Co-Delivery of Antifungal Agents: Toxicity and Efficacy in Invasive Candidiasis

描述（由申请人提供）：尽管最近可用于治疗全身性真菌疾病的抗真菌剂数量有所增加，但发病率和死亡率仍然很高;注意侵袭性念珠菌病（IC）是美国医院内血流感染的第四常见原因，主要发生在免疫功能低下的患者中，并且IC与所有血流感染中最高的粗死亡率相关（约. 40%）。鉴于IC的不良结局，越来越多地考虑联合使用抗真菌药物。然而，在剂量选择、剂量分割、预测性PD指数（PDI）和抗生素后效应（PAE）方面，已建立和新型抗真菌药物组合的药效学（PD）特性定义不清，与治疗疗效和宿主毒性有关。本研究项目的主要目标是在IC的血小板减少小鼠模型中表征已建立和新型抗真菌药物组合的PD特性，旨在超越目前的研究和治疗范围（通常基于单药），获得IC的新见解和进展。为了实现体内PD研究，我们在通过自组装聚合物组合递送（共递送）阿替霉素B（Am B）与其他抗真菌剂方面取得了令人兴奋的进展，满足了溶解性、安全性、稳定性和协同作用的要求，这可以通过同时施用的组合抗真菌剂的同时作用来实现。我们假设，AmB和5-氟胞嘧啶（5-FC）一起静脉给药将发挥有效的抗真菌活性，口服5-FC后观察到5-FC转化为5-氟尿嘧啶（5-FU）的转化率较低或无转化，导致骨髓毒性降低。我们推测AmB和17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG），热休克蛋白90（Hsp 90）抑制剂，将发挥有效的抗真菌活性与低肾毒性。具体目标：（1）表征胶束AmB和5-FC的PK、IC的血小板减少小鼠模型中的抗真菌活性以及单次和多次给药（剂量分级）方案中的毒性：PAE;预测性PDI（最大抗真菌疗效和最佳给药方案）;以及相对于口服5-FC的血液学。(2)表征胶束AmB和17-AAG的PK、IC的血小板减少小鼠模型中的抗真菌活性以及单次和多次给药方案中的毒性：PAE;预测性PDI;以及肾脏和肝脏毒性。(3)表征胶束AmB、5-FC和胶束17- AAG的PK、IC的血小板减少小鼠模型中的抗真菌活性以及单次和多次给药方案中的毒性：PAE、预测性PDI、血液学、肾毒性和主要器官的组织病理学。

DESCRIPTION (provided by applicant): Despite recent increase in the number of antifungal agents available for the treatment of systemic fungal diseases, morbidity and mortality are substantial; noting that invasive candidiasis (IC) is the fourth most common cause of nosocomial bloodstream infection in the United States chiefly among immunocompromised patients and that IC is associated with the highest crude mortality of all bloodstream infections (ca. 40%). Given the dismal outcomes for IC, combination of antifungal agents is increasingly being considered. However, pharmacodynamic (PD) properties for established and novel combinations of antifungal agents are ill-defined in terms of dose selection, dose fractionation, predictive PD index (PDI), and post-antibiotic effect (PAE) in relation to treatment efficacy and host toxicity. The major goal of this research project is to characterize the PD properties of established and novel combinations of antifungal agents in a neutropenic murine model of IC, aiming for novel insights and progress in IC beyond the present scope of research and therapy, which is usually single agent-based. Towards enabling in vivo PD studies, we made exciting progress in combination delivery (co-delivery) of amphotericin B (AmB) with other antifungal agents via self-assembled polymers, fulfilling requirements in solubility, safety, stability, and synergy, which ca now be achieved by the coincident action of combination antifungal agents administered simultaneously. We hypothesize that AmB and 5-fluoro- cytosine (5-FC) delivered together intravenously will exert potent antifungal activity, with low or no conversion of 5-FC into 5-fluorouracil (5-FU), observed after oral 5-FC, resulting in decreased bone marrow toxicity. We hypothesize that AmB and 17-allylamino-17-demethoxygeldanamycin (17-AAG), a heat shock protein 90 (Hsp90) inhibitor, will exert potent antifungal activity with low renal toxicity. Specifc Aims: (1) To characterize PK of micellar AmB and 5-FC, antifungal activity in a neutropenic murine model of IC, and toxicity in single and multiple dose (dose fractionation) regimens: PAE; predictive PDI (for maximum antifungal efficacy and optimal dosing regimen); and hematology relative to oral 5-FC. (2) To characterize PK of micellar AmB and 17-AAG, antifungal activity in a neutropenic murine model of IC, and toxicity in single and multiple dose regimens: PAE; predictive PDI; and renal and hepatic toxicity. (3) To characterize PK of micellar AmB, 5-FC, and micellar 17- AAG, antifungal activity in a neutropenic murine model of IC, and toxicity in single and multiple dose regimens: PAE; predictive PDI; hematology; renal toxicity; and histopathology in major organs.