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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2019, Vol. 39 Issue (9): 25-32    DOI: 10.13523/j.cb.20190904
研究报告     
伊马替尼血药浓度监测指导慢性粒细胞白血病患者的研究
张暕1,姜志平1,徐萍2,何群1,王清2,朱艳2,赵谢兰1,*()
1 中南大学湘雅医院 长沙 410008
2 中南大学湘雅二医院 长沙 410011
Study on Monitoring of Imatinib Serum Level Guides Management of Chronic Myelogenous Leukemia Patients
ZHANG Jian1,JIANG Zhi-ping1,XU Ping2,HE Qun1,WANG Qing2,ZHU Yan2,ZHAO Xie-lan1,*()
1 Department of Hematology Xiangya Hospital Central South University, Changsha 410008, China
2 Department of Pharmacy the Second Xiangya Hospital of Central South University, Changsha 410011, China
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摘要：

目的 观察是否可以通过对伊马替尼(Imatinib,IM)进行血药浓度监测提高疗效,减少药物不良反应。方法 选取2013~2018年就诊于我院的慢性粒细胞白血病(chronic myelogenous leukemia, CML)患者,分为试验组(药物监测组),对照组(常规经验治疗组)。对服药3个月、6个月、12个月、18个月,进行疗效及不良反应评估及比较。结果 共有51人入选此次临床试验。其中试验组35人,对照组16人。结果 服用伊马替尼400mg/d时,血药浓度568.00~3 989.66ng/ml,均数(标准差):1 716.46ng/ml(788.96);服用伊马替尼300mg/d时,血药浓度720.89~1 497.11ng/ml,均数(标准差):971.67ng/ml(204.02)。达到主要分子学反应(major molecular response, MMR)的伊马替尼血药浓度高于未达到稳态时的伊马替尼血药浓度。两组不良反应评级有统计学差异。试验组III级及以上不良反应发生率明显小于对照组。结论 伊马替尼的稳态血浆药物谷浓度存在较大个体差异,这种个体差异与疗效和不良反应存在相关性。通过治疗药物监测(therapeutic drug monitoring, TDM)可以在确保疗效的同时,减少伊马替尼在治疗慢性粒细胞白血病中的不良反应。结果尚需大样本临床试验进一步验证。伊马替尼药物代谢个体差异的原因需要大样本遗传药理学研究进一步探讨。
关键词： 慢性粒细胞白血病;  伊马替尼;  治疗药物监测    
Abstract:

Objective: To assess if therapeutic drug monitoring (TDM)of imatinib used for chronic myelogenous leukemia (CML) patients led to improve clinical outcome and reduce side effects compared to empiric adjustments.Methods: Patients followed between 2013 to 2018 at CML Center of Xiangya Hospital are performed. Primary outcomes are composite remission at 3, 6, 12 and 18 months in those with empiric adjustments versus TDM-guided optimization.Results: There are 51 patients who are included in the study. Among them, 35 are in the experimental group and 16 are in the control group. The results show that when taking imatinib 400mg/d, the serum level is 568.00~3 989.66ng/ml, the mean (standard deviation): 1 716.46ng/ml (788.96); when taking imatinib 300mg/d, serum level is 720.89~1 497.11ng/ml, mean (standard deviation): 971.67ng/ml (204.02). The serum level at the time of achieving a stable molecular response is higher than that the time when the stable molecular response is not achieved. There are significant differences in adverse reaction ratings between the two groups. The incidence of adverse reactions of grade III and above in the experimental group is significantly smaller than that of the control group.Conclusions: There is a large individual difference in the steady serum level of imatinib, and this individual difference is related to efficacy and adverse reactions. TDM can reduce the adverse effects while ensuring efficacy in the treatment of CML patients. The results still require further validation of large sample clinical trials. The reasons for individual differences in imatinib drug metabolism require further investigation of large sample pharmacogenetics studies.

Key words: Chronic myelogenous leukemia    Imatinib    Therapeutic drug monitoring
收稿日期: 2019-08-06 出版日期: 2019-09-20
ZTFLH:  R557  
通讯作者: 赵谢兰     E-mail: zhaoxl9198@163.com
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张暕
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引用本文:

张暕,姜志平,徐萍,何群,王清,朱艳,赵谢兰. 伊马替尼血药浓度监测指导慢性粒细胞白血病患者的研究[J]. 中国生物工程杂志, 2019, 39(9): 25-32.

ZHANG Jian,JIANG Zhi-ping,XU Ping,HE Qun,WANG Qing,ZHU Yan,ZHAO Xie-lan. Study on Monitoring of Imatinib Serum Level Guides Management of Chronic Myelogenous Leukemia Patients. China Biotechnology, 2019, 39(9): 25-32.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.20190904    或    https://manu60.magtech.com.cn/biotech/CN/Y2019/V39/I9/25

图1  TDM流程
患者特点均值(标准差) 实验组 对照组 P值
年龄/年 40(10.19) 46(8.15) 0.047
确诊时间/月 48(27.63) 55(19.24) 0.152
服药时间/月 43(18.03) 53(19.05) 0.116
性别
男 23(64%) 14(87%)
女 12(36%) 2(13%) 0.106
Sokal评分 4.46(6.57) 5.72(11.15) 0.411
Hasford评分 1 103.46(850.52) 1 348.66(1 019.77) 0.542
表1  患者一般情况
图2  400mg/d血药浓度
图3  300mg/d血药浓度
图4  TDM调整剂量前后对比
图5  伊马替尼临床疗效
图6  血药浓度与疗效关系
组别 血液学反应 消化道反应 心血管系统反应 皮肤反应 疼痛 水肿
试验组 18(51%) 9(26%) 3(9%) 7(20%) 10(29%) 7(27%)
对照组 8(50%) 3(20%) 1(6%) 3(19%) 4(25%) 4(25%)
P值 0.925 0.586 0.775 0.917 0.791 0.687
表2  试验组对照组各系统不良反应发生率比较
组别 I II级 III级 IV级 V级
试验组 9(26%) 25(71%) 1(3%) 0 0
对照组 6(38%) 7(44%) 2(12%) 1(6%) 0
P值 0.000
表3  试验组对照组不良反应评级发生率比较
图7  试验组对照组各系统不良反应发生率比较
图8  试验组对照组不良反应评级发生率比较
图9  血药浓度与不同等级不良反应关系
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