1346. 四唑 VT-1598 在具有霉菌活性 CYP51 抑制剂预期的 PK/PD 的侵袭性曲霉病小鼠模型中是有效的,Open Forum Infectious Diseases

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1346. 四唑 VT-1598 在具有霉菌活性 CYP51 抑制剂预期的 PK/PD 的侵袭性曲霉病小鼠模型中是有效的
Open Forum Infectious Diseases ( IF 3.8 ) Pub Date : 2018-11-01 , DOI: 10.1093/ofid/ofy210.1177
Edward P Garvey ₁ , Andrew Sharp ₂ , Peter Warn ₂ , Christopher M Yates ₁ , Robert J Schotzinger ₁

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摘要背景 VT-1598 是一种新型真菌 CYP51 抑制剂，对酵母、霉菌和地方性致病真菌具有有效的体外活性（Wiederhold，JAC，2017）。其基于四唑的合理药物设计比人类 CYP 具有更高的选择性（Yates，BMCL，2017），这可以减少人类 CYP 相关的副作用和 DDI。我们在此报告 VT-1598 在侵袭性曲霉病 (IA) 模型中的体内活性。方法 MIC 的确定如 CLSI M38-A2 中所述。在没有接种真菌的中性粒细胞减少的 ICR 小鼠中口服给药 4 天后测量血浆 PK。在接种烟曲霉 (AF) ATCC 204305（每剂 N = 10）的中性粒细胞减少小鼠的尾静脉 IA 模型中测定了体内抗真菌活性。进行了两项独立的研究，在接种前 48 小时（预防）或接种后 5 小时（延迟）开始口服 VT-1598 治疗，接种后给药 4 天，最后一次给药后 1 天通过 CFU 和 qPCR 测量肾真菌负荷。药物对照为 10 mg/kg AmBisome iv 结果 VT-1598 对 AF 204305 的 MIC 为 0.25 μg/mL。VT-1598 的血浆 PK 在 5 和 40 mg/kg 每日一次剂量之间呈线性比例，两种剂量的 AUC 分别为 155 和 1,033 μg h/mL。与预防相比，VT-1598 在延迟治疗中在减少真菌负荷方面同样有效，并且两项研究都证明了完全剂量反应（即没有到完全减少真菌负荷）。在比较每个剂量组的真菌负荷与治疗开始时的真菌负荷时，VT-1598 达到真菌停滞的剂量范围为 20.5 至 25.9 mg/kg，达到 1-log10 真菌杀灭的剂量范围为 30.9 至 50.5 mg/kg。使用先前测量的小鼠血浆结合 (>99.9%)，停滞和 1-log10 杀死的游离 AUC /MIC 值分别介于 2.1–2.7 和 3.2–5.2 之间。这些值在泊沙康唑和艾沙康唑报道的 1-11 范围内（Lepak，AAC，2013）。结论 VT-1598 在 IA 小鼠模型中具有有效的抗真菌活性。PK/PD 关系与临床使用的霉菌活性 CYP51 药物相同，表明它可能具有相似的临床疗效。如果正确，基于四唑的更高选择性可能会显着区分 VT-1598 与当前的 IA 疗法。披露 EP Garvey, Viamet Pharmaceuticals, Inc.：员工、薪水。一个尖锐物，Evotec (UK) Ltd.：员工，薪水。P. Warn，Evotec (UK) Ltd.：员工，薪水。CM Yates，Viamet Pharmaceuticals, Inc.：员工、薪水。RJ Schotzinger，Viamet Pharmaceuticals, Inc.：董事会成员和雇员，薪水。

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1346. The Tetrazole VT-1598 Is Efficacious in a Murine Model of Invasive Aspergillosis with a PK/PD Expected of a Mold-Active CYP51 Inhibitor

Abstract Background VT-1598 is a novel fungal CYP51 inhibitor with potent in vitro activity against yeast, mold, and endemic pathogenic fungi (Wiederhold, JAC, 2017). Its tetrazole-based rational drug design imparts much greater selectivity vs. human CYPs (Yates, BMCL, 2017), which could reduce human CYP-related side effects and DDIs. We report here VT-1598’s in vivo activity in an invasive aspergillosis (IA) model. Methods MIC was determined as outlined in CLSI M38-A2. Plasma PK was measured after 4 days of oral doses in neutropenic ICR mice without fungal inoculation. In vivo antifungal activity was determined in a tail-vein IA model in neutropenic mice inoculated with A. fumigatus (AF) ATCC 204305 (N = 10 per dose). Two separate studies were conducted, with oral VT-1598 treatment starting either 48 hours prior (prophylaxis) or 5 hours postinoculation (delayed), with 4 days of postinoculation dosing, and kidney fungal burden measured 1 day post last dose by both CFU and qPCR. Drug control was 10 mg/kg AmBisome i.v. Results The MIC for VT-1598 against AF 204305 was 0.25 μg/mL. The plasma PK of VT-1598 was linearly proportional between the 5 and 40 mg/kg once-daily doses, with AUCs of 155 and 1,033 μg h/mL for the two doses, respectively. VT-1598 was similarly effective in reducing fungal burden when given in delayed treatment compared with prophylaxis, and both studies demonstrated a full dose–response (i.e., no to full reduction of fungal burden). When comparing fungal burdens of each dose group to the fungal burden at the start of treatment, the dose of VT-1598 to achieve fungal stasis ranged from 20.5 to 25.9 mg/kg and to achieve a 1-log10 fungal kill ranged from 30.9 to 50.5 mg/kg. Using the previously measured mouse plasma binding (>99.9%), the free AUC /MIC values for stasis and 1-log10 kill ranged from 2.1–2.7 and 3.2–5.2, respectively. These values are within the range of 1–11 that have been reported for posaconazole and isavuconazole (Lepak, AAC, 2013). Conclusion VT-1598 had potent antifungal activity in a murine model of IA. The PK/PD relationship was the same as clinically used mold-active CYP51 agents, suggesting that it could have similar clinical efficacy. If correct, the tetrazole-based greater selectivity may significantly differentiate VT-1598 from current IA therapies. Disclosures E. P. Garvey, Viamet Pharmaceuticals, Inc.: Employee, Salary. A. Sharp, Evotec (UK) Ltd.: Employee, Salary. P. Warn, Evotec (UK) Ltd.: Employee, Salary. C. M. Yates, Viamet Pharmaceuticals, Inc.: Employee, Salary. R. J. Schotzinger, Viamet Pharmaceuticals, Inc.: Board Member and Employee, Salary.

更新日期：2018-11-01

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