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: 8402238
• 负责人: Awewura Jacob Kwara
• 金额: $ 60.31万
• 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/8402238
• 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 PUBLIC HEALTH RELEVANCE: Globally, ~one million new cases of TB (with or with HIV coinfection) and ~130,000 TB deaths occur in children each year. The treatment of TB, and TB/HIV coinfection in children can reduce the high death rates, but it is complicated by poor drug absorption, drug-drug interactions, and lack of appropriate drug formulations. Currently, there is lack of adequate pharmacology data for commonly prescribed medications in children with TB and TB/HIV coinfection in sub-Saharan Africa, the most affected region. This situation 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 pharmacology of available and new anti-TB and anti-HIV medications in children in West Africa. In the long-term, we hope that our research will provide urgently needed evidence to guide rational decisions about prescribing anti-TB and anti-HIV medications in children. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

描述（由申请人提供）：儿童的结核病（TB）是全球主要的公共卫生挑战。据估计，大约15-20％的全球结核病案件发生在<15岁的儿童中。儿童也很容易受到人类免疫缺陷病毒（HIV）和TB的双重流行病的影响。感染HIV的儿童患主动性结核病和与TB相关的死亡的风险更高。由于药物吸收，药物相互作用，高药丸负担和缺乏适当的配方，TB的治疗以及儿童中结核病/HIV共同感染的复杂性。此外，针对儿童的剂量建议通常从成人的药代动力学（PK）研究中推断出来。因此，抗TB和抗逆转录病毒药物的建议剂量与高频率亚治疗等离子体浓度有关。缺乏针对结核病和结核病/艾滋病毒感染儿童通常处方药的小儿PK数据，这是对儿童安全有效治疗的主要障碍。我们的长期目标是制定一项多学科研究计划，以研究撒哈拉以南非洲儿童的可用PK和新的抗TB和抗HIV药物。该提案的目的是确定一线抗TB和抗HIV药物的PK，并表征与西非加纳儿童中可变的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次优浓度的风险。我们的假设将通过三个特定目标提出。 AIM 1将确定WHO推荐的剂量增加了异烟肼，利福平，吡嗪酰胺和乙硫二醇是否为活性结核病感染（有或没有HIV感染）的非洲儿童施用，可实现成人等效的治疗药物浓度，并确定子治疗浓度的可能预测因子。 AIM 2将确定与接受抗TB疗法的Nevirapine治疗相比，与接受Nevirapine治疗的儿童相比，在年轻TB/HIV共感染的儿童中是否会诱导含有Nevirapine的年轻儿童的药物清除。 AIM 3将确定与没有抗TB治疗的情况下接受类似治疗方案的HIV感染儿童相比，含有Rifampin的TB治疗是否显着影响年龄较大的TB/HIV共感染儿童的Efavirenz浓度。拟议研究的成功完成将为这些常规药物生成基本的PK数据，并提供对儿童可变PK的预测指标的见解。没有这样的数据，就不可能在儿童中开处方抗TB和抗HIV药物的合理决策。 PHS 398/2590（Rev. 11/07）页面延续格式页面 公共卫生相关性：在全球范围内，每年儿童发生约100万例新的结核病病例（与HIV共感染或艾滋病毒共感染），约有130,000个结核病死亡。 TB的治疗以及儿童中结核病/HIV共同感染可以降低高死亡率，但由于药物吸收，药物相互作用和缺乏适当的药物制剂而使其复杂化。目前，缺乏足够的药理学数据来用于最受影响地区的撒哈拉以南非洲的结核病和结核病/艾滋病毒共同感染儿童的普遍处方药。这种情况是对儿童安全有效治疗的安全有效治疗的主要障碍。我们的长期目标是制定一项多学科研究计划，以研究西非儿童的可用药理学和新的抗TB和抗HIV药物。从长远来看，我们希望我们的研究将提供迫切需要的证据，以指导有关儿童抗结核和抗HIV药物的合理决定。 PHS 398/2590（Rev. 11/07）页面延续格式页面