STUDY 26PK, RIFAPENTINE PKS IN CHILDREN RECEIVING WEEKLY ISONIAZID FOR TB (HIV)

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: Primary objective is to determine in subjects with latent tuberculosis infection if rifapentine exposure (estimated from rifapentine concentration 24 hours after drug ingestion) is equivalent (~20% to +25%) between children (ages 2 to < 12 years) receiving weight based dosing and adults receiving rifapentine 900 mg. Secondary objectives include: correlating estimated refapentine exposure with toxicity in young children receiving rifapentine and isoniazid for latent tuberculosis infection; validating the accuracy of estimated rifapentine exposure with pediatric rifapentine dose based on weight; determining estimated durg bioavailability in pediatric subjects given higher mg/kg doses of rifapentine; determining the association in adults between polymorphisms of KDR1 genotype (P-glycoprotein) and rifapentine estimated exposure; and determining the frequency of lower antitubercular drug concentrations in adults with acetylator status determined by N-acetyltransferase genotypes and of rifapentine by C-24 and by KDR1 genotypes. RESEARCH PLAN: This study will use a parallel group design with adults (age > 18 years) to serve as control cases for children (ages 2 to <12 years). All eligible children enrolled in Study 26 will be candidates for the pharmacokinetic substudy. With the enrollment of a child, an adult control will be eligible for enrollment. Preferences for adult controls will be in the following order: 1) child's same sex biological parent; 2) child's biological parent; or 3) next eligible same sex adult at the same TBTC site. METHODS: Pharmacokinetic sampling will be performed 24 hours after the third or subsequent once-weekly refapentine plus isoniazid treatment. Children - blood will be drawn by phlebotomy for rifapentine concentration (2 ml). Adults - blood will be collected for refapentine concentration (2 ml) and for genetic studies, MDR1 and NAT2 genotypes (10 ml). Blood samples should be obtained within 60 minutes of the 24 hour post-drug administration time-point (23 to 25 hours after drug administration). Before and during the pharmacokinetic study period: participants will be interviewed to obtain additional information about medical symptoms, and description and timing of meals, snacks, and concomitant medications relative to study drug administration; and body temperature and weight will be measured. Adults should abstain from consuming alcohol for 24 hours before and after refapentine administration. CLINICAL RELEVANCE: 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. A recently completed initial evaluation of refapentine 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. The purpose of Study 26PK is to evaluate the adequacy of the doses chosen for young children who enrolled in Study 26.