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

Sponsor

Centers for Disease Control and Prevention (U.S. Fed)

Overall Status

Completed

CT.gov ID

NCT00164450

Collaborator

US Department of Veterans Affairs (U.S. Fed)

230

Enrollment

Locations

Duration (Months)

9.6

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: Rifapentine + isoniazid once weekly for 3 months	N/A

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 Design

Study Type:

Interventional

Anticipated Enrollment :

230 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Sep 1, 2005

Actual Primary Completion Date :

Aug 1, 2008

Actual Study Completion Date :

Aug 1, 2008

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.

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

Contacts and Locations

Locations

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