Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children

儿童抗结核和抗逆转录病毒药物的药代动力学

• 批准号: 8508996
• 负责人: Awewura Jacob Kwara
• 金额: $ 53.84万
• 依托单位: MIRIAM HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508996
• 关键词: 15 year old; 3 year old; Adult; Affect; Africa; Africa South of the Sahara; African; Age; Am 80; Anti-Retroviral Agents; Antitubercular Agents; CYP3A4 gene; Cessation of life; Child; Childhood; Data; Death Rate; Disease; Dose; Drug Formulations; Drug Interactions; Drug Kinetics; Enzymes; Epidemic; Ethambutol; Frequencies; Genetic Polymorphism; Ghana; Goals; HIV; Infection; Interdisciplinary Study; Lead; Nevirapine; Pharmaceutical Preparations; Pharmacology; Plasma; Positioning Attribute; Principal Investigator; Public Health; Publishing; Pyrazinamide; Recommendation; Regimen; Research; Resources; Rifampin; Risk; Safety; Technology Transfer; Testing; Therapeutic; Tuberculosis; Weight; World Health Organization; absorption; age group; aged; base; clinical care; developmental genetics; dosage; drug clearance; drug metabolism; efavirenz; effective therapy; enzyme activity; experience; high risk; innovation; insight; isoniazid; non-nucleoside reverse transcriptase inhibitors; pill; programs; tuberculosis drugs; tuberculosis treatment

DESCRIPTION (provided by applicant): Tuberculosis (TB) in children is a major global public health challenge. It is estimated that about 15 -20% of the global TB caseload occur in children < 15 years old. Children are also highly susceptible to the dual epidemics of human immunodeficiency virus (HIV) and TB. HIV-infected children are at a higher risk of developing active TB and TB-related death. The treatment of TB, as well as TB/HIV coinfection in children is complicated by poor drug absorption, drug-drug interactions, high pill burden and lack of appropriate formulations. In addition, dosage recommendations for children are often extrapolated from pharmacokinetic (PK) studies in adults. Consequently, the recommended dosages of the anti-TB and antiretroviral medications have been associated with a high frequency of sub-therapeutic plasma concentrations. The lack of pediatric PK data for commonly prescribed medications in children with TB and TB/HIV coinfection represents a major obstacle to the safe and effective treatment of these conditions in children. Our long-term goal is to develop a multidisciplinary research program to study the PK of available and new anti-TB and anti-HIV medications in children in sub-Saharan Africa. The objective of this proposal is to determine the PK of the first-line anti-TB and anti-HIV drugs, as well as characterize the factors associated with variable PK and drug-drug interactions in children in Ghana, West Africa. Our overarching hypothesis is that previous studies have underestimated the effect of developmental and genetic differences in drug metabolism, drug-drug interactions, as well as the risk for suboptimal drug concentrations in children. Our hypotheses will be pursued through three specific aims. Aim 1 will determine whether the WHO recommended increased dosages of isoniazid, rifampin, pyrazinamide and ethambutol administered to African children with active TB infection (with or without HIV co- infection) achieve adult-equivalent therapeutic drug concentrations, and identify possible predictors of sub- therapeutic concentrations. Aim 2 will determine whether rifampin-containing TB therapy induces drug clearance substantially in young TB/HIV co-infected children resulting in reduced nevirapine exposure as compared to children receiving nevirapine therapy without anti-TB therapy. Aim 3 will determine whether rifampin-containing TB therapy significantly influence efavirenz concentrations in older TB/HIV co-infected children compared to HIV-infected children treated with a similar regimen in the absence of anti-TB treatment. Successful completion of the proposed studies will generate fundamental PK data for these commonly prescribed medications, as well as provide insights into predictors of the variable PK in children. Without such data, rational decisions about prescribing anti-TB and anti-HIV medications in children are not possible. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

描述（由申请人提供）：儿童结核病是一项重大的全球公共卫生挑战。据估计，全球结核病病例中约有15 -20%发生在15岁以下的儿童中。儿童也极易受到人类免疫缺陷病毒（艾滋病毒）和结核病双重流行病的影响。感染艾滋病毒的儿童患活动性结核病和结核病相关死亡的风险较高。由于药物吸收不良、药物-药物相互作用、药丸负担高和缺乏适当的配方，结核病以及儿童结核/艾滋病毒合并感染的治疗变得复杂。此外，儿童的剂量建议通常是从成人的药代动力学（PK）研究中推断出来的。因此，抗结核和抗逆转录病毒药物的推荐剂量与亚治疗性血浆浓度的高频率相关。缺乏结核病和结核/艾滋病毒合并感染儿童常用处方药的儿科PK数据是安全有效治疗这些儿童疾病的主要障碍。我们的长期目标是制定一个多学科研究计划，研究撒哈拉以南非洲儿童现有和新的抗结核病和抗艾滋病毒药物的PK。本提案的目的是确定一线抗结核和抗艾滋病毒药物的PK，以及表征与西非加纳儿童的可变PK和药物-药物相互作用相关的因素。我们的首要假设是，以前的研究低估了发育和遗传差异对药物代谢的影响，药物-药物相互作用，以及儿童药物浓度不理想的风险。我们的假设将通过三个具体目标来实现。目标1将确定世卫组织推荐的对活动性结核感染（合并或不合并艾滋病毒感染）的非洲儿童增加异烟肼、利福平、吡嗪酰胺和乙胺丁醇的剂量是否达到与成人相当的治疗药物浓度，并确定亚治疗浓度的可能预测因素。目标2将确定，与接受奈韦拉平治疗而不接受抗结核治疗的儿童相比，含利福平的结核病治疗是否能在年轻的结核病/艾滋病毒合并感染儿童中显著诱导药物清除，从而减少奈韦拉平暴露。目的3将确定在没有抗结核治疗的情况下，与使用类似方案治疗的艾滋病毒感染儿童相比，含有利福平的结核病治疗是否显著影响老年结核病/艾滋病毒合并感染儿童的依非韦伦浓度。成功完成拟议的研究将产生这些常用处方药的基本PK数据，并为儿童变量PK的预测因素提供见解。没有这些数据，就不可能做出合理的决定，给儿童开抗结核和抗艾滋病毒药物。小灵通398/2590 （Rev. 11/07）页延续格式页