Sputum Pharmacokinetics of TB Drugs and Bacterial Drug Resistance

Study Overview
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Brief Summary
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Background: Many people around the world get tuberculosis (TB) and non-tuberculous mycobacteria (NTM) infections. Sometimes medicine that treats these infections does not get to where the bacteria are in the lungs. Researchers want to find a way to tell if enough medicine is getting to where it is needed in the lungs. They will look at how much medicine is in your sputum (what you cough up) compared to how much is in your blood. They will also investigate a new test to quickly figure out what medicines are likely to treat TB effectively. Objective: To determine the relationship between the concentration of TB drugs in plasma and sputum over time. Eligibility: People ages 18 and older who have TB or NTM infection that is suspected to be drug resistant. They must be taking TB or NTM medicines. Design: Participants will be screened with medical history. Participants will be in the study for 2 8 days. Participants will give 3 or more sputum samples over at least 2 different days. They will cough sputum into a cup. Participants will have blood drawn 4 times a day on 2 different days.

Detailed Description
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This study will support two avenues of research, pharmacokinetics (PK) of drugs used to treat tuberculosis and resistance to those drugs that has been developed by the pathogen. Given the high inter-individual variability in TB drug exposure, therapeutic drug monitoring would be of value to adjust the drug dose in TB patients in order to improve clinical outcome and minimize toxicity. It is not practiced in most settings for reasons associated with costs but also because blood collection is an invasive procedure. Sputum on the other hand is often produced spontaneously and discarded as waste. Drug levels can be measured in sputum just as in plasma. Here we will test the hypothesis that sputum drug levels are predictive of drug concentrations in plasma and/or in specific lesion compartments such as the caseum of open cavities. We will also characterize the exposure of standard 1st and 2nd line TB drugs at one of the sites of infection, since sputum is in direct contact with cavity caseum. The subjects will contribute three or more sputum samples spontaneously produced over at least two days and four blood samples following drug administration on two different days (8 blood samples total). The data will be analyzed using population PK modeling approaches to generate concentration-time profiles and 24-hour area under the curve (AUC) of each study drug in sputum. Correlations between these values, plasma and lesion AUCs will be examined. We will draw from a recently completed TB lesion pharmacokinetic study (www.ClinicalTrials.gov #NCT00816426) to seek correlations between drug exposure in sputum and in pulmonary lesions. In addition to drug concentrations, sputum will be cultured by standard methods to isolate Mycobacterium tuberculosis (Mtb), determine the drug resistance profile, and be saved for testing a second generation of the Xpert TB XDR assay.

Official Title
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Sputum Pharmacokinetics of TB Drugs and Bacterial Drug Resistance

Conditions
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Tuberculosis, Non-Tuberculosis Mycobacteria

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: At least 18 years of age Diagnosis of TB (and/or NTM for NIH clinical center subjects) Ongoing signs and/or symptoms of pulmonary TB (and/or NTM at the NIH CC) Suspected drug resistance (drug susceptible allowed at the NIH CC) Available to provide at least 3 sputa over 2 or more days Taking anti-tuberculosis medicines (or NTM meds at NIH CC) during the time sputa are provided Thought likely to be Mycobacterium culture positive (including NTM infected for the NIH CC) by enrolling physician GeneXpert MTB/RIF sputum TBpositive (China subjects only) Likely able to produce sputum samples while on study Willing to provide blood samples Willing to have samples stored EXCLUSION CRITERIA: Acute liver or kidney disease Conditions which compromise the subject s ability to take or absorb oral drugs

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sputum and blood participants<br>These participants will contribute both blood and sputum to the study | |
| Sputum only participants<br>These participants will only contribute sputum to the study | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint is the AUC (0-24) in sputum and blood. | drug-specific correlation coefficients of the AUCs for sputum and blood | 0-24 hrs | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| drug-specific time-concentration curves, as well as drug exposure in sputum relative to that in cavity caseum | Estimation of time-concentration curves, as well as variance components of sputum PK parameters to better inform sputum PK sampling in future studies. Additionally, the relationship between drug-specific exposures in cavity caseum, from historical data, and that in sputum will be evaluated using correlation coefficients. | Throughout | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetic-Moedeling, Tuberculosis, Therapeutic Drug Monitoring, Drug-Levels, Caseum, Natural History