Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
Antimicrob Agents Chemother. 2018 Mar 27;62(4). doi: 10.1128/AAC.02542-17. Print 2018 Apr.
APX001 is the prodrug of APX001A, which is a first-in-class small molecule with a unique mechanism of action that inhibits the fungal enzyme Gwt1 in the glycosylphosphatidylinositol (GPI) biosynthesis pathway. The goal of the present study was to determine which pharmacokinetic/pharmacodynamic (PK/PD) index and magnitude best correlated with efficacy in the murine disseminated candidiasis model for ( = 5), ( = 5), and ( = 4). MIC values ranged from 0.002 to 0.03 mg/liter for , from 0.008 to 0.06 mg/liter for , and from 0.004 to 0.03 mg/liter for Plasma APX001A pharmacokinetic measurements were performed in mice after oral administration of 4, 16, 64, and 256 mg/kg of body weight APX001. Single-dose pharmacokinetic studies exhibited maximum plasma concentration () values of 0.46 to 15.6 mg/liter, area under the concentration-time curve (AUC) from time zero to infinity (AUC) values of 0.87 to 70.0 mg · h/liter, and half-lives of 1.40 to 2.75 h. A neutropenic murine disseminated candidiasis model was utilized for all treatment studies, and drug dosing was by the oral route. Dose fractionation was performed against K1, with total doses ranging from 4 to 1,024 mg/kg/day of APX001 fractionated into regimens of dosing every 3, 6, 8, and 12 h for a 24-h treatment duration. Nonlinear regression analysis was used to determine which PK/PD index best correlated with efficacy on the basis of the reduction in the number of CFU/kidney at 24 h. The 24-h free-drug AUC/MIC ratio (AUC/MIC) was the PK/PD index that best correlated with efficacy (coefficient of determination [] = 0.88). Treatment studies with the remaining strains utilized regimens of 1 to 256 mg/kg of APX001 administered every 6 h for a 24-h duration with and a 96-h study duration with and The dose required to achieve 50% of the maximum effect (ED) and stasis AUC/MIC targets were as follows: for , 3.67 ± 3.19 and 20.60 ± 6.50, respectively; for , 0.38 ± 0.21 and 1.31 ± 0.27, respectively; and for , 7.14 ± 4.54 and 14.67 ± 8.30, respectively. The present studies demonstrated and APX001A and APX001 potency, respectively, against , , and These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints. The identification of a lower AUC/MIC ratio target for suggests that species-specific susceptibility breakpoints should be explored.
APX001 是 APX001A 的前药，APX001A 是一种具有独特作用机制的首创小分子，可抑制真菌酶 Gwt1 在糖基磷脂酰肌醇 (GPI) 生物合成途径中的活性。本研究的目的是确定哪种药代动力学/药效学 (PK/PD) 指数和幅度与在用于 ( = 5)、 ( = 5) 和 ( = 4) 的小鼠播散性念珠菌病模型中的疗效相关性最好。MIC 值范围为 0.002 至 0.03 毫克/升用于 ，0.008 至 0.06 毫克/升用于 ，0.004 至 0.03 毫克/升用于 。在小鼠口服给予 4、16、64 和 256 毫克/千克体重的 APX001 后，进行了 APX001A 的血浆药代动力学测量。单次剂量药代动力学研究显示，最大血浆浓度 () 值为 0.46 至 15.6 毫克/升，从时间 0 到无穷大的浓度-时间曲线下面积 (AUC) 值为 0.87 至 70.0 毫克·h/升，半衰期为 1.40 至 2.75 小时。所有治疗研究均使用中性粒细胞减少症小鼠播散性念珠菌病模型进行，药物给药途径为口服。针对 K1 进行了剂量分割，APX001 的总剂量范围为 4 至 1024 毫克/千克/天，分为每 3、6、8 和 12 小时一次的方案，持续 24 小时治疗。采用非线性回归分析确定哪种 PK/PD 指数与基于 24 小时时肾脏 CFU/数量减少的疗效相关性最好。24 小时游离药物 AUC/MIC 比值 (AUC/MIC) 是与疗效相关性最好的 PK/PD 指数 (决定系数 [] = 0.88)。对其余菌株的治疗研究采用了 1 至 256 毫克/千克的 APX001 方案，每 6 小时给药一次，持续 24 小时，用 进行研究，用 进行 96 小时的研究。达到最大效应 50% (ED) 和静止 AUC/MIC 目标所需的剂量如下：对于 ，3.67 ± 3.19 和 20.60 ± 6.50；对于 ，0.38 ± 0.21 和 1.31 ± 0.27；对于 ，7.14 ± 4.54 和 14.67 ± 8.30。本研究表明 分别具有 和 APX001A 和 APX001 的效力，分别针对 、 和 。这些结果对于临床剂量选择和评估敏感性断点具有潜在相关性。对于 ，确定较低的 AUC/MIC 比值目标表明应该探索物种特异性敏感性断点。
