Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children

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。儿童还极易感染人体免疫缺陷病毒（艾滋病毒）和结核病这两种流行病。感染艾滋病毒的儿童患活动性结核病和与结核病有关的死亡的风险更高。由于药物吸收不良、药物间相互作用、药丸负担重和缺乏适当的配方，使儿童结核病和结核病/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TB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中常用处方药的儿科PK数据是安全有效治疗这些儿童疾病的主要障碍。我们的长期目标是开发一个多学科研究项目，以研究现有的和新的抗结核病和抗艾滋病药物在撒哈拉以南非洲儿童中的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，并描述与西非加纳儿童可变PK和药物相互作用相关的因素。我们的总体假设是，以前的研究低估了药物代谢，药物相互作用以及儿童药物浓度低于最佳水平的风险的发育和遗传差异的影响。我们的假设将通过三个具体目标来实现。目标1将确定WHO推荐的增加剂量的异烟肼、利福平、吡嗪酰胺和乙胺丁醇给予非洲活动性结核感染儿童（合并或不合并HIV感染）是否达到成人等效治疗药物浓度，并确定亚治疗浓度的可能预测因素。目的2将确定与接受奈韦拉平治疗但未接受抗结核治疗的儿童相比，含利福平的结核治疗是否能显著诱导年轻结核/HIV合并感染儿童的药物清除，从而降低奈韦拉平暴露。目的3将确定含利福平的TB治疗是否显著影响老年TB/HIV合并感染儿童中的依法韦仑浓度，与在没有抗TB治疗的情况下接受类似方案治疗的HIV感染儿童相比。成功完成拟定研究将生成这些常用处方药的基本PK数据，并提供对儿童变量PK预测因子的见解。没有这些数据，就不可能做出合理的决定，为儿童开抗结核病和抗艾滋病毒药物。PHS 398/2590（Rev. 11/07）

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