PK/PD Optimized Cephalosporins Based Treatment Regimens for Children With MDR-TB

基于头孢菌素的 PK/PD 优化儿童耐多药结核病治疗方案

• 批准号: 10449269
• 负责人: Shashi Kant
• 金额: $ 30.62万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449269
• 关键词: Address; Adopted; Adult; Age; Amikacin; Anatomy; Anti-Bacterial Agents; Antibiotics; Antitubercular Agents; Applications Grants; Bacteria; Biological Models; Case Study; Cefazolin; Ceftriaxone; Cephalexin; Cephalosporins; Cessation of life; Child; Childhood; Clinical; Clinical Distribution; Clinical Trials; Conduct Clinical Trials; Containment; Custom; Cycloserine; Data; Development; Diagnosis; Disease; Dose; Drug Combinations; Drug Exposure; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Ensure; Epidemic; Ethambutol; Ethionamide; European; Exposure to; Extinction (Psychology); Felis catus; Fiber; Formulation; Genus Mycobacterium; Goals; Human; Immunologics; Injectable; Investigation; Laboratories; Levaquin; Measures; Medicine; Microbiology; Minimum Inhibitory Concentration measurement; Modeling; Monobactams; Monte Carlo Method; Moxifloxacin; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Nature; Oral; Oral Administration; Outcome; Oxazolidinones; Palate; Pathology; Penetration; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Population; Preclinical Drug Development; Process; Public Health; Pyrazinamide; Regimen; Reporting; Resistance; Rifampin; Risk; Safety; Science; Study models; System; Taste Perception; Testing; Therapeutic; Time; Tissues; Toxic effect; Translating; Treatment Protocols; Tuberculosis; United States Food and Drug Administration; Vertebral column; Vulnerable Populations; Weight; Work; World Health Organization; acquired drug resistance; antagonist; antimicrobial; base; beta-Lactams; design; drug development; drug metabolism; drug repurposing; drug-sensitive; effective therapy; hearing impairment; in silico; interest; isoniazid; mathematical model; novel; novel drug combination; optimal treatments; pathogen; pill; screening; simulation; synergism; therapy duration; tool development; treatment duration; treatment strategy; tuberculosis drugs

Project summary/Abstract Children exposed to tuberculosis (TB) bacterium have a greater risk of progressing to active TB disease. Younger children (<2 years) are especially susceptible to developing disseminated disease due to ineffective immunologic containment. As per World Health Organization 2017 report, ~1 million children become ill with TB each year representing nearly 10% of the total TB cases. In 2016, ~3% of the reported cases in children diagnosed to have multi-drug resistant (MDR) TB (defined as being resistant to the two most potent first-line anti-TB drugs, isoniazid and rifampin). One of the hurdles in pediatric TB management is the availability of a safe and effective treatment regimen for MDR-TB designed specifically for children considering the age specific pharmacokinetic variability. Our broad objective is to use our hollow fiber system model for TB to streamline TB drug development. Given that the pipeline for novel TB drugs is still slim, there is renewed interest in repurposing old drugs for new use. β-lactam antibiotics are the backbone of many antibacterial treatment regimens; however, their efficacy against Mycobacterium tuberculosis (Mtb) have not been fully explored. We screened 13 drugs from the β-lactams class of the antibiotics including the cephalosporins sub-class, against drug resistant clinical strains of Mtb. In this grant application we will advance 6 cephalosporins to the next phase of investigations. Cephalosporins have an advantage because the pharmacokinetic and safety profile in children is well defined. We will combine the leading cephalosporins with two other oral drugs—moxifloxacin, an integral backbone of MDR-TB treatment regimens in people of all ages, and tedizolid, a new oxazolidinone effective against gram-positive pathogens as well as Mtb to create a potent regimen effective against MDR-TB in children. Our drug and combination regimen development approach apply pharmacokinetic/pharmacodynamic science using our validated hollow fiber system model for intracellular Mtb (HFS-TB). We have information on each drug’s optimal exposure target for maximal Mtb kill as monotherapy from the HFS-TB studies performed to collect preliminary data. The workflow of the current application will be - (1) use of checkerboard studies to evaluate additivity, synergy or antagonism of each cephalosporin with moxifloxacin, (2) add tedizolid at concentration to achieve optimal exposure target to the cephalosporins-moxifloxacin drug pair(s) to test in the HFS-TB comparing Mtb kill rates with a second-line MDR-TB regimen of five drugs (amikacin-levofloxacin-ethionamide-cycloserine-pyrazinamide) using MDR-TB clinical strains, (3) mathematical modeling of the HFS-TB results to predict Mtb time-to-extinction that will inform optimal duration of therapy with the proposed novel drug combination regimens, (4) in silico clinical trial simulations incorporating pediatric-specific pharmacokinetic variability as well as Mtb-strain minimum inhibitory concentration variability to establish optimal dose of each drug to achieve exposure targets among pediatric populations. The outcome will be novel treatment regimen(s) specially designed for MDR-TB in children in relatively short time span, addressing a major unmet clinical need in the global era of TB elimination.

项目概要/摘要 接触结核菌的儿童发展为活动性结核病的风险更大。雅戈尔 儿童（<2 岁）由于免疫系统无效而特别容易患播散性疾病 遏制。根据世界卫生组织 2017 年报告，每年约有 100 万儿童患结核病 占结核病总数的近 10%。 2016 年，约 3% 的儿童报告病例被诊断患有 耐多药 (MDR) 结核病（定义为对两种最有效的一线抗结核药物异烟肼具有耐药性） 和利福平）。儿科结核病管理的障碍之一是能否获得安全有效的治疗方法 考虑到特定年龄的药代动力学变异性，专门为儿童设计了耐多药结核病治疗方案。 我们的总体目标是利用我们的结核病中空纤维系统模型来简化结核病药物开发。给定 由于新型结核病药物的研发渠道仍然有限，人们对将旧药物重新用于新用途重新产生了兴趣。 β-内酰胺抗生素是许多抗菌治疗方案的支柱；然而，它们的功效 结核分枝杆菌 (Mtb) 尚未得到充分探索。我们筛选了 13 种 β-内酰胺类药物 包括头孢菌素亚类在内的抗生素，用于对抗结核分枝杆菌的耐药临床菌株。在这个 根据拨款申请，我们将推进 6 种头孢菌素进入下一阶段的研究。头孢菌素类药物具有 优势是因为儿童的药代动力学和安全性已明确。我们将结合领先的 头孢菌素与另外两种口服药物——莫西沙星，耐多药结核病治疗方案的组成部分 适用于所有年龄段的人群，特地唑胺是一种新的恶唑烷酮，可有效对抗革兰氏阳性病原体以及 Mtb 创造了一种有效对抗儿童耐多药结核病的有效疗法。我们的药物和联合治疗方案 开发方法使用我们经过验证的中空纤维应用药代动力学/药效学科学 细胞内 Mtb (HFS-TB) 系统模型。我们有关于每种药物的最佳暴露目标的信息 作为单一疗法的最大 Mtb 杀灭率来自为收集初步数据而进行的 HFS-TB 研究。工作流程 当前应用的主要内容是 - (1) 使用棋盘研究来评估可加性、协同性或拮抗性 每种头孢菌素与莫西沙星，(2) 添加泰地唑胺浓度以达到最佳暴露目标 在 HFS-TB 中测试的头孢菌素-莫西沙星药物对，比较 Mtb 杀灭率与二线药物 使用耐多药结核病的五种药物（阿米卡星-左氧氟沙星-乙硫异烟胺-环丝氨酸-吡嗪酰胺）的耐多药结核病治疗方案 临床菌株，(3) HFS-TB 结果的数学模型，以预测 Mtb 灭绝时间，这将提供信息 所提出的新型药物组合方案的最佳治疗持续时间，(4) 计算机临床试验 模拟结合了儿科特定的药代动力学变异性以及 Mtb 菌株最小抑制 浓度变异性以确定每种药物的最佳剂量，以实现儿童的暴露目标 人口。结果将是专为儿童耐多药结核病设计的新治疗方案 相对较短的时间跨度，解决了全球消除结核病时代未满足的主要临床需求。