Measurement of Anti-TB Drugs in Lung Tissue From Patients Having Surgery to Treat Tuberculosis
Condition: Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Rifampicin; Isoniazid; Pyrazinamide; Kanamycin; Moxifloxacin
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): Rifampicin or rifampin (RIF) is a semi-synthetic compound derived from Amycolatopsis rifamycinica. It is mostly used in combination to treat TB, while other disease indications include brucellosis, leprosy, legionnaire's disease and problematic drug-resistant staphylococcal infections. RIF inhibits DNA-dependent RNA polymerase in bacterial cells by binding its beta-subunit, thus preventing transcription to RNA. Its MIC against replicating TB bacilli is 0.1 g/ml and its minimum bactericidal activity (MBC) is 0.5 g/mL. It is one of the rare anti-TB drugs with some activity against nonreplicating cells.; Isoniazid (INH) is a first-line antituberculous medication discovered in 1952 and used in the prevention (alone) and treatment (in combination) of tuberculosis. Isoniazid is a prodrug and must be activated by a bacterial catalase to inhibit the synthesis of mycolic acids in the mycobacterial cell wall. Consequently, INH is bactericidal to rapidly-dividing mycobacteria, with an MIC of 0.05 g/ml and an MBC of 1 g/ml, but is inactive if the mycobacterium is nonreplicating or slow-growing.; Pyrazinamide (PZA) is a synthetic derivative of nicotinamide requiring ctivation by the mycobacterial enzyme pyrazinamidase, only active under acidic conditions which are thought to be found within the phagolysosomal compartment of macrophages. The conversion product, pyrazinoic acid, inhibits fatty acid synthetase I, required by the bacterium to synthesize fatty acids, though this has been disputed. It has an MIC of 6 g/ml and is not cidal under in vitro conditions. Overall, its mechanism of action and reasons for good sterilizing activity in vivo are poorly understood. It is part of the 4-drug combination recommended by the WHO to treat drugsensitive tuberculosis and is also included in most econd-line regimens.; Kanamycin (KM) is an aminoglycoside antibiotic belonging to the same class of drugs as Streptomycin, one of the first drugs used to treat TB in the 50 s. It kills sensitive bacteria by binding to the 30S ribosomal subunit and interfering with protein synthesis. Its MIC and MBC against MTB are 2 and 6 g/mL, respectively, with a remarkably low MBC/MIC ratio. However, KM is only used to treat serious bacterial infections due to severe renal toxicity and ototoxicity. No interaction with the metabolism of other drugs has been reported. The drug is approved by the Korean Ministry of Food and Drug Safety (MFDS) but not the US FDA for use against pulmonary TB.; Moxifloxacin (MXF) is a synthetic fluoroquinolone antibiotic. It inhibits bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, which are essential enzymes playing a crucial role in the replication and repair of bacterial DNA. Its MIC, MBC and intracellular activity against MTB are 0.5, 2 and 1 g/mL, respectively, with again a low MBC/MIC ratio.
Intervention MeSH terms: Moxifloxacin; Rifampin; Isoniazid; Pyrazinamide; Kanamycin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Tuberculosis; Lesions; Pharmacokinetics; Maldistribution; Histopathology