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中国防痨杂志 ›› 2022, Vol. 44 ›› Issue (3): 219-226.doi: 10.19982/j.issn.1000-6621.20210696

• 论著 • 上一篇    下一篇

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

谢莉1, 朱慧2, 高静韬3, 刘忠泉2, 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1, 刘宇红3(), 陆宇2(), 逄宇4(), 高孟秋1()   

  1. 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
  • 收稿日期:2021-12-08 出版日期:2022-03-10 发布日期:2022-03-08
  • 通信作者: 刘宇红,陆宇,逄宇,高孟秋 E-mail:liuyuhong0516@126.com;luyu4876@hotmail.com;pangyupound@163.com;gaomengqiu@hotmail.com
  • 基金资助:
    “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)

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

XIE Li1, ZHU Hui2, GAO Jing-tao3, LIU Zhong-quan2, MA Li-ping1, ZHANG Li-qun1, GE Qi-ping1, NIE Li-hui1, KONG Zhong-shun1, WU Xiao-guang1, LIU Rong-mei1, CHEN Hong-mei1, SONG Yan-hua1, LI Qiang1, LYU Zi-zheng1, LIU Yu-hong3(), LU Yu2(), PANG Yu4(), GAO Meng-qiu1()   

  1. 1Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
    2Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
    3Clinical Center on TB, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
    4Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
  • Received:2021-12-08 Online:2022-03-10 Published:2022-03-08
  • Contact: LIU Yu-hong,LU Yu,PANG Yu,GAO Meng-qiu E-mail:liuyuhong0516@126.com;luyu4876@hotmail.com;pangyupound@163.com;gaomengqiu@hotmail.com
  • Supported by:
    The 13th Five-Year National Science and Technology Major Project(2018ZX10722301-001);Beijing Science and Technology Planning Project(Z191100006619077);Capital Funds for Improvement and Research(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>500ms,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>500ms;36例(30.3%)出现QTcF>450ms;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(<2.3mmol/L)更容易导致QT间期延长[OR(95%CI)值分别为7.056(1.841~27.043)、3.850(1.236~11.989)、2.786(1.029~7.541)]。结论: 贝达喹啉的半衰期较长,有效浓度可维持至停药24周,且治疗耐药肺结核患者时延长使用贝达喹啉至36周是安全有效的;服药期间,患者QTc间期延长的发生率较高但无严重不良反应,应加强对高龄、低体质量指数、低钙血症等患者的心电图监测。

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

Abstract:

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 >500ms 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 (0.6 μg/ml) after bedaquiline was discontinued for 24 weeks. The trend for the QTcF value was basically consistent with that of bedaquiline plasma concentration which presented gradual increase with bedaquiline accumulated administration and hit the peak before and after its discontinuation, then decreased gradually. Eight cases (6.7%) had QTcF>500ms, 36 cases (30.3%) had QTcF>450ms and no serious ventricular arrhythmia was found in all patients during the above observation period. Multivariate analysis indicated that elder age (≥55 years), low body mass index (<18.5) and hypocalcemia (<2.3 mmol/L) were the risk factors for occurrence of QTc interval prolongation (OR (95%CI)=7.056 (1.841-27.043),3.850 (1.236-11.989), 2.786 (1.029-7.541)). Conclusion: Given the long half-life of bedaquiline, its effective plasma concentration could maintain until 24 weeks post its discontinuation. Moreover, extending bedaquiline exposure to 36 weeks presented safe and effective.During bedaquiline administration, the occurrence of QTc interval prolongation was relatively high but severity grade was mainly mild to moderate. ECG monitoring should be intensified for patients with elder age, low body mass index and hypocalcemia.

Key words: Bedaquiline, Tuberculosis,multidrug-resistant, Drug monitoring, Electrocardiograph, Factor analysis,statistical

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