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

项目摘要/摘要 接触结核病(TB)细菌的儿童发展为活动性结核病的风险更大。年轻化 儿童(&lt；2岁)由于免疫无效，特别容易患上播散性疾病 遏制。根据世界卫生组织2017年的报告，每年约有100万儿童患上结核病 占结核病病例总数的近10%。2016年，约3%的报告病例被诊断为 多药耐药(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 耐多药结核病的治疗方案是专门为儿童设计的，考虑到年龄特定的药代动力学变异性。 我们的广泛目标是使用我们针对结核病的中空纤维系统模型来简化结核病药物的开发。vt.给出 由于新的结核病药物的流水线仍然很小，人们对重新调整旧药物的用途以用于新用途重新产生了兴趣。 β-内酰胺类抗生素是许多抗菌治疗方案的支柱；然而，它们对 结核分枝杆菌(Mtb)尚未得到充分研究。我们从β-内酰胺类中筛选出13种药物 包括头孢菌素亚类在内的抗生素，用于对抗耐药的临床结核分枝杆菌。在这 批准申请我们将推进6种头孢菌素进入下一阶段的研究。头孢菌素类药物有 优势是因为儿童的药代动力学和安全性特征被很好地定义。我们将把领先的 头孢菌素与另外两种口服药物-莫西沙星联合使用，这是耐多药结核病治疗方案不可或缺的支柱 在所有年龄段的人中，以及替唑胺，一种新的恶唑烷酮对革兰氏阳性病原体以及 MTB创建了一种有效对抗儿童耐多药结核病的有效方案。我们的药物和联合疗法 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 细胞内结核分枝杆菌的系统模型(HFS-TB)。我们有关于每种药物最佳暴露目标的信息 从HFS-TB研究中收集初步数据作为单一疗法的最大结核分枝杆菌杀伤率。工作流程 目前的应用将是-(1)使用棋盘研究来评估相加、协同或拮抗 每种头孢菌素与莫西沙星配伍，(2)添加浓度的替氮唑胺以达到最佳暴露目标 头孢菌素-莫西沙星药物对(S)在HFS-TB试验中与二线结核分枝杆菌杀伤率比较 耐多药结核病的五种药物(amikacin-levofloxacin-ethionamide-cycloserine-pyrazinamide)方案 临床菌株，(3)HFS-TB结果的数学模型，以预测结核分枝杆菌的灭绝时间，这将通知 建议的新药物组合方案的最佳疗程，(4)在电子临床试验中 包含儿科特定药代动力学变异性以及结核分枝杆菌最小抑菌作用的模拟 浓度变异性确定每种药物的最佳剂量以实现儿科患者的暴露目标 人口。结果将是专门为中国儿童耐多药结核病设计的新治疗方案(S) 时间跨度相对较短，解决了全球消除结核病时代尚未得到满足的主要临床需求。

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.