Clinical trial NCT00164463: TBTC Study 27/28 PK: Moxifloxacin Pharmacokinetics During TB Treatment
Official title: TBTC Study 27/28 PK: Pharmacokinetic Issues in the Use of Moxifloxacin for Treatment of Tuberculosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculosis
Keywords: tuberculosis
TB
Lead sponsor: Centers for Disease Control and Prevention
Sponsor class: FED
Collaborators: name: US Department of Veterans Affairs
name: Bayer
name: National Institutes of Health (NIH)
First posted: 2005-09-14
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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:

  * 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.

Primary outcomes:
measure: Compare in healthy volunteers the pharmacokinetics of moxifloxacin alone versus moxifloxacin administered with rifampin.
timeFrame: study period
measure: 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.
timeFrame: study period
Secondary outcomes:
measure: Determine variation of moxifloxacin pharmacokinetics (PK) among patients with pulmonary TB during treatment.
timeFrame: study period
measure: 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.
timeFrame: study period
measure: Compare serum concentrations of rifampin, pyrazinamide and ethambutol among patients being treated with moxifloxacin versus patients being treated with isoniazid as the fourth drug
timeFrame: study period
measure: Determine the association between polymorphisms of MDR1 genotype (P-glycoprotein) and rifampin PK parameters.
timeFrame: study period
measure: Determine the effect of polymorphisms of MDR1 genotype and/or rifampin PK on isoniazid PK parameters adjusted for N-acetyltransferase genotype (NAT2).
timeFrame: study period
measure: Determine the effects of polymorphisms of MDR1 and UGT genotypes on moxifloxacin PK parameters.
timeFrame: study period
measure: Determine by multivariate regression analyses the associations between moxifloxacin or rifampin PK parameters and markers of disease severity.
timeFrame: study period
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California Medical Center
state: California
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Fort Worth
country: United States
facility: University of North Texas Health Science Center
state: Texas
city: Houston
country: United States
facility: Houston Veterans Administration Medical Center
state: Texas
city: San Antonio
country: United States
facility: Audie L Murphy Memorial Veterans Administration Medical Center
state: Texas
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Kampala
country: Uganda
facility: Makerere University Medical School
Study officials:
affiliation: VAMC and University of Texas Health Science Center San Antonio
name: Marc Weiner, MD
role: STUDY_CHAIR
affiliation: Denver Public Health
name: William Burman, MD
role: STUDY_CHAIR
References:
citation: Weiner M, Peloquin C, Burman W, Luo CC, Engle M, Prihoda TJ, Mac Kenzie WR, Bliven-Sizemore E, Johnson JL, Vernon A. Effects of tuberculosis, race, and human gene SLCO1B1 polymorphisms on rifampin concentrations. Antimicrob Agents Chemother. 2010 Oct;54(10):4192-200. doi: 10.1128/AAC.00353-10. Epub 2010 Jul 26.
citation: Weiner M, Burman W, Luo CC, Peloquin CA, Engle M, Goldberg S, Agarwal V, Vernon A. Effects of rifampin and multidrug resistance gene polymorphism on concentrations of moxifloxacin. Antimicrob Agents Chemother. 2007 Aug;51(8):2861-6. doi: 10.1128/AAC.01621-06. Epub 2007 May 21.
citation: Weiner M, Gelfond J, Johnson-Pais TL, Engle M, Peloquin CA, Johnson JL, Sizemore EE, Mac Kenzie WR. Elevated Plasma Moxifloxacin Concentrations and SLCO1B1 g.-11187G>A Polymorphism in Adults with Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2018 Apr 26;62(5):e01802-17. doi: 10.1128/AAC.01802-17. Print 2018 May.