贝达喹啉血药浓度在耐药肺结核治疗中的变化及其与QTc间期延长的相关性  

Changes of plasma concentration of bedaquiline during the treatment of drug-resistant pulmonary tuberculosis and its assocation with QTc interval prolongation

作　　者：谢莉[1] 朱慧 高静韬[3] 刘忠泉 马丽萍[1] 张立群[1] 戈启萍[1] 聂理会[1] 孔忠顺[1] 吴晓光[1] 刘荣梅[1] 陈红梅[1] 宋艳华[1] 李强[1] 吕子征 刘宇红[3] 陆宇 逄宇 高孟秋[1] XIE Li;ZHU Hui;GAO Jing-tao;LIU Zhong-quan;MA Li-ping;ZHANG Li-qun;GE Qi-ping;NIE Li-hui;KONG Zhong-shun;WU Xiao-guang;LIU Rong-mei;CHEN Hong-mei;SONG Yan-hua;LI Qiang;LYU Zi-zheng;LIU Yu-hong;LU Yu;PANG Yu;GAO Meng-qiu(Department of Tuberculosis,Beijing Chest Hospital,Capital Medical University,Beijing 101149,China;Department of Pharmacology,Beijing Chest Hospital,Capital Medical University,Beijing 101149,China;Clinical Center on TB,Beijing Chest Hospital,Capital Medical University,Beijing 101149,China;Department of Bacteriology and Immunology,Beijing Chest Hospital,Capital Medical University,Beijing 101149,China)

机构地区：[1]首都医科大学附属北京胸科医院结核科,北京101149 [2]首都医科大学附属北京胸科医院药物学研究室,北京101149 [3]首都医科大学附属北京胸科医院临床中心办公室,北京101149 [4]首都医科大学附属北京胸科医院细菌免疫室,北京101149

出　　处：《中国防痨杂志》2022年第3期219-226,共8页Chinese Journal of Antituberculosis

基　　金：“十三五”国家科技重大专项(2018ZX10722301-001);北京市科技计划课题(Z191100006619077);首都卫生发展科研专项(首发2020-2-2162)。

摘　　要：目的:探索贝达喹啉血药浓度在耐药肺结核患者治疗中的变化规律及与心电图QTc间期延长的相关性。方法:采用前瞻性研究的方法,参照入组标准纳入2018年2月至2020年2月就诊于首都医科大学附属北京胸科医院的119例耐多药/利福平耐药肺结核(MDR/RR-PTB)患者,由专家组对其制定含贝达喹啉在内的个体化治疗方案。收集患者服用贝达喹啉前的基线资料,并记录治疗后不同时间点的血电解质(钾、钙、镁)、血常规、尿常规、肝肾功能、心电图QTcF值,以及贝达喹啉的血药浓度。采用单因素和多因素logistic回归分析影响QTc间期延长的因素。结果:119例患者均完成了72周抗结核治疗,处于停药随访中。其中,5例(4.2%)患者因在服用贝达喹啉24周内出现QTcF>500 ms,提前停用贝达喹啉;114例完成贝达喹啉治疗,包括53例完成24周(24周组),61例完成36周(36周组)。对于完成贝达喹啉治疗的114例患者,其第2周末时贝达喹啉的血药浓度谷浓度最高[1.753(1.365,2.412)μg/ml],明显高于第4周末[0.830(0.586,1.035)μg/ml]和第24周末[1.098(0.909,1.440)μg/ml],差异均有统计学意义(Z=-9.222,P<0.001;Z=-7.798,P<0.001),且第24周末时的谷浓度明显高于第4周末谷浓度(Z=-7.826,P<0.001)。无论是24周组还是36周组患者,停用贝达喹啉12周后的血药浓度[0.769(0.500,0.947)μg/ml和0.824(0.642,1.023)μg/ml]均恢复到服药后第4周末水平;停用24周后血药浓度仍接近有效血药浓度(0.6μg/ml)。心电图QTcF值的变化规律与贝达喹啉血药浓度的变化规律基本一致。在服用贝达喹啉后均逐渐升高,停用贝达喹啉前后时达峰,随后均逐渐下降。8例(6.7%)出现心电图QTcF>500 ms;36例(30.3%)出现QTcF>450 ms;所有患者在观察期间均未出现严重的室性心律失常。多因素logistic回归分析结果显示,高龄(≥55岁)、低体质量指数(<18.5)、低钙血症(<2.3 mmol/L)更容易导致QT间期延长[OR(95%CI)值分别为7.Objective:To explore the changes of plasma concentration of bedaquiline during the treatment in patients with drug-resistant pulmonary tuberculosis and its association with QTc interval prolongation.Methods:All 119 patients with multidrug-resistant/rifampicin resistant pulmonary tuberculosis(MDR/RR-PTB)were enrolled prospectively according to the inclusion criteria in Beijing Chest Hospital from Feb.2018 to Feb.2020,provided with individualized bedaquiline-containing regimen by the expert group.Baseline information were collected before the first dose of bedaquiline and electrolyte(potassium,calcium and magnesium),blood routine,urine routine,hepatic and renal function,QTcF value and plasm drug concentration of bedaquiline were serially recorded at different time points post treatment initiation.Univariate and multivariate logistic regression analysis were performed to analyze the risk factors associated with QTc interval prolongation.Results:All 119 patients had completed full course of 72 week-treatment and were in period of post treatment follow-up.Out of them,5(4.2%)had QTcF>500 ms within 24 weeks and bedaquiline was discontinued as per protocol;114 patients completed full doses of bedaquiline,among which 53 took for 24 weeks and 61 took for 36 weeks.For the 114 patients who completed full administration of bedaquiline,their trough concentration was highest at the end of week 2(1.753(1.365,2.412)μg/ml),significantly higher(Z=-9.222,P<0.001;Z=-7.798,P<0.001)than that at the end of week 4(0.830(0.586,1.035)μg/ml)and week 24(1.098(0.909,1.440)μg/ml)while it was higher at the end of week 24 than that at week 4 with significance(Z=-7.826,P<0.001).No matter patients with 24-week or 36-week bedaquiline exposure,the plasma concentration of it returned to the level at the end of week 4(0.769(0.500,0.947)μg/ml and 0.824(0.642,1.023)μg/ml)respectively after bedaquiline was discontinued for 12 weeks.Furthermore,the plasma concentration of it was still close to the effective value(0.6μg/ml)after bedaquiline was disco

关 键 词：贝达喹啉 结核 抗多种药物性 药物监测 心电描记术 因素分析 统计学 

分 类 号：R978.3[医药卫生—药品] R521[医药卫生—药学]