Clinical trial NCT00164450: TBTC Study 26 PK: Rifapentine Pharmacokinetics in Children During Treatment of Latent TB Infection
Official title: TBTC Study 26 PK: Rifapentine Pharmacokinetics in Children Receiving Once Weekly Rifapentine and Isoniazid for the Treatment of Latent Tuberculosis Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Tuberculosis
Keywords: tuberculosis
TB
pharmacokinetics
children
Lead sponsor: Centers for Disease Control and Prevention
Sponsor class: FED
Collaborators: name: US Department of Veterans Affairs
First posted: 2005-09-14
Enrollment: 230
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Eligibility criteria: 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

Primary outcomes:
measure: Determine whether rifapentine exposure (level 24 hours after drug ingestion) is equivalent in young children receiving weight-based dosing to adults receiving 900 mg.
timeFrame: 24 hours after drug ingestion
Secondary outcomes:
measure: Correlate estimated rifapentine exposure with toxicity in young children receiving rifapentine and isoniazid for latent tuberculosis infection.
timeFrame: During the three months of taking rifapentine
measure: Validate the accuracy of estimated rifapentine exposure with pediatric rifapentine dose based on weight.
timeFrame: 24 hours after drug ingestion
measure: Determine estimated drug bioavailability in pediatric subjects (ages 2 to < 12 years) given higher mg/kg doses of rifapentine.
timeFrame: 24 hours after drug ingestion
measure: Determine the association in adults between polymorphisms of MDR1 genotype (P-glycoprotein) and rifapentine estimated exposure.
timeFrame: at the time of blood draw
measure: 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.
timeFrame: at the time of blood draw
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Central Arkansas Veterans Health System
state: Arkansas
city: Los Angeles
country: United States
facility: University of Southern California Medical Center
state: California
city: San Diego
country: United States
facility: University of California at San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Denver
country: United States
facility: Denver Public Health Department
state: Colorado
city: Washington
country: United States
facility: Washington DC Veterans Administration Medical Center
state: District of Columbia
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: Northwestern University School of Medicine
state: Illinois
city: Hines
country: United States
facility: Hines Veterans Administration Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Newark
country: United States
facility: New Jersey School of Medicine
state: New Jersey
city: New York
country: United States
facility: Columbia University
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Nashville
country: United States
facility: Veterans Administration Tennessee Valley Health Care System
state: Tennessee
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 VA Hospital
state: Texas
city: Seattle
country: United States
facility: Seattle-King County Health Department
state: Washington
city: Rio de Janeiro
country: Brazil
facility: Hopital Universitario Clementino Fraga Filho
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Winnepeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Montreal
country: Canada
facility: Montreal Chest Institute
state: Quebec
city: Barcelona
country: Spain
facility: Agencia de Salut Publica
Study officials:
affiliation: VAMC and University of Texas Health Science Center San Antonio
name: Marc Weiner, MD
role: STUDY_CHAIR
References: