Measuring Intralesional Bedaquiline Exposures in Cavitary TB Using Noninvasive In Vivo PET Imaging

使用无创体内 PET 成像测量空洞结核病灶内贝达喹啉暴露

基本信息

批准号：
9894300
负责人：
Sanjay Jain
金额：
$ 24.56万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-11 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894300
关键词：
3-Dimensional Aftercare Animal Model Animals Antibiotic Therapy Antibiotics Area Under Curve Autopsy Autoradiography Bacteria Biodistribution Blood Vessels Brain Bromine Cardiac Cerebrospinal Fluid Chemicals Clinical Clinical Research Clinical Trials Complement Complex Data Development Disease Progression Dose Drug Kinetics Drug resistance Event Excision Future Goals Granuloma Hour Human Image In Situ Infection Kinetics Knowledge Lead Lesion Lung Mass Spectrum Analysis Measurement Measures Methods Modeling Morphologic artifacts Multi-Drug Resistance Multidrug-Resistant Tuberculosis Mus Mycobacterium Infections Mycobacterium tuberculosis National Institute of Allergy and Infectious Disease Necrosis Necrotic Lesion Organ Organism Oryctolagus cuniculus Parents Pathologic Pathology Patients Penetration Performance Pharmaceutical Preparations Phase Physiology Plasma Pneumonia Positron Positron-Emission Tomography Predisposition Pulmonary Tuberculosis Radiolabeled Recommendation Relapse Reporting Research Resistance Resolution Resources Rifampin Risk Factors Safety Sampling Sampling Biases Site Strategic Planning Technology Thick Time Tissues Toxic effect Treatment Failure Treatment Protocols Tuberculosis United States Food and Drug Administration appropriate dose base bioimaging brain tissue capsule clinically translatable cohort cost drug development drug distribution first-in-human improved improved outcome in vivo novel novel therapeutics pharmacokinetic model preclinical study radiochemical tool transmission process treatment optimization treatment response tuberculosis drugs tuberculosis treatment

项目摘要

Current antibiotic dosing recommendations and breakpoints for drug susceptibility are based on plasma concentrations and historic measures of efficacy, without specific information at the infection sites. Since inappropriate antibiotic concentrations in target tissues can lead to treatment failure, selection of resistant organisms, or toxicity, several studies and the U.S. Food and Drug Administration (FDA) support measuring drug concentrations in infected tissues. However, current tools to detect tissue drug levels are invasive (require tissue resection), which is difficult in humans and generally limited to a single time point even in animals. Our overarching hypothesis is that multiple, heterogeneous pathological states, e.g. cavitation, pneumonia, and necrotic lesions in pulmonary tuberculosis (TB), occur simultaneously in the same patient. Moreover, these lesions can also have distinct bacterial burdens and antibiotic exposures, which also change with disease progression and antibiotic treatment. Cavitation is a key pathological feature of human TB and a well- recognized risk factor for transmission of infection, relapse, and emergence of drug resistance after treatment. While cavitary walls have high bacterial burden (107-109), they are poorly vascularized with thick fibrous capsules. Therefore, while adequately high antibiotic levels are need to effectively kill bacteria in cavities, using PET bioimaging in patients with pulmonary TB, we have demonstrated that rifampin exposure is paradoxically the lowest in cavitary walls. Bedaquiline, a bromine-containing diarylquinoline, was recently approved for the treatment of multi-drug resistant (MDR) tuberculosis (TB). However, bedaquiline distribution into infected tissues (e.g. granulomas and cavitary lesions) has not been studied extensively whilst preliminary preclinical studies have reported variability in the treatment response in mice with caseous necrotic granulomas. While highly effective in treating MDR- TB, bedaquiline can also cause cardiac events (QT-interval prolongation) leading to safety warnings by regulatory agencies. Therefore, there is a need for noninvasive methods to measure the biodistribution of bedaquiline in infected tissues (e.g. cavities) and other target organs to inform appropriate dosing and develop effective, antibiotic treatments with minimal toxicities. The overall goals of this project are to leverage our expertise in animal models of TB and in vivo PET, a clinically translatable technology. We will develop efficient radiolabeling methods for 76Br-bedaquiline. Using Mycobacterium tuberculosis infections as a model for heterogeneous necrotic-lesions in multiple-compartments, quantitative 76Br-bedaquiline PET in live animals and post-mortem high-resolution / sensitivity autoradiography (<10 µm resolution, sub-nanogram sensitivity) will be utilized in animal models of cavitary TB to provide detailed biodistribution and temporal kinetics of intralesional bedaquiline exposures in multiple-compartments. This proposal fulfills an important research gap in TB drug development and aligned with the NIAID Strategic Plan for TB Research.

目前的抗生素剂量建议和药物敏感性折点基于血浆浓度和历史疗效测量，没有感染部位的具体信息。靶组织中抗生素浓度不适当可能导致治疗失败、耐药菌株的选择生物体或毒性，多项研究和美国食品和药物管理局 (FDA) 支持测量然而，目前检测组织药物水平的工具是侵入性的（需要组织切除术），这对人类来说很困难，而且即使在动物中也通常仅限于单个时间点。我们的首要假设是多种异质的病理状态，例如空化、肺炎、肺结核（TB）中的坏死病灶和坏死病灶同时发生在同一患者身上。病变也可能有不同的细菌负荷和抗生素暴露，这些也随着疾病而变化空化是人类结核病的一个关键病理特征，也是一种进展公认的感染传播、复发和治疗后出现耐药性的危险因素。虽然空腔壁的细菌负荷很高 (107-109)，但它们的血管化程度很差，纤维很厚因此，虽然需要足够高的抗生素水平来有效杀死蛀牙中的细菌，但使用胶囊。肺结核患者的 PET 生物成像，我们已经证明利福平暴露是矛盾的空洞壁中最低的。 Bedaquiline 是一种含溴二芳基喹啉，最近被批准用于治疗多种药物然而，贝达喹啉会分布到感染组织（例如肉芽肿和结核病）中。空洞病变）尚未得到初步研究，而初步的临床前研究报告了变异性治疗干酪样坏死肉芽肿小鼠的治疗反应，同时对治疗 MDR- 非常有效。结核病、贝达喹啉还会导致心脏事件（QT 间期延长），从而导致安全警告因此，需要非侵入性方法来测量生物分布。在受感染的组织（例如空腔）和其他靶器官中使用贝达喹啉，以告知适当的剂量和发展该项目的总体目标是利用我们的药物来进行有效的、毒性最小的抗生素治疗。我们将开发高效的结核病动物模型和体内 PET 技术，这是一种可临床转化的技术。使用结核分枝杆菌感染作为模型的 76Br-bedaquiline 放射性标记方法。活体动物多室异质坏死病灶定量 76Br-bedaquiline PET 和尸检高分辨率/灵敏度放射自显影（<10 µm 分辨率，亚纳克灵敏度）将用于空洞结核动物模型，以提供详细的生物分布和时间动力学该提案填补了一个重要的研究空白。结核病药物开发，并与 NIAID 结核病研究战略计划保持一致。