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: 10223394
• 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/10223394
• 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; 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; 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.

项目摘要/摘要 暴露于结核病（TB）细菌的儿童患活跃结核病的风险更大。年轻 由于免疫学无效，儿童（<2岁）特别容易受到发展传播疾病的影响 遏制。根据2017年世界卫生组织的报告，每年约有100万儿童患有结核病 几乎占结核病总案例的10％。 2016年，约有3％的报告的病例被诊断出患有 多药耐药（MDR）TB（定义为对两种有效的一线抗TB药物的抗性，Isoniaiazid 和利福平）。小儿结核病管理中的障碍之一是可用安全有效的治疗 考虑到年龄特异性药代动力学变异性，专门为儿童设计的MDR-TB方案。 我们的广泛目标是将我们的空心纤维系统模型用于结核病，以简化结核病药物的开发。给出 新型结核病药物的管道仍然很小，人们对重新利用旧药物的新兴趣新兴趣。 β-内酰胺抗生素是许多抗菌治疗方案的支柱。但是，他们反对的效率 结核分枝杆菌（MTB）尚未得到充分探索。我们从β-内酰胺类筛选了13种药物 包括头孢菌素亚类的抗生素，针对MTB的耐药性临床菌株。在这个 授予应用程序我们将使6个头孢菌素升级到下一阶段的调查。头孢菌素有一个 优势是因为儿童的药代动力学和安全性得到很好的定义。我们将结合领导 头孢菌素和另外两种口服药物 - 马利洛沙星，MDD-TB治疗方案的积分骨架 在各个年龄段的人和泰济（Tedizolid MTB创建对儿童MDR-TB有效的潜在方案。我们的药物和组合方案 开发方法使用我们经过验证的空心纤维应用药代动力学/药效学科学 细胞内MTB（HFS-TB）的系统模型。我们有有关每种药物的最佳暴露目标的信息 从HFS-TB研究中，最大的MTB杀死作为单一疗法，用于收集初步数据。工作流程 当前的应用程序将是 - （1）使用棋盘研究来评估添加性，协同作用或对抗 用莫西沙星的每种头孢菌素的孢子素，（2）在浓度下加入tedizolid，以实现最佳的暴露目标 头孢菌素马利黄素药物对（S）在HFS-TB中测试，将MTB杀伤率与二线进行比较 使用MDR-TB 临床菌株，（3）HFS-TB结果的数学建模，以预测MTB的延伸时间，这将告知 拟议的新型药物组合方案（4）在硅临床试验中的最佳治疗持续时间 拟合小儿特异性药代动力学变异性以及MTB-strain最小抑制性的仿真 浓度可变性以建立每种药物的最佳剂量以实现小儿的暴露靶标 人群。结果将是专为儿童MDR-TB设计的新型治疗方案 相关时间短，解决了全球消除结核病时代的主要未满足临床需求。