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

描述（由申请人提供）：尽管最近用于治疗全身性真菌疾病的抗真菌药物数量有所增加，但发病率和死亡率仍然很高；注意到侵袭性念珠菌病（IC）是美国医院血液感染的第四大常见原因，主要发生在免疫功能低下的患者中，IC与所有血液感染中最高的粗死亡率相关（约40%）。鉴于IC的预后不佳，越来越多的人开始考虑联合使用抗真菌药物。然而，在剂量选择、剂量分割、预测PD指数（PDI）和与治疗效果和宿主毒性相关的抗生素后效应（PAE）方面，已建立的和新型抗真菌药物组合的药效学（PD）特性尚不明确。本研究项目的主要目标是在嗜中性粒细胞减少的IC小鼠模型中表征已建立的和新的抗真菌药物组合的PD特性，旨在超越目前基于单一药物的研究和治疗范围，为IC提供新的见解和进展。为了在体内进行PD研究，我们在两性霉素B （AmB）通过自组装聚合物与其他抗真菌药物联合递送（共递送）方面取得了令人兴奋的进展，满足了溶解度、安全性、稳定性和协同性的要求，现在可以通过联合抗真菌药物同时施用来实现。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很少或没有转化为5-氟尿嘧啶（5-FU），从而降低骨髓毒性。我们假设AmB和17-烯丙基氨基-17-去甲氧基格尔达霉素（17-AAG），一种热休克蛋白90 （Hsp90）抑制剂，将发挥有效的抗真菌活性和低肾毒性。具体目的：(1)表征胶束AmB和5-FC的PK，中性粒细胞减少小鼠IC模型的抗真菌活性，以及单次和多次剂量（剂量分割）方案的毒性：PAE；预测PDI（最大抗真菌效果和最佳给药方案）；与口服5-FC相关的血液学。(2)表征胶束AmB和17-AAG的PK，中性粒细胞减少小鼠IC模型的抗真菌活性，以及单次和多次给药方案的毒性：PAE；预测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、中性粒细胞减少小鼠IC模型的抗真菌活性以及单次和多次给药方案的毒性：PAE；预测PDI;血液学;肾毒性;以及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.