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, t=3.557, P=0.004]. Among the blood samples of 57 patients receiving IM 300 mg/d, the IM plasma concentration of the advanced patients was significantly lower than that of the non-advanced patients [(795.6±225.8) μg/L vs. (992.2±484.4) μg/L, t=2.088, P=0.042]. Among the 137 blood samples of patients receiving IM 400 mg/d, the IM plasma concentration was higher in patients aged >60 years than those aged ≤60 years [(1461.0±595.3) μg/L vs. (1240.0±380.9) μg/L, t=2.528, P=0.013] and the IM plasma concentration of cases with diarrhea was significantly lower than that of those without diarrhea [(745.8±249.6) μg/L vs. (1382.0±486.9) μg/L, t=6.794, P<0.001]. Gender, primary location, surgical procedure, mutated gene, mutation type, or time of administration was associated with IM plasma concentration no matter in patients taking IM doses of 400 mg/d or 300 mg/d (all P>0.05). Regression analysis showed that body mass (P=0.004 and P=0.019), body mass index (P=0.016 and P=0.042), and body surface area (P=0.007 and P=0.028) were all negatively correlated with IM plasma concentrations in patients taking IM doses of 300 mg/d and 400 mg/d. Within the 137 patients who received a fixed oral dose of 400 mg/d IM, 17 patients received oral 200 mg BID, whose IM plasma drug concentration was not significantly different compared with that of 120 patients who received 400 mg IM QD [(1488.0±408.3) μg/L vs. (1319.0±509.7) μg/L, t=1.307, P=0.193]. Conclusions: Monitoring IM plasma concentration is significant throughout the whole process of management of GIST patients receiving IM treatment. In particular, regular monitoring IM plasma concentration and developing appropriate treatment strategies can bring better therapeutic benefits for patients with low doses, diarrhea, advanced condition and older age.
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IM 400 mg/d，KIT外显子9突变的患者及IM 400 mg/d治疗期间疾病进展者一次口服IM 600 mg/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22~24 h，两次服药者为每天第一次服药前2 h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300 mg/d和400 mg/d的患者，IM血药浓度分别为（942.4±433.5）μg/L和（1 340.0±500.1）μg/L（t=6.317，P<0.001）；服药剂量为600 mg/d的患者，IM血药浓度为（2 188.0± 875.5）μg/L，高于剂量为400 mg者（t=3.557，P=0.004）；差异均具有统计学意义。在服药剂量为300 mg/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400 mg/d的患者中，年龄>60岁者的IM药物浓度高于年龄≤60岁者[（1 461.0±595.3）μg/L比（1 240.0±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（1 382.0±486.9）μg/L，t=6.794，P<0.001]；差异也均具有统计学意义。无论服药剂量是400 mg/d还是300 mg/d的患者中，不同性别、原发位置和手术方式以及不同突变基因、不同突变类型、不同服药时间患者间的IM血药浓度差异均无统计学意义（均P>0.05）。直线回归分析结果显示，在IM服药剂量为300 mg/d和400 mg/d的患者中，体质量（P=0.004和P=0.019）、体质指数（P=0.016和P=0.042）、体表面积（P=0.007和P=0.028）均与IM血药浓度呈负相关。 结论： IM血药浓度监测应始终贯穿于接受IM治疗的GIST患者全程化管理中，尤其定期监测药物剂量较低、伴有腹泻、晚期以及高龄患者并制定相应对策，能为其带来较好的治疗效益。.
Keywords: Gastrointestinal stromal tumor; Imatinib; Plasma concentration.