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

研究 26PK，利福喷汀 PKS 在每周接受异烟肼治疗结核病 (HIV) 的儿童中的应用

• 批准号: 7718711
• 负责人: MARC H WEINER
• 金额: $ 0.01万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7718711
• 关键词: ABCB1 gene; Adolescent; Adult; Age; Alcohols; Antitubercular Agents; Biological; Biological Availability; Blood; Blood specimen; Body Temperature; Child; Childhood; Computer Retrieval of Information on Scientific Projects Database; Data; Dose; Drug Kinetics; Enrollment; Evaluation; Frequencies; Functional disorder; Funding; Genetic; Genetic Polymorphism; Genotype; Grant; HIV Infections; Hepatic; Hour; Infection; Ingestion; Institution; Interview; Measures; Medical; Modeling; NAT2 gene; Oral; P-Glycoprotein; P-Glycoproteins; Parents; Participant; Patients; Pharmaceutical Preparations; Publishing; Purpose; Relative (related person); Research; Research Personnel; Resources; Safety; Sampling; Site; Source; Symptoms; Time; Toxic effect; Tuberculosis; United States National Institutes of Health; Venous blood sampling; Weight; base; case control; clinically relevant; design; human NAT2 protein; isoniazid; preference; rifapentine; sex

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 目的：主要目的是确定潜伏性结核感染受试者中接受基于体重给药的儿童（2 岁至 < 12 岁）与接受 900 mg 利福喷汀的成人之间的利福喷汀暴露量（根据药物摄入后 24 小时的利福喷汀浓度估计）是否相等（约 20% 至 +25%）。 次要目标包括：将估计的瑞福喷汀暴露量与接受利福喷汀和异烟肼治疗潜伏性结核感染的幼儿的毒性联系起来；验证基于体重的儿童利福喷丁剂量估计利福喷丁暴露量的准确性；确定给予较高 mg/kg 剂量利福喷丁的儿科受试者的估计药物生物利用度；确定成人 KDR1 基因型（P-糖蛋白）多态性与利福喷丁估计暴露量之间的关联；确定成人中较低抗结核药物浓度的频率，其乙酰化状态由N-乙酰转移酶基因型确定，利福喷丁由C-24和KDR1基因型确定。 研究计划：本研究将采用成人（年龄 > 18 岁）的平行分组设计作为儿童（2 岁至 <12 岁）的对照病例。 所有参加研究 26 的符合条件的儿童都将成为药代动力学亚研究的候选者。 儿童注册后，成人对照也将有资格注册。 成人对照的偏好将按以下顺序排列：1）孩子的同性亲生父母； 2）孩子的亲生父母；或 3) 同一 TBTC 站点的下一个符合条件的同性成人。 方法：在第三次或随后每周一次的瑞法喷丁联合异烟肼治疗后 24 小时进行药代动力学采样。 儿童 - 通过静脉切开术抽取血液以测定利福喷丁浓度（2 毫升）。 成人 - 将收集血液用于瑞法喷丁浓度（2 ml）和基因研究、MDR1 和 NAT2 基因型（10 ml）。 应在给药后 24 小时时间点（给药后 23 至 25 小时）后 60 分钟内采集血样。 在药代动力学研究期间和之前：将对参与者进行访谈，以获取有关医学症状的更多信息，以及与研究药物给药相关的膳食、零食和伴随药物的描述和时间安排；并将测量体温和体重。 成人在服用瑞福喷丁前后 24 小时内应禁酒。 临床相关性：利福喷汀的药代动力学已在成人、青少年（12-15 岁）以及肝功能障碍和 HIV 感染患者中进行了研究。 然而，尚无关于利福喷汀在儿童中的疗效、安全性或药代动力学的公开数据。 最近完成的一项对接受单剂量利福喷汀的儿童中瑞福喷汀药代动力学的初步评估表明，当儿童接受基于体重的剂量选择与成人 600 mg 口服剂量相当时，儿童中利福喷汀的暴露量显着低于成人。 这种暴露量的减少表明儿童需要比成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中的利福喷丁剂量，这将导致与研究 26 中成人使用的 900 mg 剂量相似的暴露量。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。