Tuberculosis
Conditions
Keywords
tuberculosis, TB, pharmacokinetics, children
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
Interventions
DRUGIsoniazid
Isoniazid daily, oral, nine months
DRUGRifapentine
Rifapentine plus Isoniazid taken orally, weekly, by direct observation for 12 weeks
Sponsors
Centers for Disease Control and Prevention
US Department of Veterans Affairs
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rifapentine Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity, AUC0-inf | 24 hours after study-drug administration; AUC0-inf estimated using a nonlinear mixed-effects pharmacokinetic model incorporating the 24-hour rifapentine concentration, C24. | Rifapentine exposure was estimated in children and adults receiving once-weekly rifapentine plus isoniazid. A sparse sampling design used a plasma sample collected 24 hours after administration of study drugs. |
| Correlation Between Rifapentine C24 and AUC0-inf | 24 hours after study-drug administration | Value represents the coefficient of determination (R-squared) for the relationship between rifapentine C24 and AUC0-inf. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rifapentine AUC0-inf by Tablet Administration Method in Children | 24 hours after study-drug administration | Comparison of rifapentine AUC0-inf between participants receiving crushed and whole rifapentine tablets. |
Countries
Brazil, Canada, Spain, United States
Contacts
STUDY_CHAIRMarc Weiner, MD
VAMC and University of Texas Health Science Center San Antonio
Participant flow
Recruitment details
Participants were enrolled in a pharmacokinetic substudy of the PREVENT-TB trial evaluating once-weekly rifapentine plus isoniazid for treatment of latent tuberculosis infection.
Pre-assignment details
A total of 158 participants were enrolled. One enrolled participant was not included in the pharmacokinetic analysis population. Participant Flow and Results are based on the 157 participants included in the pharmacokinetic substudy analysis.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 80 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 77 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 118 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants |
| Race (NIH/OMB) Black or African American | 29 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 118 Participants |
| Sex: Female, Male Female | 76 Participants |
| Sex: Female, Male Male | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| other Total, other adverse events | 5 / 80 | 13 / 77 |
| serious Total, serious adverse events | 0 / 80 | 0 / 77 |
Outcome results
None listed