TBTC Study 27/28 PK: Moxifloxacin Pharmacokinetics During TB Treatment
Study Details
Study Description
Brief Summary
This substudy of TBTC Studies 27 and 28 compares 1) the pharmacokinetics of moxifloxacin alone versus moxifloxacin administered with rifampin in healthy volunteers and 2) the pharmacokinetics of moxifloxacin among patients with tuberculosis being treated with multidrug therapy (isoniazid or ethambutol, rifampin, and pyrazinamide) to those of healthy volunteers receiving moxifloxacin plus rifampin. It also evaluates the association between polymorphisms of MDR1 genotype (P-glycoprotein) and rifampin pharmacokinetic parameters, the effect of polymorphisms of MDR1 genotype and/or rifampin pharmacokinetics on isoniazid pharmacokinetic parameters adjusted for N-acetyltransferase genotype (NAT2), and determines by multivariate regression analyses the associations between moxifloxacin or rifampin pharmacokinetic parameters and markers of tuberculosis disease severity including the covariates of two-month culture positivity, cavitary lung disease, Body Mass Index, weight, duration of study treatment prior to PK, co-morbidities and C-reactive protein. Healthy volunteers and TB patients receive frequent scheduled blood draws during a 24 hour period after ingesting a dose of TB drugs.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Moxifloxacin Moxifloxacin 400 mg po qd given 5 of 7 days per week |
Drug: Moxifloxacin
400 mg po qd 5/7 days per week
|
| Active Comparator: Isoniazid Isoniazid 300 mg po qd given 5/7 days per week |
Drug: Isoniazid
isoniazid 300 mg po qd 5/7 days per week
|
Outcome Measures
Primary Outcome Measures
- Compare in healthy volunteers the pharmacokinetics of moxifloxacin alone versus moxifloxacin administered with rifampin. [study period]
- Compare the pharmacokinetics of moxifloxacin among patients with tuberculosis being treated with multidrug therapy (isoniazid or ethambutol, rifampin, and pyrazinamide) to those of healthy volunteers receiving moxifloxacin plus rifampin. [study period]
Secondary Outcome Measures
- Determine variation of moxifloxacin pharmacokinetics (PK) among patients with pulmonary TB during treatment. [study period]
- Compare serum concentrations of isoniazid rifampin and pyrazinamide among patients being treated with moxifloxacin versus patients being treated with ethambutol as the fourth drug in multidrug treatment. [study period]
- Compare serum concentrations of rifampin, pyrazinamide and ethambutol among patients being treated with moxifloxacin versus patients being treated with isoniazid as the fourth drug [study period]
- Determine the association between polymorphisms of MDR1 genotype (P-glycoprotein) and rifampin PK parameters. [study period]
- Determine the effect of polymorphisms of MDR1 genotype and/or rifampin PK on isoniazid PK parameters adjusted for N-acetyltransferase genotype (NAT2). [study period]
- Determine the effects of polymorphisms of MDR1 and UGT genotypes on moxifloxacin PK parameters. [study period]
- Determine by multivariate regression analyses the associations between moxifloxacin or rifampin PK parameters and markers of disease severity. [study period]
Eligibility Criteria
Criteria
Inclusion Criteria:
For Healthy Volunteers:
-
Provision of informed consent for the study.
-
Age > 18 years.
-
Willingness to be available for 2 weeks of DOT.
-
Willingness to be admitted to a GCRC or hospital on two occasions.
-
Women of child-bearing potential must agree to practice an adequate method of birth control. Barrier methods of contraception or abstinence from sexual activity are satisfactory methods.
-
Willingness to have HIV testing done if documented results are not available. (A prior negative result must be obtained within one year and consists of a negative HIV ELISA. A positive result must be both a positive HIV ELISA and Western Blot, or a plasma HIV PCR RNA level greater than 5000 copies/ml).
-
Laboratory screening (if not already available) within 30 days of the first PK admission:
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Serum potassium within normal limits
-
Hematocrit > 35%
-
Absolute neutrophil count > 1000 /mm3
-
AST < 3 times the upper limit of normal
-
Bilirubin < 2 times the upper limit of normal
-
Creatinine < 2 times the upper limit of normal
-
Eligible and enrolled for medical health care sponsored by the United States federal government (such as the Veterans Administration enrollment Priority 1 through 7, VHA Directive 2003-003).
For Patients with Tuberculosis Enrolled in TBTC Study 27 or Study 28:
-
Any patient enrolled in TBTC Study 27 or Study 28 receiving a daily (5-7 days per week) regimen.
-
Provision of informed consent for the study.
-
Willingness to be admitted to a GCRC or hospital on one occasion.
Exclusion Criteria:
For Healthy Volunteers:
-
Karnofsky score less than 90
-
Pregnancy or breast-feeding. (A negative pregnancy test is required for women of childbearing potential within 14 days before the first dose of moxifloxacin.)
-
Known allergy to any fluoroquinolone or rifamycin antibiotic
-
Current or planned therapy during the study with drugs having unacceptable interactions with rifampin
-
History of prolonged QT syndrome or current or planned therapy with quinidine, procainamide, amiodarone, sotalol, or ziprasidone during period of administration of moxifloxacin and for one week after treatment
For Patients with Tuberculosis Enrolled in TBTC Study 27 or Study 28:
-
Severe anemia as defined by a hematocrit less than 25% (most recent value, measured within 30 days of the PK study).
-
History of severe liver disease classified as Child Pugh Class C.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Southern California Medical Center | Los Angeles | California | United States | 90033 |
| 2 | Johns Hopkins University | Baltimore | Maryland | United States | 21231 |
| 3 | Duke University Medical Center | Durham | North Carolina | United States | 27710 |
| 4 | University of North Texas Health Science Center | Fort Worth | Texas | United States | 76104 |
| 5 | Houston Veterans Administration Medical Center | Houston | Texas | United States | 77030 |
| 6 | Audie L Murphy Memorial Veterans Administration Medical Center | San Antonio | Texas | United States | 78284 |
| 7 | University of British Columbia | Vancouver | British Columbia | Canada | V5Z 1L8 |
| 8 | Makerere University Medical School | Kampala | Uganda |
Sponsors and Collaborators
- Centers for Disease Control and Prevention
- US Department of Veterans Affairs
- Bayer
- National Institutes of Health (NIH)
Investigators
- Study Chair: Marc Weiner, MD, VAMC and University of Texas Health Science Center San Antonio
- Study Chair: William Burman, MD, Denver Public Health
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CDC-NCHSTP-4222