Pharmacokinetics of Standard First and Second Line Anti-TB Drugs in the Lung and Lesions of Subjects Elected for Resection Surgery
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 19
- 试验地点
- 3
- 主要终点
- Comparison between the relative permeability coefficients of RIF and KM in pathologically defined large caseous necrotic nodules.
研究概览
简要总结
This study, conducted jointly by researchers at the National Masan TB Hospital, Asan and Samsung Medical Centers in Seoul, Republic of Korea, and the Yonsei University and the NIH in the United States, will examine why some patients with tuberculosis (TB) develop disease that is harder to treat than most cases. TB is an infection of the lung that usually can be successfully treated with anti-TB drugs. However, some people get a more serious kind of disease (called multi-drug resistant TB or extensively drug-resistant TB) that is very difficult to treat and may not be cured by the regular medicines available. This study will try to find out if some of the common TB drugs are getting to the place where the TB bacteria are. It will also look at how current anti-TB drugs might be used more effectively and how better drugs might be developed.
People 20 years of age and older with hard-to-treat TB who have elected to undergo surgical removal of part of their lung at the National Masan Tuberculosis Hospital, Masan, the Asan Medical Center, and the Samsung Medical Center, may be eligible for this study.
Participants undergo the following procedures:
- Medical history and physical examination, including sputum sample.
- Blood tests at various times during the study.
- Drug administration. Subjects are given one dose each of five common TB drugs rifampicin, isoniazid, pyrazinamide, kanamycin and moxifloxacin before they undergo surgery to remove part of their lung. After surgery, some of the lung tissue and fluid around the lungs that was removed during surgery will be examined to determine the regions where the TB bacteria live and analyze the lung tissue itself.
- Dynamic MRI (magnetic resonance imaging) scan. This type of scan uses a magnetic field and radio waves to produce pictures of the lung. Subjects lie very still on a table inside the cylindrical scanner with their head on a soft cradle and their hands over their head. Several images are obtained for less than 5 minutes at a time.
详细描述
It takes 6 to 24 months of intensive combination therapy to cure tuberculosis (TB) with antibiotics that have proven activity in vitro. In contrast, many pulmonary infectious diseases can be cured following single drug treatment with similar drugs for only one to a few weeks. We hypothesize that the unusual complexity of TB lesions and the degree of sequestration of TB bacilli within these lesions may limit access of the drugs to their site of action, leading to treatment failure, long treatment duration and the emergence of drug resistance. To test the hypothesis that drug maldistribution into lesions impacts on treatment duration and failure, we propose to examine the lesion-specific penetration properties of 5 standard anti-TB drugs in the lungs of subjects selected for lung surgery. The study is designed to understand what lesion types are the most difficult to penetrate. This aspect of TB drug pharmacokinetics has been largely neglected so far, probably owing to the lack of adequate technology and the limited availability of human TB lesion samples. Fifteen patients who elect lung resection surgery will be asked to participate in the study. Consented subjects will receive 4-5 first and second line anti-TB drugs concomitantly at 1 of 5 pre-determined times prior to surgery. At the time of resection, drug levels will be measured in plasma, in uninvolved lung tissue and in lesions using standard analytical methods as well as imaging Mass Spectrometry (MS) where drug concentration gradients can be visualized across tissue sections. The major aim of this study is to determine actual concentrations and permeability coefficients of the 5 study drugs in various lesion types contained within subjects surgically removed lung tissue. Data analysis will also provide the relative exposure of each drug in plasma versus lung tissue and lesion. If conclusive, the results may be taken into consideration when selecting drug doses and dosing regimens. Additionally, images generated by standard of care (SOC) High Resolution Computed Tomography (HRCT), and Dynamic MRI for each subject will provide information regarding lesion structure and anatomy, lesional blood flow and microvascular function. Lesion-specific correlations will be established between CT radiology and drug pharmacokinetic (PK) to identify which histopathologic lesion types may be particularly difficult to sterilize and to evaluate the potential impact of drug penetration on treatment outcome. The long term goal of this study is to identify the factors behind poor lesion penetration, so that new agents can be optimized with better penetration properties to target harder-to-sterilize lesion' types.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
1
Dosing 2 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Rifampicin (Drug)
1
Dosing 2 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Isoniazid (Drug)
1
Dosing 2 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Pyrazinamide (Drug)
1
Dosing 2 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Kanamycin (Drug)
1
Dosing 2 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Moxifloxacin (Drug)
2
Dosing 4 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Rifampicin (Drug)
2
Dosing 4 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Isoniazid (Drug)
2
Dosing 4 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Pyrazinamide (Drug)
2
Dosing 4 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Kanamycin (Drug)
2
Dosing 4 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Moxifloxacin (Drug)
3
Dosing 8 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Moxifloxacin (Drug)
3
Dosing 8 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Rifampicin (Drug)
3
Dosing 8 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Isoniazid (Drug)
3
Dosing 8 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Pyrazinamide (Drug)
3
Dosing 8 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Kanamycin (Drug)
4
Dosing 12 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Rifampicin (Drug)
4
Dosing 12 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Moxifloxacin (Drug)
4
Dosing 12 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Isoniazid (Drug)
4
Dosing 12 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Pyrazinamide (Drug)
4
Dosing 12 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Kanamycin (Drug)
5
Dosing 24 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Rifampicin (Drug)
5
Dosing 24 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Isoniazid (Drug)
5
Dosing 24 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Pyrazinamide (Drug)
5
Dosing 24 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Kanamycin (Drug)
5
Dosing 24 hours before surgery. -Rifampicin (RIF) will be dosed orally at 600mg or 50mg for subjects under 50kg of bodyweight;-Isoniazid (INH) will be dosed orally at 300mg;-Pyrazinamide (PZA) will be dosed orally at 1.5g;-Moxifloxacin (MXF) will be dosed orally at 400mg;-Kanamycin (KM) will be dosed intramuscularly at 1g or 750mg for subjects under 50kg of body weight
干预措施: Moxifloxacin (Drug)
结局指标
主要结局
Comparison between the relative permeability coefficients of RIF and KM in pathologically defined large caseous necrotic nodules.
时间窗: Dosing given 24 hours- 2 hours before surgery
次要结局
- The comparison between the relative permeability coefficients of RIF, KM, INH, PZA and MXF in caseous necrotic nodules versus open cavities(Dosing given 24 hours -2 hours before surgery, then endpoint assessed from time of surgery.)
- The comparison between the absolute permeability coefficients of each of the five drugs in uninvolved lung and in closed necrotic lesions(Dosing given 24 hours -2 hours before surgery, then endpoint assessed from time of surgery.)
- The comparison between the exposure ratio or ratio between the Area Under the Curve (AUC0-24) in lesions (AUClesion), uninvolved lung (AUClung) and plasma (AUCplasma) for RIF and KM in large caseous necrotic nodules(Dosing given 24 hours -2 hours before surgery, then endpoint assessed from time of surgery.)