Laboratório Especial de Micologia, Disciplina de Infectologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil.
Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, United Kingdom.
J Infect Dis. 2018 Mar 13;217(7):1118-1127. doi: 10.1093/infdis/jix479.
Aspergillus flavus is one of the most common agents of invasive aspergillosis and is associated with high mortality. The orotomides are a new class of antifungal agents with a novel mechanism of action. An understanding of the pharmacodynamics (PD) of the lead compound F901318 is required to plan safe and effective regimens for clinical use.
The pharmacokinetics (PK) and PD of F901318 were evaluated by developing new in vitro and in vivo models of invasive fungal sinusitis. Galactomannan was used as a pharmacodynamic endpoint in all models. Mathematical PK-PD models were used to describe dose-exposure-response relationships.
F901318 minimum inhibitory concentrations (MICs) ranged from 0.015 to 0.06 mg/L. F901318 induced a concentration-dependent decline in galactomannan. In the in vitro model, a minimum concentration:MIC of 10 resulted in suppression of galactomannan; however, values of approximately 10 and 9-19 when assessed by survival of mice or the decline in galactomannan, respectively, were equivalent or exceeded the effect induced by posaconazole. There was histological clearance of lung tissue that was consistent with the effects of F901318 on galactomannan.
F901318 is a potential new agent for the treatment of invasive infections caused by A flavus with PDs that are comparable with other first-line triazole agents.
黄曲霉菌是侵袭性曲霉病最常见的病原体之一，与高死亡率相关。奥托米德是一类新型抗真菌药物，具有新颖的作用机制。为了制定安全有效的临床应用方案，需要了解先导化合物 F901318 的药代动力学（PK）和药效学（PD）。
通过开发侵袭性真菌性鼻窦炎的新的体外和体内模型，评估 F901318 的 PK 和 PD。所有模型均使用半乳甘露聚糖作为药效学终点。采用数学 PK-PD 模型来描述剂量-暴露-反应关系。
F901318 的最低抑菌浓度（MIC）范围为 0.015 至 0.06mg/L。F901318 诱导半乳甘露聚糖浓度依赖性下降。在体外模型中，最低浓度：MIC 为 10 可抑制半乳甘露聚糖；然而，当通过小鼠存活率或半乳甘露聚糖下降来评估时，大约为 10 和 9-19 的值与泊沙康唑诱导的作用相当或超过其作用。肺部组织的组织学清除与 F901318 对半乳甘露聚糖的作用一致。
F901318 是一种有潜力的新型抗真菌药物，可用于治疗由黄曲霉菌引起的侵袭性感染，其 PD 与其他一线三唑类药物相当。
