TBTC Study 27/28 PK: Moxifloxacin Pharmacokinetics During TB Treatment

NCT00164463 | Completed Phase 2 DMC

• 1 other identifier: CDC-NCHSTP-4222
• Study Type: interventional
• Target: 72
• Locations: 3 countries
• Sites: 8

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.

Conditions

Tuberculosis

Keywords

tuberculosis; TB

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (7)

• 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

Study Arms (2)

Moxifloxacin

EXPERIMENTAL

Moxifloxacin 400 mg po qd given 5 of 7 days per week

Drug: Moxifloxacin

Isoniazid

ACTIVE COMPARATOR

Isoniazid 300 mg po qd given 5/7 days per week

Drug: Isoniazid

Interventions

Moxifloxacin DRUG

400 mg po qd 5/7 days per week

Moxifloxacin

Isoniazid DRUG

isoniazid 300 mg po qd 5/7 days per week

Isoniazid

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Centers for Disease Control and Prevention: lead
• US Department of Veterans Affairs: collaborator
• Bayer: collaborator
• National Institutes of Health (NIH): collaborator

Study Sites (8)

University of Southern California Medical Center

Los Angeles, California, 90033, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21231, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

University of North Texas Health Science Center

Fort Worth, Texas, 76104, United States

Location

Houston Veterans Administration Medical Center

Houston, Texas, 77030, United States

Location

Audie L Murphy Memorial Veterans Administration Medical Center

San Antonio, Texas, 78284, United States

Location

University of British Columbia

Vancouver, British Columbia, V5Z 1L8, Canada

Location

Makerere University Medical School

Kampala, Uganda

Location

Related Publications (3)

• 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.

  PMID: 20660695 RESULT

• 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.

  PMID: 17517835 RESULT

• 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.

  PMID: 29463526 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

Moxifloxacin; Isoniazid

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Marc Weiner, MD

  VAMC and University of Texas Health Science Center San Antonio

  STUDY CHAIR

• William Burman, MD

  Denver Public Health

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED

Study Record Dates

• First Submitted: September 10, 2005
• First Posted: September 14, 2005
• Study Start: July 1, 2004
• Primary Completion: August 1, 2007
• Study Completion: August 1, 2007
• Last Updated: June 8, 2011

Record last verified: 2011-06

Locations

UG (1); US (6); CA (1)