一线抗结核药物血药浓度与早期痰菌阴转的相关性研究  

The relationship between plasma concentrations of the first-line anti-tuberculosis drugs and sputum negative conversion atearlystage

作　　者：刘其会 孙峰 孙涛[2] 贾小芳[2] 苏菲菲 施伎蝉 张丽军[2] 蒋贤高 张文宏 

机构地区：[1]复旦大学附属华山医院感染科,上海200040 [2]上海市公共卫生临床中心I期临床试验中心 [3]温州市中心医院感染科

出　　处：《中国防痨杂志》2018年第2期157-160,共4页Chinese Journal of Antituberculosis

摘　　要：目的了解利福平（R）、异烟肼（H）、乙胺丁醇（E）在我国结核病患者中的药代动力学特点，并探讨抗结核药物药代动力学参数与治疗疗效的相关性。方法采用前瞻性研究方法，招募温州市中心医院2015年10月1日至2016年1月31日住院部的肺结核患者作为研究对象，共72例。研究对象为初治或复治不超过1次，包括菌阳和菌阴患者。所有研究对象口服标准四联一线抗结核药物方案治疗1周后，采集服药前0．5h，服药后2h、4h、6h、8h的血浆标本，通过液相色谱一串联质谱联用（LC-MS-MS）方法检测血药浓度值。同时随访治疗2个月末痰菌阴转情况，评估治疗2个月末痰菌阴转与血药浓度的相关性。结果72例研究对象中1例患者痰培养结果为耐多药肺结核，1例失访，最终纳入70例进行分析。其中，菌阴肺结核患者16例，菌阳肺结核患者54例。研究对象服药1周达到稳态药物浓度后进行采血检测，25．7％（18／70）的患者R的峰值浓度（G。）低于推荐范围（〈8μg／ml），38．6％（27／70）的患者H的ck低于推荐范围（〈3ug／ml），65．7%（46／70）的患者E的Ck低于推荐范围（〈2μg／m1）。54例菌阳肺结核患者抗结核药物治疗2个月末，48例痰菌阴转，6例未阴转。痰菌阴转者血浆中E服药后2h浓度（C2h）、Cmax、服药后8h曲线下面积（AUC0～8）值分别为（1．81±0．91）μg／ml、（1．81±0．85）μg／ml、（7．67±3．25）μg·h·ml^-1，高于痰菌未阴转者[C2h、Cmax、AUC0～8分别为（0．93±0．32）μg／ml、（1．06±0．25）μg／ml、（4．93±0．72）μg·h·ml^-1]，差异有统计学意义（t=4．74，P〈0．01；t=4．93，P〈0．01；t=4．95，P〈0．01）；痰菌阴转者血浆中H的C2h和Cmax值分别为（3．67±1．64）／ag／ml、（3．85±1．59）μg／ml，均高于痰菌未阴转者[Gh、Cmax分别为（2．11±1．14）μg／ml、（2．11±1．14�Objective To study the pharmaeokineties of the first-line anti-tuberculosis drugs including rifam- picin, isoniazid, and ethambutol in a cohort of Chinese patients with tuberculosis and to determine the relationship between the pharmacokinetic parameters of these anti-tuberculosis drugs and the clinical treatment outcomes. Methods A prospective study was conducted to recruit patients diagnosed with pulmonary tuberculosis from the Inpatient Department of the Wenzhou Central Hospital from October 1, 2015 to January 31, 2016. A total of 72 patients were enrolled. Subjects were initially treated or retreated once, and both bacteriologically confirmed and clinically diagnosed cases were eligible. Plasma samples were collected 0.5 h before and 2 h, 4 h, 6 h, 8 h after taking standard quadruple drugs for one week doses. Plasma concentrations were determined using LC-MS/MS. Patients were followed up 2 months after the initiation of treatment to assess the relationships between sputum nega- tive conversion and plasma concentrations. Results Among the 72 patients, one patient was confirmed to have multidrug-resistant tuberculosis and one patient was lost to follow up. Thus, 70 patients were analyzed at last, among whom 16 patients were bacteriologically negative and 54 patients were bacteriologically positive at initial diagnosis. The plasma exposures at steady state after one week of drug administration were analyzed. 25.7% （18/70） patients had a plasma peak concentration （Cmax） of rifampicin lower than the recommended range （〈 8μg/ml）, 38.6% （27/70） cases had a Cmax of isoniazid lower than the recommended range （〈3 μg/ml）, whereas 65.7% （46/70） patients had a Cmax of ethambutol lower than the recommended range （〈2 μg/ml）. After 2-month of treat- ment, among the 54 patients who were sputum bacteria positive at initial diagnosis, 48 patients conversed to sputum bacteria negative, while sputum bacteria were still detected in 6 patients. The C2 h, C and AUC0-8 of ethambutol were significa

关 键 词：利福平 异烟肼 乙胺丁醇 药代动力学 前瞻性研究 

分 类 号：R521.05[医药卫生—内科学]