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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目的：主要目的是确定在潜伏性结核感染受试者中，接受基于体重给药的儿童（2至< 12岁）与接受利福喷丁900 mg的成人之间的利福喷丁暴露量（根据药物摄入后24小时的利福喷丁浓度估计）是否相等（约20%至+25%）。 次要目的包括：将估计的利福喷丁暴露与接受利福喷丁和异烟肼治疗潜伏性结核病感染的幼儿中的毒性相关联;用基于体重的儿科利福喷丁剂量验证估计的利福喷丁暴露的准确性;确定给予较高mg/kg剂量的利福喷丁的儿科受试者中估计的杜尔格生物利用度;确定成人中KDR 1基因型多态性与（P-糖蛋白）和利福喷丁的估计暴露量;并确定具有乙酰化状态的成人中抗结核药物浓度较低的频率，乙酰转移酶基因型和利福喷丁的C-24和KDR 1基因型。 研究：本研究将使用成人（年龄> 18岁）作为儿童（年龄2至<12岁）的对照病例的平行组设计。 入组研究26的所有合格儿童都将成为药代动力学子研究的候选人。 随着儿童的入组，成人对照组将有资格入组。 成人对照的首选顺序如下：1）儿童的同性生物学父母; 2）儿童的生物学父母;或3）同一TBTC研究中心的下一个合格同性成人。 方法：药代动力学采样将在第三次或后续每周一次的瑞喷丁+异烟肼治疗后24小时进行。 儿童-将通过静脉切开术抽取血液用于利福喷丁浓度（2 ml）。 成人-将采集血液用于瑞喷汀浓度（2 ml）和遗传学研究、MDR 1和NAT 2基因型（10 ml）。 应在给药后24小时时间点（给药后23 - 25小时）的60分钟内采集血样。 药代动力学研究期间和之前：将对受试者进行访谈，以获得关于医学症状的其他信息，以及与研究药物给药相关的进餐、零食和合并用药的描述和时间;将测量体温和体重。 成人应在refapentine给药前后24小时内戒酒。 临床相关性：已在成人、青少年（12-15岁）和肝功能障碍和HIV感染患者中研究了利福喷丁的药代动力学。 然而，尚无关于利福喷丁在儿童中的疗效、安全性或药代动力学的已发表数据。 最近完成的一项在接受单剂量利福喷丁的儿童中对利福喷丁药代动力学的初步评价表明，当儿童接受与成人600 mg口服剂量相当的基于体重的剂量时，儿童中利福喷丁的暴露量显著低于成人。 这种暴露量降低表明儿童需要比成人更高的基于体重的剂量，并构建了一个模型来估计儿童中的利福喷丁剂量，该剂量将导致与研究26中用于成人的900 mg剂量相似的暴露量。 研究26 PK的目的是评价为入组研究26的幼儿选择的剂量的适当性。