Candida endophthalmitis is a serious sight-threatening complication of candidemia that may occur before or during antifungal therapy. Hematogenous Candida meningoencephalitis (HCME) is also a serious manifestation of disseminated candidiasis in premature infants, immunosuppressed children, and immunocompromised adults. We evaluated the antifungal efficacy and pharmacokinetics of the prodrug fosmanogepix (APX001) in a rabbit model of endophthalmitis/HCME. Manogepix (APX001A), the active moiety of prodrug fosmanogepix, inhibits the fungal enzyme Gwt1 and is highly active in vitro and in vivo against Candida spp., Aspergillus spp., and other fungal pathogens. Plasma pharmacokinetics of manogepix after oral administration of fosmanogepix on day 6 at 25, 50, and 100 mg/kg resulted in maximum concentration of drug in plasma (C_max) of 3.96 ± 0.41, 4.14 ± 1.1, and 11.5 ± 1.1 μg/ml, respectively, and area under the concentration-time curve from 0 to 12 h (AUC_0–12) of 15.8 ± 3.1, 30.8 ± 5.0, 95.9 ± 14 μg·h/ml, respectively. Manogepix penetrated the aqueous humor, vitreous, and choroid with liquid-to-plasma ratios ranging from 0.19 to 0.52, 0.09 to 0.12, and 0.02 to 0.04, respectively. These concentrations correlated with a significant decrease in Candida albicans burden in vitreous (>10¹ to 10³ log CFU/g) and choroid (>10¹ to 10³ log CFU/g) (P ≤ 0.05 and P ≤ 0.001, respectively). The aqueous humor had no detectable C. albicans in treatment and control groups. The tissue/plasma concentration ratios of manogepix in meninges, cerebrum, cerebellum, and spinal cord were approximately 1:1, which correlated with a >10² to 10⁴ decline of C. albicans in tissue versus control (P ≤ 0.05). Serum and cerebrospinal fluid (CSF) (1→3)-β-d-glucan levels demonstrated significant declines in response to fosmanogepix treatment. These findings provide an experimental foundation for fosmanogepix in treatment of Candida endophthalmitis and HCME and derisk the clinical trials of candidemia and invasive candidiasis.

中文翻译：

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Fosmanogepix (APX001) 治疗非中性粒细胞减少兔念珠菌眼内炎和血源性脑膜脑炎的疗效和药代动力学

念珠菌眼内炎是念珠菌血症的严重威胁视力的并发症，可能在抗真菌治疗之前或期间发生。血源性念珠菌脑膜脑炎 (HCME) 也是早产儿、免疫抑制儿童和免疫功能低下的成人播散性念珠菌病的严重表现。我们在眼内炎/HCME 兔模型中评估了前药 fosmanogepix (APX001) 的抗真菌功效和药代动力学。Manogepix (APX001A) 是前药 fosmanogepix 的活性部分，可抑制真菌酶 Gwt1，在体外和体内对念珠菌属、曲霉属具有高度活性spp. 和其他真菌病原体。在第 6 天以 25、50 和 100 mg/kg 口服给予 fosmanogepix 后，manogepix 的血浆药代动力学导致血浆中药物的最大浓度 ( C _max ) 为 3.96 ± 0.41、4.14 ± 1.1 和 11.5 ± 1.1 μg/ml分别为 15.8 ± 3.1、30.8 ± 5.0、95.9 ± 14 μg · h/ml，0 至 12 小时的浓度-时间曲线下面积 (AUC _0-12 ) 。Manogepix 以 0.19 至 0.52、0.09 至 0.12 和 0.02 至 0.04 的液体与血浆比率分别穿透房水、玻璃体和脉络膜。这些浓度与玻璃体中白色念珠菌负荷的显着降低相关（>10 ¹至 10 ³log CFU/g) 和脉络膜 (>10 ¹至 10 ³ log CFU/g)（分别为P ≤ 0.05 和P ≤ 0.001）。治疗组和对照组的房水中没有可检测到的白色念珠菌。脑膜、大脑、小脑和脊髓中 manogepix 的组织/血浆浓度比约为 1:1，这与组织中白色念珠菌的下降>10 ²至 10 ⁴下降相关（P ≤ 0.05）。血清和脑脊液 (CSF) (1→3)-β- d-葡聚糖水平表现出对 fosmanogepix 治疗的反应显着下降。这些发现为 fosmanogepix 治疗念珠菌眼内炎和 HCME提供了实验基础，并降低了念珠菌血症和侵袭性念珠菌病的临床试验的风险。