Efficacy of APX2039 in a Rabbit Model of Cryptococcal Meningitis.
Efficacy of APX2039 in a Rabbit Model of Cryptococcal Meningitis.
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DOI：
10.1128/mbio.02347-22
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发表时间：
2022-12-20
期刊：
影响因子：
6.4
通讯作者：
Shaw, Karen Joy
中科院分区：
文献类型：
--
作者：
Giamberardino, Charles D.;Schell, Wiley A.;Tenor, Jennifer L.;Toffaletti, Dena L.;Palmucci, Julia R.;Marius, Choiselle;Boua, Jane-Valeriane K.;Soltow, Quinlyn;Mansbach, Robert;Moseley, M. Arthur;Thompson, J. Will;Dubois, Laura G.;Hope, William;Perfect, John R.;Shaw, Karen Joy
如果不治疗，隐球菌脑膜炎（CM）是致命的，而且治疗选择有限。我们之前报道了新型Gwt1抑制剂APX2039的前药APX2096在CM小鼠模型中的活性。本实验研究了APX2039对小鼠和家兔CM模型的作用。在小鼠模型中，对照组的平均肺真菌负荷为5.95 log10 CFU/g，而氟康唑-、两性霉素B-和apx2039治疗组的肺真菌负荷分别为3.56、4.59和1.50 log10 CFU/g。在脑内，对照组真菌负荷均值为7.97 log10 CFU/g，氟康唑、两性霉素B和APX2039组真菌负荷均值分别为4.64、7.16和1.44 log10 CFU/g。在CM兔模型中，APX2039按50 mg/kg体重每日2次口服（BID）可使脑脊液（CSF）真菌负荷迅速下降，感染后第10天负荷降至检出限以下。在8天的治疗过程中，有效杀真菌活性（EFA）为- 0.66 log10 CFU/mL/天，从平均4.75 log10 CFU/mL降至0 CFU/mL，与人类的良好临床结果（脑脊液真菌负荷减少- 0.4 log10 CFU/mL/天）相比较，值得注意的是，在该模型中两性霉素B脱氧胆酸酯的EFA为- 0.33 log10 CFU/mL/天)的2倍。25 ~ 50 mg·h/L的APX2039在0 ~ 24 h浓度-时间曲线下的总暴露面积（auc0 ~ 24）具有接近最大的抗真菌活性。这些数据支持APX2039作为一种新的口服杀真菌单药治疗CM的进一步临床前和临床评价。
Cryptococcal Meningitis (CM) is uniformly fatal if not treated, and treatment options are limited. We previously reported on the activity of APX2096, the prodrug of the novel Gwt1 inhibitor APX2039, in a mouse model of CM. Here, we investigated the efficacy of APX2039 in mouse and rabbit models of CM. In the mouse model, the controls had a mean lung fungal burden of 5.95 log10 CFU/g, whereas those in the fluconazole-, amphotericin B-, and APX2039-treated mice were 3.56, 4.59, and 1.50 log10 CFU/g, respectively. In the brain, the control mean fungal burden was 7.97 log10 CFU/g, while the burdens were 4.64, 7.16, and 1.44 log10 CFU/g for treatment with fluconazole, amphotericin B, and APX2039, respectively. In the rabbit model of CM, the oral administration of APX2039 at 50 mg/kg of body weight twice a day (BID) resulted in a rapid decrease in the cerebrospinal fluid (CSF) fungal burden, and the burden was below the limit of detection by day 10 postinfection. The effective fungicidal activity (EFA) was −0.66 log10 CFU/mL/day, decreasing from an average of 4.75 log10 CFU/mL to 0 CFU/mL, over 8 days of therapy, comparing favorably with good clinical outcomes in humans associated with reductions of the CSF fungal burden of −0.4 log10 CFU/mL/day, and, remarkably, 2-fold the EFA of amphotericin B deoxycholate in this model (−0.33 log10 CFU/mL/day). A total drug exposure of the area under the concentration-time curve from 0 to 24 h (AUC0–24) of 25 to 50 mg · h/L of APX2039 resulted in near-maximal antifungal activity. These data support the further preclinical and clinical evaluation of APX2039 as a new oral fungicidal monotherapy for the treatment of CM.
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