Drug Exposure and Minimum Inhibitory Concentration in the Treatment of Mycobacterium Avium Complex Lung Disease: a Prospective Observational Cohort Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 100
- 试验地点
- 1
- 主要终点
- Peak plasma concentration (Cmax) for key antimycobacterial drugs, separate and in relation to minimum inhibitory concentration
研究概览
简要总结
The incidence and prevalence of nontuberculous mycobacteria (NTM) infections have gradually increased over the years worldwide (1-3). In China, Mycobacterium avium complex (MAC) was the most prevalent NTM specie (4), while challenged by long treatment duration, frequent drug-induced adverse events, lack of treatment alternatives, poor treatment outcome and high recurrence rate (5, 6). In order to maximize the efficacy of the few available drugs and prevent the development of drug resistance, ensuring adequate plasma drug concentrations are of importance. Despite the role of pathogen susceptibility, determined by minimum inhibitory concentration (MIC), is non-negligible, the evidences regarding its association with treatment outcome are limited, especially for rifamycin and ethambutol. The difficulties in explaining the clinical values of MIC might partially be attributed to the lack of in vivo drug exposure data, which cannot be accurately predicted by the dose administered because of between-patient pharmacokinetic variability (7). Therapeutic drug monitoring (TDM) is a strategy to guide and personalize treatment by measuring plasma drug concentrations and pathogen susceptibility, which might have the potential to improve treatment response to MAC lung disease.
In this observational study, the hypothesis is that the drug exposure and/or MIC of antimycobacterial drugs are correlated to the treatment response of MAC lung disease, which is assessed from the perspective of treatment outcome, mycobacterial culture negative conversion, lung function, radiological presentation and self-reported quality of life. Consenting adult patients with culture-positive MAC lung disease will be recruited in study hospital. Respiratory samples (sputum and/or bronchoalveolar lavage fluid) will be collected regularly for mycobacterial culture on the basis of BACTEC MGIT 960 system and MIC will be determined using a commercial broth microdilution plate. Drug concentrations will be measured at 1 and/or 6 months after treatment initiation using liquid chromatography tandem mass spectrometry (LC-MS/MS). The final treatment outcome is recorded at the end of MAC treatment and defined according to an NTM-NET consensus statement (8).
详细描述
This is an observational cohort study conducted to enrol consenting adult patients with culture-positive MAC lung disease in study hospital (n=100). The diagnosis and treatment of MAC lung disease will adhere to the ATS/ERS/ESCMID/IDSA and Chinese national guidelines (9, 10). Patients treated with a regimen composed of macrolides, rifamycin and ethambutol at minimum are screened for eligibility. Detailed demographic, behaviour, clinical and laboratory information will be recorded at baseline. Respiratory samples (sputum and/or bronchoalveolar lavage fluid) will be collected at baseline and once every 3 months until treatment completion for mycobacterial culture using BACTEC MGIT 960. Time to mycobacterial culture positivity (TTP) will be recorded to estimate the bacterial load as an alternative for colony forming units count. MIC determination will be performed for baseline, six-month and/or the last available positive culture during treatment with the Sensititre™ SLOMYCO2 Susceptibility Testing Plate, to assess the development of acquired drug resistance.
Drug concentrations will be measured for all study patients at one month after treatment initiation. Rich blood sampling (0, 1, 2, 4, 6 and 8 hours after drug intake) will be implemented for the first 30 patients aged < 65 years to enable the development of population pharmacokinetic models. A limited sampling strategy (2 and 6 hours after drug intake) will be applied for the rest patients to increase the feasibility of study. Additional blood sampling will be given for patients with poor treatment response at six months with limited sampling strategy. The developed pharmacokinetic models will be used to accurately calculate the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax), as the main exposure variables. To comprehensively assess the response to MAC treatment, mycobacterial culture, lung function test, computerized tomography (CT) scan and questionnaires for well-being will be taken regularly in this study. The final treatment outcome is recorded at the end of MAC treatment and defined according to an NTM-NET consensus statement (8). Post-treatment visits are given at 6 and 12 months after treatment completion to assess the recurrence of MAC lung disease.
Together with bacteria MIC and clinical data, the Cmax/MIC and AUC/MIC for antimycobacterial drugs will be explored to deepen our understandings on the correlation of pharmacokinetic and/or pharmacodynamic indices with treatment response, which may guide development of new dosing strategies.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Culture-positive MAC lung disease
- •MAC treatment at the Shanghai Pulmonary Hospital
- •A regimen composed of at least the core drugs, i.e., macrolides, rifamycin and ethambutol, in doses not lower than recommended according to the ATS/ERS/ESCMID/IDSA and Chinese national guidelines
- •Written informed consent
排除标准
- •Pregnancy
- •Confirmed mixed infection with mycobacterial species, including M.tuberculosis and other NTM species
- •Ongoing with any antimycobacterial treatment for more than one month, including tuberculosis and NTM
- •Patients admitted to the intensive care unit
- •Off-label use for any study drugs, such as inhalation of amikacin
结局指标
主要结局
Peak plasma concentration (Cmax) for key antimycobacterial drugs, separate and in relation to minimum inhibitory concentration
时间窗: one-month of treatment
Descriptive data of the distribution of Cmax for key antimycobacterial drugs in patients with MAC lung disease, with regard to existing recommended levels. Their associations with treatment response will be investigated.
Area under the plasma concentration versus time curve (AUC) for key antimycobacterial drugs, separate and in relation to minimum inhibitory concentration
时间窗: one-month of treatment
Descriptive data of the distribution of AUC for key antimycobacterial drugs in patients with MAC lung disease, with regard to existing recommended levels. Their associations with treatment response will be investigated.
次要结局
- Number of patients with recurrence of MAC lung disease(24-30 months)
- Proportion of patients with cure of MAC lung disease(12-18 months)
- Resolution of pulmonary lesions or cavitation(12-18 months)
- Proportion of patients with improved quality of life(12-18 months)
- Time to culture conversion(12-18 months)
- Proportion of patients with significant changes in drug resistance profile(12-18 months)
- Six-month culture conversion(6 months)
- Proportion of patients with improved forced expiratory volume in 1 second (FEV1)(12-18 months)
- Proportion of patients with improved forced vital capacity (FVC)(12-18 months)
- Proportion of patients with grade 3 or 4 adverse events(12-18 months)
研究者
Wei Sha MD & PhD
Director of Clinic and Research Center of Tuberculosis, Professor
Shanghai Pulmonary Hospital, Shanghai, China