achieving steady - state plasma concentration). Patients who had severe organ dysfunction, received IM generics, or received IM simultaneously with other drugs significantly affecting IM pharmacokinetic were excluded. A total of 185 patients at the GIST Clinic of Renji Hospital, Shanghai Jiaotong University School of Medicine from August 2018 to May 2019 were enrolled, including 114 males (61.6%) and 71 females (38.4%) with a median age of 60 years old (range, 30-89 years), and 63 advanced cases. Patients receiving preoperative or postoperative adjuvant therapy were given IM 400 mg QD;patients with KIT exon 9 mutation or with disease progression during IM 400 mg QD treatment were given IM 600 mg QD. If the patient had adverse reactions such as myelosuppression during the medication, IM would be reduced or given BID per day. The peripheral venous blood was collected (22 to 24 hours after the last dose for patients who took IM QD and 2 hours before the first dose per day for those who took IM BID). IM plasma concentration was measured through high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Correlation analysis between IM plasma concentration results and clinical data was performed using linear regression analysis. Results A total of 241 stable blood samples of IM plasma concentration from 185 patients were finally collected. The IM plasma concentrations were significantly different between the doses of 300 mg/d and 400 mg/d [(942.4±433.5)μg/L vs.(1340.0±500.1)μg/L, t=6.317, P<0.001], and between 400 mg/d and 600 mg/d [(1340.0±500.1)μg/L vs.(2188.0±875.5)μg/L,

关 键 词：胃肠间质瘤 伊马替尼 血药浓度 

分 类 号：R735[医药卫生—肿瘤]