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

• 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
• 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

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断点是基于血浆的