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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：主要目的是确定在潜在结核病感染者中，接受按体重给药的儿童(2岁至12岁)和成人(接受利福喷丁900 mg)的利福喷丁暴露(从服药后24小时的浓度估算)是否相当(~20%~+25%)。次要目标包括：将再喷丁的估计暴露剂量与接受利福喷丁和异烟肼治疗潜在结核病感染的幼儿的毒性相关联；验证以体重为基础的儿童利福喷丁剂量估计利福喷丁暴露的准确性；确定服用较高mg/kg剂量利福喷丁的儿童受试者的估计药物生物利用度；确定KDR1基因(P-糖蛋白)多态性与利福喷丁估计暴露之间的关联；以及确定由N-乙酰转移酶基因型和C-24基因和KDR1基因决定的乙酰化状态成人中抗结核药物浓度较低的频率。 研究计划：本研究将采用平行分组设计，成人(18岁)作为儿童(2岁至12岁)的对照病例。所有参加第26项研究的合格儿童都将成为药代动力学分研究的候选对象。随着儿童的注册，成人控制将有资格注册。成人对照的偏好将按以下顺序排列：1)儿童的同性亲生父母；2)儿童的亲生父母；或3)同一TBTC站点的下一个合格的同性成年人。 方法：在第三次或随后的每周一次瑞芬太尼加异烟肼治疗后24小时内进行药代动力学采样。儿童-采血测定利福喷丁浓度(2毫升)。成人-将采集血液中的瑞芬太尼浓度(2毫升)，并用于遗传学研究，MDR1和NAT2基因类型(10毫升)。应在服药后24小时时间点(服药后23至25小时)后60分钟内采集血样。 在药代动力学研究之前和期间：参与者将接受采访，以获得与研究用药有关的医疗症状、膳食、零食和伴随药物的描述和时间安排；并将测量体温和体重。成人在服用瑞芬太尼前后24小时内不应饮酒。 临床意义：利福喷丁在成人、青少年(12-15岁)以及肝功能障碍和HIV感染患者中进行了药代动力学研究。然而，目前还没有关于利福喷丁在儿童中的有效性、安全性或药代动力学的公开数据。最近完成的一项在接受单剂量利福喷丁的儿童中进行的再喷丁药代动力学初步评估显示，当儿童被给予与成人600毫克口服剂量相当的体重剂量时，儿童中利福喷丁的暴露比成人低得多。这种减少的暴露表明，儿童需要比成年人更高的基于体重的剂量，并且构建了一个模型来估计儿童的利福喷丁剂量，该剂量将导致类似于研究26中成人使用的900毫克剂量的暴露。研究26PK的目的是评估为参加研究26的幼儿选择的剂量是否充足。

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.