Experimental Pharmacology and Chemical Studies of Nikkomycin Z

描述（由申请人提供）：球孢子菌病是美国西南部沙漠地区的一种区域性真菌病，对亚利桑那州和加州尤为重要。这种疾病的重要性超出了流行地区，因为人们经常到这些地方旅行。球孢子菌属感染可能导致从轻微的自限性肺部综合征到严重或危及生命的疾病。后者更可能发生在免疫力受损的患者中，如器官移植、癌症化疗或艾滋病。并发症也见于某些种族群体（非洲裔美国人和菲律宾人）、妊娠和接受抑制免疫功能药物（皮质类固醇、TNF拮抗剂）的患者。Nikkomycin Z已被FDA宣布为孤儿药，并有资格进行快速通道审查。在动物模型中，尼可霉素Z显示出从肺部病变中根除真菌的潜力，这在现有的抗真菌药物中是看不到的。NikZ在口服给药后被吸收，并且基于在人体中完成的单次给药研究，耐受性良好且安全。该提案的目标是支持NikZ的进一步开发，并补充在球虫肺炎患者中进行的I/II期研究计划。本提案的目的包括：在实验性球孢子菌病小鼠中进行PK/PD研究，建立符合GLP的分析实验室和开发优化的分析方法，以及进行支持持续临床研究所需的额外临床前研究。同时，下一项临床研究（I/II期）的计划将在NIH R34计划资助的支持下进行。需要进行PK/PD研究以确定最有效的剂量策略。这些结果可以外推到人类，并根据与人体药代动力学和现有单次给药安全性结果相关的小鼠暴露目标进行指导。NikZ在生物液体中存在稳定性问题，在进行未来的人体研究之前，需要进一步开发检测试剂盒，以确定处理程序并确保临床环境中的可靠性。此外，还需要一个GLP机构，并将其作为NikZ正在进行的所有研究的核心实验室。FDA要求在开始任何治疗研究之前进行药物代谢/药物相互作用筛查，还需要筛查心脏离子通道效应。计划中的研究将为继续发展铺平道路。 项目叙述：球孢子菌病（山谷热）是一种发生在美国西南部的真菌感染，影响居民和游客。虽然大多数受影响的人只会出现轻微的症状，不经治疗即可消退，但有些人会出现长期的，有时甚至是严重的疾病。目前可用的疗法不能完全控制这种疾病，因此我们的目标是进一步研究一种代表有希望的谷热新疗法的新药。

DESCRIPTION (provided by applicant): Coccidioidomycosis is a regional fungal disease in desert areas of the Southwestern U.S. and is of particular importance to Arizona and California. The importance of this disease extends beyond the endemic areas due to extensive travel to these locations. Infection with Coccidioides spp. may cause illness ranging from a mild, self-limiting, pulmonary syndrome to serious or life-threatening disease. The later is more likely in patients with compromised immunity as seen following organ transplant, cancer chemotherapy, or AIDS. Complications are also seen in certain racial groups (African American and Filipino), pregnancy, and in patients receiving drugs that suppress immune function (corticosteroids, TNF antagonists). Nikkomycin Z has been declared an orphan drug by the FDA and is eligible for fast track review. In animal models, nikkomycin Z has shown potential to eradicate the fungus from lung lesions which is not seen with existing antifungal drugs. NikZ is absorbed after oral administration and was well tolerated and safe based on a single dose study completed in man. The goal of this proposal is to support further development of NikZ and complement plans for a Phase I/II study in patients with coccidioidal pneumonia. The aims of this proposal include: conduct of PK/PD studies in mice with experimental coccidioidomycosis, establishment of a GLP complient analytical laboratory and development of optimized analytical methods, and conduct of additional preclinical studies needed to support continued clinical studies. Simultaneous, planning for the next clincial study (Phase I/II) will be ongoing with support from an NIH R34 planning grant. The PK/PD studies are needed to determine the most effective dose strategy. The results can be extrapolated to humans and guided by exposure targets in mice in relation to human pharmacokinetics and existing single dose safety results. NikZ has stability problems in biological fluids and further assay development is needed before future human studies are performed to define handling procedures and ensure reliability given limitations in clinical settings. Moreover, a GLP facility will be needed and will serve as a core laboratory for all studies ongoing with NikZ. The FDA is requiring drug metabolism/drug interaction screening before any treatment studies are initiated, and screening for cardiac ion channel effects is also needed. The planned studies will pave the way for continued development. Project Narrative: Coccidioidomycosis (Valley Fever) is a fungal infection occurring in the southwestern U.S. and affecting residents as well as visitors. Although most affected people develop only mild symptoms that resolve without treatment, some will develop prolonged and sometimes serious illness. Currently available therapies do not fully control this disease, thus our goal is to further study a new drug that represents a promising new therapy for Valley Fever.