胃肠间质瘤患者服药前后监测伊马替尼血浆浓度意义的中国多中心研究

A Chinese multi-center study on the significance of monitoring imatinib plasma concentration in patients with gastrointestinal stromal tumor before and after administration

目的探讨中国胃肠间质瘤（GIST）患者在治疗过程中监测伊马替尼血浆浓度的意义。方法将2014年12月至2016年4月期间国内10家中心收治的60例术后口服伊马替尼治疗的GIST患者纳入横断面研究，患者分别来自南京医科大学第一附属医院（28例）、南通大学附属医院（9例）、徐州医学院附属医院（6例）、南京鼓楼医院（5例）、南京医科大学第二附属医院（2例）、南京军区总医院（2例）、连云港第二人民医院（2例）、山东省立医院（2例）、江苏省肿瘤医院（2例）和浙江大学第一附属医院（2例）。在患者服药前后选取时间点采集血样，使用液相色谱-串联质谱分析法（LC-MS／MS）检测患者伊马替尼的血浆浓度，伊马替尼的血浆浓度与用药剂量、患者临床病理特征和不良反应的相关性分析采用直线回归分析。结果对于不能耐受每日剂量为400mg伊马替尼的GIST患者（3例），给予每日300mg后，其血浆伊马替尼浓度与400mg剂量患者（53例）相近（P=0．527）；但每日剂量为600mg的高危患者（4例）的伊马替尼血浆浓度明显高于400mg剂量患者（P=0．000）。直线回归分析显示，每日剂量为400mg、持续服用90d的患者其伊马替尼血浆浓度与其体表面积显著负相关（R2=0．074，P=0．035）；而与年龄、肌酐清除率和血浆白蛋白水平无明显相关性（均P〉0．05）。不同性别的患者以及是否服用质子泵抑制剂（PPI），其伊马替尼血浆浓度的差异没有统计学意义（均P〉0．05）。不同手术方式患者的伊马替尼血浆浓度差异有统计学意义（P=0．026），其中行胃大部切除术或全胃切除术的患者相比于楔形切除术、肠切除术及其他手术方式患者的伊马替尼血浆浓度明显降低（均P〈0．05）。持续用药超过90d后，直线回归分析显示，每日剂量为400mg的患者伊马替尼血浆浓度与白细胞计数呈负相关（R2=0．103，P=0．013），与血浆丙氨酸转移酶（ALT）浓度呈正相关（R2=0．076，P=0．033）。结论体表面积较大、行胃大部切除术或全胃切除术的患者伊马替尼血浆浓度可能较低，对该类患者可考虑适量加大伊马替尼的给药剂量，以达到有效的血浆浓度。而患者伊马替尼的血浆浓度过高会造成白细胞计数降低和肝功能损伤等不良反应。因此，监测伊马替尼血浆水平，适时调整伊马替尼剂量，将伊马替尼血浆浓度稳定维持在有效且安全的范围对临床获得最佳的治疗效果有重要意义。

Objective To investigate the factors which may influence the imatinib plasma concentration in Chinese patients with gastrointestinal stromal tumor （GIST）, and to illuminate the significance of monitoring imatinib plasma concentration in adjuvant therapy for patients with GIST. Methods A cross-sectional study with 60 GIST patients who accepted the imatinib therapy after surgery was conducted. They were respectively administrated in 10 domestic hospitals from December 2014 to April 2016, including The First Affiliated Hospital of Nanjing Medical University （n = 28）, The Affiliated Hospital of Nantong University（n = 9）, The Affiliated Hospital of Xuzhou Medical College（n = 6）, Nanjing Drum Tower Hospital （n = 5）, The Second Affiliated Hospital of Nanjing Medical University （n = 2）, Jingling Hospital （n = 2）, The Second People＇s Hospital of Lianyungang （n = 2）, Shandong Provincial Hospital（n = 2）, Jiangsu Province Tumor Hospital（n = 2）, and The First Affiliated Hospital of Zhejiang University （n = 2）. Some specific time points for collecting blood sample before and after taking imatinib were determined, then liquid chromatography-tandem mass spectrometry （LC-MS/ MS） method was used for monitoring imatinib plasma concentration in patients with GIST. Linear regression analysis was used for the correlation analysis of imatinib plasma concentration with dosage, clinicopathologic feature and side effect. Results Patients who could not tolerate 400 mg imatinib per day （n = 3） received 300 mg per day. There was no significant difference in imatinib plasma concentration between patients with 300 mg and those with 400 mg imatinib （n = 53）（P = 0.527）. However, the imatinib plasma concentration in patients with 600 mg imatinib per day （n = 4） was significantly higher as compared to those with 400 mg（P= 0.000）. Linear regression analysis indicated a negative correlation between the imatinib plasma concentration in patients with 400mg imatinib per day for 90 days continuously and body surface area （R2 = 0.074, P = 0.035）, but no significant correlations of with age, creatinine clearance and serum albumin concentration were observed （all P 〉 0.05）. The differences in imatinib plasma concentration were not statistically significant between patients of different gender and those taking proton-pump inhibitor （PPI） or not （both P 〉 0.05）. Difference in imatinib plasma concentration between patients with different surgery was significant （P = 0.026）. Compared to patients who underwent wedge resection, enterectomy and other surgeries, the imatinib plasma concentration of patients with subtotal gastrectomy or total gastrectomy decreased significantly （all P 〈 0.05）. After 90 days of taking imatinib continuously, linear regression analysis revealed a negative correlation between imatinib plasma concentration in patients with 400 mg imatinib per day and white blood cell count （R2 = 0.103, P = 0.013）, and a positive correlation with serum alanine aminotransferase （ALT） concentration （R2=0.076, P = 0.033）. Conclusions The imatinib plasma concentration in patients with larger body surface area, subtotal gastrectomy or total gastrectomy may be lower. For these patients, dosage of imatinib should be considered to increase in order to achieve effective plasma concentration. Excessive imatinib plasma concentration can result in some side effects, such as decrease of white blood cells and liver damage. Therefore, it is significant for receiving optimal clinical therapeutic efficacy to monitor imatinib plasma concentration, adjust imatinib dosage timely and keep imatinib plasma concentration in effective and safe range. [Key words] Gastrointestinal stromal tumor; Plasma concentration; Imatinib