Inhaled Caprazamycin for Tuberculolsis Therapy

描述（由申请人提供）：结核病仍然是一种严重的全球性传染病，每年造成至少200万人死亡。耐多药结核病的发病率可以说是二十一世纪最严重的公共卫生威胁。CPZEN-45是卡拉霉素的衍生物，其已被结核病治疗界的领导者鉴定为具有巨大的疾病治疗潜力。在过去的30年里，开发的新药很少，而且还没有一种进入市场。CPZEN-45通过常规给药途径的生物利用度较差。以前，我们已经证明了几种药物在气雾剂给药至肺部后具有活性的潜力。非常低的剂量（几十个5g/kg）输送到豚鼠的肺部，导致细菌负荷显着减少。这种方法将补充药物组合的护理标准，而不会增加毒性。卷曲霉素以更高的剂量（mg/kg）递送，并且比通过IM途径递送更有效。该药物有可能补充或替代（基于达到全身MIC水平）当前MDR-TB标准治疗中的卷曲霉素IM。据推测，将卡普拉霉素衍生物（CPZEN-45）直接局部递送至感染豚鼠的肺部将导致足够高的局部浓度，以快速根除细菌种群并可能使肺部灭菌。证明这种作用的意义可能是通过增加现有治疗来减少实现耐药结核病治愈所需的化疗时间。喷雾干燥的CPZEN制剂将以适合于气溶胶递送的粒度制备。(a)将在低剂量感染的豚鼠模型中评估吸入的CPZEN的药代动力学和（B）药效学。了解（a）气雾剂给药后药物的分布（局部和全身）和（B）其对降低代表局部和全身区域的各种器官中细菌负荷的作用是提出人体应用的先决条件。

DESCRIPTION (provided by applicant): Tuberculosis remains a serious global infectious disease responsible for at least 2 million deaths per year. The incidence of multiple drug resistant tuberculosis arguably poses the most significant public health threat for the twenty first century. CPZEN-45 is a derivative of caprazamycin which has been identified by leaders in the tuberculosis treatment community as having great potential for disease therapy. There have been very few new drugs developed in the last 30 years and none have yet come to market. CPZEN-45 is poorly bioavailable by the conventional routes of administration. Previously, we have demonstrated the potential for several drugs to be active following aerosol administration to the lungs. Very low doses (tens of 5g/kg) delivered to the lungs of guinea pigs resulted in a significant reduction in the burden of bacteria. This approach would supplement the standard of care for drug combinations without increasing toxicity. Capreomycin has been delivered in higher doses (mg/kg) and is more potent than delivered by the IM route. This drug has the potential to supplement or replace (based on achieving systemic MIC levels) capreomycin IM in the current standard of care for MDR-TB. It is postulated that direct, topical delivery of the caprazamycin derivative (CPZEN-45) to the lungs of infected guinea pigs will result in sufficiently high local concentrations to quickly eradicate bacterial populations and potentially sterilize the lungs. The implications of demonstrating this effect may be to reduce the duration of chemotherapy necessary to achieve a cure in drug resistant tuberculosis by ADDING to the current therapy. Spray dried CPZEN formulations will be prepared in particle sizes suitable for aerosol delivery. (a) Pharmacokinetics and (b) pharmacodynamics of inhaled CPZEN will be assessed in the low dose infected guinea pig model. Understanding (a) the distribution (local and systemic) of drug following aerosol administration and (b) its effect on reducing the burden of bacteria in various organs representing local and systemic regions is a prerequisite for proposing a human application.