TBTC Study 26 PK: Rifapentine Pharmacokinetics in Children During Treatment of Latent TB Infection

TBTC Study 26 PK: Rifapentine Pharmacokinetics in Children Receiving Once Weekly Rifapentine and Isoniazid for the Treatment of Latent Tuberculosis Infection

Compared to adults, children appear to require higher weight-based doses of rifapentine to acheive comparable drug levels. TBTC Study 26, a study of the effectiveness and tolerability of weekly rifapentine/isoniazid for three months versus daily isoniazid for nine months for the treatment of latent tuberculosis infection, has been amended to include children ages 2-11 based on an initial single-dose study and pharmacokinetic modeling. Study 26PK evaluates the adequacy of the doses chosen for young children enrolled in Study 26 with a single blood draw, 24 hours after the third or subsequent weekly Study 26 dose of rifapentine and isoniazid. An adult control is enrolled for each child enrolled.

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Drug: Rifapentine + isoniazid once weekly for 3 months

Detailed Description

The pharmacokinetics of rifapentine have been studied in adults, adolescents (ages 12-15 years), and patients with hepatic dysfunction and HIV infection. However, there are no published data on the efficacy, safety or pharmacokinetics of rifapentine in children. This lack of data has precluded till now enrollment of children less than 12 years old in TBTC Study 26, a study of the effectiveness and tolerability of weekly rifapentine/isoniazid for three months versus daily isoniazid for nine months for the treatment of latent tuberculosis infection, a phase 3 treatment trial that will enroll 8000 persons with latent tuberculosis infection. A recently completed initial evaluation of rifapentine pharmacokinetics among children receiving a single dose of rifapentine demonstrated significantly lower exposures of rifapentine among children compared to adults, when children were given weight-based doses chosen to be comparable to a 600 mg oral dose in adults. This reduced exposure suggested that children require higher weight-based doses than adults and a model was constructed to estimate rifapentine doses in children that would result in exposures similar to the 900 mg dose used for adults in Study 26. Study 26 has been amended to include children ages 2-11 based on the initial single-dose study and pharmacokinetic modeling. The purpose of Study 26PK is to evaluate the adequacy of the doses chosen for young children who enrolled in Study 26.

Briefly, this study aims to:

• determine whether rifapentine exposure is equivalent in young children receiving weight-based dosing to adults receiving 900 mg.
• correlate rifapentine exposure with toxicity in young children
• validate accuracy of weight-based dosing in children
• determine rifapentine bioavailability in children
• determine association in adults between polymorphisms of MDR1 genotype and rifapentine exposure
• correlate isoniazid concentrations in adults with acetylator status

• Study Type: Interventional
• Enrollment (Anticipated): 230
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil, 2194.590
    • Hopital Universitario Clementino Fraga Filho
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4R4
      • University of British Columbia
  • Manitoba
    • Winnepeg, Manitoba, Canada, R3A 1R8
      • University of Manitoba
  • Quebec
    • Montreal, Quebec, Canada, H2X 2P4
      • Montreal Chest Institute
• Spain
  • Barcelona, Spain, 080023
    • Agencia de Salut Publica
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Central Arkansas Veterans Health System
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California Medical Center
    • San Diego, California, United States, 92103
      • University of California at San Diego
    • San Francisco, California, United States, 94110
      • University of California, San Francisco
  • Colorado
    • Denver, Colorado, United States, 80204
      • Denver Public Health Department
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
      • Washington DC Veterans Administration Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 21231
      • Northwestern University School Of Medicine
    • Hines, Illinois, United States, 60141
      • Hines Veterans Administration Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University Medical Center
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • New Jersey School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Veterans Administration Tennessee Valley Health Care System
  • Texas
    • Fort Worth, Texas, United States, 76104
      • University of North Texas Health Science Center
    • Houston, Texas, United States, 77030
      • Houston Veterans Administration Medical Center
    • San Antonio, Texas, United States, 78284
      • Audie L. Murphy VA Hospital
  • Washington
    • Seattle, Washington, United States, 98104
      • Seattle-King County Health Department

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Enrolled in TBTC Study 26 randomized to treatment with once weekly isoniazid and rifapentine:

   • Child between the ages of 2 to less than 12 years for whom informed consent by a guardian and of assent (if applicable) have been obtained.
   • Adult greater than age 18 for whom informed consent has been obtained.
2. Willingness to undergo a blood phlebotomy 24 hours following dosing of isoniazid and rifapentine after receiving at least three once-weekly doses of rifapentine plus isoniazid.

If as a result of a contact investigation, both a parent and child are enrolled in Study 26, both may be co-enrolled into the pharmacokinetic substudy with the adult serving as the control for the child. Preference will be given to a biologic parent of the same gender. If no eligible biologic parent is available for study, the next adult of the same gender and at the same TBTC site, who is substudy eligible, will serve as the adult control.

Exclusion Criteria:

• None

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Determine whether rifapentine exposure (level 24 hours after drug ingestion) is equivalent in young children receiving weight-based dosing to adults receiving 900 mg.	24 hours after drug ingestion

Secondary Outcome Measures

Outcome Measure	Time Frame
Correlate estimated rifapentine exposure with toxicity in young children receiving rifapentine and isoniazid for latent tuberculosis infection.	During the three months of taking rifapentine
Validate the accuracy of estimated rifapentine exposure with pediatric rifapentine dose based on weight.	24 hours after drug ingestion
Determine estimated drug bioavailability in pediatric subjects (ages 2 to < 12 years) given higher mg/kg doses of rifapentine.	24 hours after drug ingestion
Determine the association in adults between polymorphisms of MDR1 genotype (P-glycoprotein) and rifapentine estimated exposure.	at the time of blood draw
Determine the frequency of lower antitubercular drug concentrations in adults with acetylator status determined by N-acetyltransferase genotypes and of rifapentine by C24 and by MDR1 genotypes.	at the time of blood draw

Collaborators and Investigators

• Sponsor: Centers for Disease Control and Prevention
• Collaborators: US Department of Veterans Affairs

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (ACTUAL): August 1, 2008
• Study Completion (ACTUAL): August 1, 2008

Study Registration Dates

• First Submitted: September 10, 2005
• First Submitted That Met QC Criteria: September 10, 2005
• First Posted (ESTIMATE): September 14, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): August 25, 2008
• Last Update Submitted That Met QC Criteria: August 22, 2008
• Last Verified: August 1, 2008

More Information

Terms related to this study

• Keywords: children; pharmacokinetics; TB; tuberculosis
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Leprostatic Agents; Antitubercular Agents; Antibiotics, Antitubercular; Fatty Acid Synthesis Inhibitors; Rifapentine; Isoniazid
• Other Study ID Numbers: CDC-NCHSTP-4679