Sputum Pharmacokinetics of TB Drugs and Bacterial Drug Resistance

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.

Study Overview

• Status: Completed
• Conditions: Tuberculosis; Non-Tuberculosis Mycobacteria

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 215

Contacts and Locations

Study Locations

• China
  • Zhengzhou,, China
    • Henan Provincial Chest Hospital
• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

This is a prospective trial of the pharmacokinetics of TB drugs in the sputum and blood of drug susceptible and drug resistant subjects at the Henan Provincial Chest Hospital in Zhengzhou, China and at the NIH Clinical Center in Bethesda, MD. Patients (inpatients or outpatients) being treated for TB (including those with NTM at the NIH CC) were asked to join the study.@@@@@@@@@@@@

Description

• INCLUSION CRITERIA:

  1. At least 18 years of age
  2. Diagnosis of TB (and/or NTM for NIH clinical center subjects)
  3. Ongoing signs and/or symptoms of pulmonary TB (and/or NTM at the NIH CC)
  4. Suspected drug resistance (drug susceptible allowed at the NIH CC)
  5. Available to provide at least 3 sputa over 2 or more days
  6. Taking anti-tuberculosis medicines (or NTM meds at NIH CC) during the time sputa are provided
  7. Thought likely to be Mycobacterium culture positive (including NTM infected for the NIH CC) by enrolling physician
  8. GeneXpert MTB/RIF sputum TBpositive (China subjects only)
  9. Likely able to produce sputum samples while on study
  10. Willing to provide blood samples
  11. Willing to have samples stored

EXCLUSION CRITERIA:

1. Acute liver or kidney disease
2. Conditions which compromise the subject s ability to take or absorb oral drugs

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Sputum and blood participants; These participants will contribute both blood and sputum to the study
Sputum only participants; These participants will only contribute sputum to the study

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Wilkins JJ, Savic RM, Karlsson MO, Langdon G, McIlleron H, Pillai G, Smith PJ, Simonsson US. Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption. Antimicrob Agents Chemother. 2008 Jun;52(6):2138-48. doi: 10.1128/AAC.00461-07. Epub 2008 Apr 7.
• Dartois V. Drug forgiveness and interpatient pharmacokinetic variability in tuberculosis. J Infect Dis. 2011 Dec 15;204(12):1827-9. doi: 10.1093/infdis/jir662. Epub 2011 Oct 21. No abstract available.
• Peloquin C. Use of therapeutic drug monitoring in tuberculosis patients. Chest. 2004 Dec;126(6):1722-4. doi: 10.1378/chest.126.6.1722. No abstract available.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2016
• Primary Completion (Actual): December 31, 2020
• Study Completion (Actual): December 31, 2020

Study Registration Dates

• First Submitted: August 26, 2015
• First Submitted That Met QC Criteria: August 26, 2015
• First Posted (Estimate): August 28, 2015

Study Record Updates

• Last Update Posted (Actual): March 29, 2022
• Last Update Submitted That Met QC Criteria: March 25, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Natural History; Tuberculosis; Therapeutic Drug Monitoring; Pharmacokinetic-Moedeling; Drug-Levels; Caseum
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: 150187; 15-I-0187