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

基本信息

批准号：
9319908
负责人：
Awewura Jacob Kwara
金额：
$ 58.66万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319908
关键词：
15 year old 3 year old Adult Affect Africa Africa South of the Sahara African Age 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 Formulation 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 co-infection 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

项目摘要

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 (TB) 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。儿童也极易感染人类免疫缺陷病毒（HIV）和结核病的双重流行病。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。儿童结核病以及结核病/艾滋病毒合并感染的治疗由于药物吸收差、药物间相互作用、药物负担高和缺乏适当的制剂而变得复杂。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血浆浓度的高频率相关。缺乏结核病和结核病/艾滋病毒合并感染儿童常用处方药物的儿科 PK 数据，是安全有效治疗儿童这些疾病的主要障碍。我们的长期目标是制定一个多学科研究计划，研究现有和新型抗结核病和抗艾滋病毒药物在撒哈拉以南非洲儿童中的药代动力学。该提案的目的是确定西非加纳儿童一线抗结核病和抗艾滋病毒药物的 PK，并描述与可变 PK 和药物间相互作用相关的因素。我们的首要假设是，之前的研究低估了发育和遗传差异对药物代谢、药物间相互作用以及儿童药物浓度不理想的风险的影响。我们的假设将通过三个具体目标来实现。目标 1 将确定世界卫生组织建议增加对活动性结核感染（有或没有艾滋病毒合并感染）的非洲儿童服用的异烟肼、利福平、吡嗪酰胺和乙胺丁醇的剂量是否达到成人等效治疗药物浓度，并确定亚结核病的可能预测因素。治疗浓度。目标 2 将确定含利福平的结核病治疗是否能显着诱导结核病/艾滋病毒合并感染儿童的药物清除，从而与接受奈韦拉平治疗但未接受抗结核治疗的儿童相比，奈韦拉平暴露量减少。目标 3 将确定与在没有抗结核治疗的情况下接受类似方案治疗的艾滋病毒感染儿童相比，含利福平的结核病治疗是否显着影响老年结核病/艾滋病毒双重感染儿童的依非韦伦浓度。成功完成拟议研究将为这些常用处方药物生成基本 PK 数据，并提供对儿童变量 PK 预测因素的见解。如果没有这些数据，就不可能对儿童的抗结核和抗艾滋病药物处方做出合理的决定。 PHS 398/2590（修订版 11/07）页面延续格式页面