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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 目的：主要目的是确定在患有潜在结核病感染的受试者中，如果利福丁暴露（在摄入药物后24小时根据轮胎素浓度估算）相当于儿童（2至<12岁）接受基于体重的剂量和接受Rifapentine 900 mg的儿童（2至<12岁）之间的等效性（约20％至 +25％）。 次要目的包括：将估计的浮碱暴露与接受利福丁的毒性和毒性相关联，接受利福丁和异尼氏二氮齐德感染了潜在的结核病；根据体重验证小儿利福丁剂量的估计利福丁暴露的准确性；确定较高的Mg/kg利福丁剂剂量的小儿受试者中估计的DURG生物利用度；确定成年人在KDR1基因型（P-糖蛋白）的多态性和利福丁估计暴露之间的关联；并确定由N-乙酰基转移酶基因型和通过C-24和KDR1基因型确定的乙酰基状态的较低抗结核药物浓度的频率。 研究计划：这项研究将使用与成年人（年龄> 18岁）的平行群体设计作为儿童的控制病例（2至<12岁）。 所有参加研究26的合格儿童将是药代动力学子公司的候选者。 随着儿童入学率，成人控制将有资格参加。 成人对照的偏好将按以下顺序：1）孩子的性别生物父母； 2）孩子的亲生父母；或3）接下来在同一TBTC网站上合格的同性成人。 方法：将在第三次或随后每周一次重新替丁氨酸治疗中进行药代动力学抽样。 儿童 - 将通过静脉切开术以利福丁浓度（2 mL）吸收血液。 成人 - 将收集血液以仰卧浓度（2 mL）和遗传研究，MDR1和NAT2基因型（10 mL）。 血液样本应在药物后24小时内60分钟内（药物给药后23至25小时）获得。 在药代动力学研究期之前和期间：将接受采访参与者，以获取有关医疗症状，餐食，小吃和伴随药物的其他信息的其他信息；体温和体重将被测量。 成年人应在倒塌前后戒酒24小时戒酒。 临床相关性：在成年人，青少年（12-15岁）和肝功能障碍和HIV感染的患者中，已经研究了利福丁的药代动力学。 但是，没有关于儿童利福丁的功效，安全性或药代动力学的公开数据。 与成年人相比，接受单剂利福丁的儿童中最近完成的重新启动药代动力学的初步评估表明，在儿童中，在儿童中，在儿童中的暴露率明显较低，而儿童被选择可与成人的600 mg口腔剂量相当。 这种减少的暴露表明，儿童需要比成人更高的体重剂量，并构建了一种模型，以估计儿童的利福鱼剂量，这将导致与研究26中成人使用的900 mg剂量相似的暴露。