Measurement of Anti-TB Drugs in Lung Tissue From Patients Having Surgery to Treat Tuberculosis

Condition(s) targeted: Tuberculosis

Intervention: RIF (Drug); INH (Drug); PZA (Drug); KM (Drug); MXF (Drug)

Phase: N/A

Status: Not yet recruiting

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Overall contact:
Veronique Dartois, Ph.D., Phone: Not Listed

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.

Official title: Pharmacokinetics of Standard First and Second Line Anti-TB Drugs in the Lung and Lesions of Subjects Elected for Resection Surgery

Study design: Other, Randomized, Open Label, Uncontrolled, Parallel Assignment, Pharmacokinetics Study

Primary outcome: Comparison between the relative permeability coefficients of RIF and KM in pathologically defined large caseous necrotic nodules.

Secondary outcome: Comparison between the relative permeability coefficients of INH, PZA, and MXF in caseous necrotic nodules to that of RIF and KM; comparison between the relative permeability coefficients of RIF, KM, INH, and MXF.

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 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.

Minimum age: 20 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

- INCLUSION CRITERIA:

1. Males and females age 20 and above

2. Selected for lung resection due to anti-tuberculous treatment failure, multidrug resistant disease, or other reason determined by the treating physician

3. Radiographic evidence of tuberculous disease of the lung(s)

4. If already on an aminoglycoside, ability and willingness to substitute this aminoglycoside with KM for the one study dose

5. Willingness to receive MRI scan and marker and Gadolinium injection

6. Willingness to have samples stored

7. Ability and willingness to give written or oral informed consent

8. EKG without evidence of QT* prolongation within 1 week of study.

- QT prolongation is considered when the QTc interval is greater than 440 ms

(men) and 460 ms (women), although arrhythmias are most often associated with values of 500 ms or more.

EXCLUSION CRITERIA:

1. Subjects less than 20 years of age

2. Women of childbearing potential who are pregnant, breast feeding, or unwilling to avoid pregnancy (i. e., the use of appropriate contraception including oral and subcutaneous implantable hormonal contraceptives, condoms, diaphragm, intrauterine device (IUD), or abstinence from sexual intercourse) [Note: Prospective female participants of childbearing potential must have negative pregnancy test (urine) within 48 hours prior to study entry.]

3. Allergy or hypersensitivity to any of the 5 study drugs,

4. Those with severe gout

5. Severe claustrophobia or Gadolinium hypersensitivity (tbc)

6. Renal, hepatic, auditory and/or vestibular impairment.

1. Serum creatinine greater than 2. 0 mg/dL (renal)

2. Aspartate aminotransferase (AST or SGOT) greater than 100 IU/L (LFTs)

3. Alanine aminotransferase (ALT or SGPT) greater than 100 IU/L (LFTs)

4. Total bilirubin greater than 2. 0 mg/dL (LFTs)

7. Documented QT prolongation

8. The use of any of Rifampicin (RIF), Rifapentine or Rifabutin within 30 days prior to the study

9. HIV infection, determined by a positive HIV test performed with the past 6 months

10. The use of any of the following drugs within 30 days prior to study:

1. Systemic cancer chemotherapy

2. Systemic corticosteroids

3. Systemic IND agents other than Pimonidazole HCl or Linezolid

4. Antiretroviral medications

5. Growth factors

11. The need for ongoing therapy with warfarin, phenytoin, lithium cholestrymine, levodopa, cimetidine, disulfiram, ergot derivatives, fosphenytoin, carbamazepine, cyclosporine, tacrolimus, sirolimus, amiodarone or Phenobarbital

Veronique Dartois, Ph.D., Phone: Not Listed

Samsung Medical Center, Seoul, Korea, Republic of

Asan Medical Center, Seoul, Korea, Republic of

National Masan Tuberculosis Hospital (NMTH), Masan, Korea, Republic of

Related publications:

Assandri A, Ratti B, Cristina T. Pharmacokinetics of rifapentine, a new long lasting rifamycin, in the rat, the mouse and the rabbit. J Antibiot (Tokyo). 1984 Sep;37(9):1066-75.

Della Bruna C, Schioppacassi G, Ungheri D, Jabès D, Morvillo E, Sanfilippo A. LM 427, a new spiropiperidylrifamycin: in vitro and in vivo studies. J Antibiot (Tokyo). 1983 Nov;36(11):1502-6.

Murdoch MB, Peterson LR. Antimicrobial penetration into polymorphonuclear leukocytes and alveolar macrophages. Semin Respir Infect. 1991 Jun;6(2):112-21.

Starting date: December 2008
Ending date: January 2011
Last updated: October 10, 2009