University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
Antimicrob Agents Chemother. 2018 Oct 24;62(11). doi: 10.1128/AAC.01315-18. Print 2018 Nov.
VT-1129 is a novel fungal enzyme-specific Cyp51 inhibitor with potent cryptococcal activity. Because of its long half-life (>6 days in mice) and our desire to quickly reach potent efficacy, we evaluated a VT-1129 loading dose-maintenance dose strategy against cryptococcal meningitis. VT-1129 plasma and brain pharmacokinetics were first studied in healthy mice, and these data were used to model loading dose-maintenance dose regimens to generate different steady-state concentrations. Mice were inoculated intracranially with , and oral treatment began 1 day later. Treatment consisted of placebo or one of three VT-1129 loading dose-maintenance dose regimens, i.e., loading dose of 1, 3, or 30 mg/kg on day 1, followed by once-daily maintenance doses of 0.15, 0.5, or 5 mg/kg, respectively. In the fungal burden arm, therapy continued for 14 days and brains were collected on day 15 for fungal burden assessments. In the survival arm, treatment continued for 10 days, after which mice were monitored without therapy until day 30. VT-1129 plasma and brain concentrations were also measured. All VT-1129 doses significantly improved survival and reduced fungal burdens, compared to placebo. VT-1129 plasma and brain levels correlated with fungal burden reductions ( = 0.72 and = 0.67, respectively), with a plasma concentration of 1 μg/ml yielding a reduction of ∼5 log CFU/g. With the highest loading dose-maintenance dose regimen, fungal burdens were undetectable in one-half of the mice in the fungal burden arm and in one-fourth of the mice in the survival arm, 20 days after the final dose. These data support a loading dose-maintenance dose strategy for quickly reaching highly efficacious VT-1129 concentrations for treating cryptococcal meningitis.
VT-1129 是一种新型真菌酶特异性 Cyp51 抑制剂，具有强大的隐球菌活性。由于其半衰期长（在小鼠中 >6 天），并且我们希望快速达到有效的疗效，我们评估了 VT-1129 负荷剂量-维持剂量方案对隐球菌性脑膜炎的疗效。首先在健康小鼠中研究了 VT-1129 的血浆和脑药代动力学，这些数据用于建立负荷剂量-维持剂量方案的模型，以产生不同的稳态浓度。小鼠颅内接种 ，在第 1 天开始口服治疗。治疗包括安慰剂或 VT-1129 的三种负荷剂量-维持剂量方案之一，即第 1 天给予 1、3 或 30mg/kg 的负荷剂量，随后每天给予 0.15、0.5 或 5mg/kg 的维持剂量。在真菌负荷组中，治疗持续 14 天，第 15 天收集大脑进行真菌负荷评估。在生存组中，治疗持续 10 天，然后在没有治疗的情况下监测小鼠，直到第 30 天。还测量了 VT-1129 的血浆和脑浓度。与安慰剂相比，所有 VT-1129 剂量均显著提高了生存率并降低了真菌负荷。VT-1129 的血浆和脑水平与真菌负荷的降低相关（分别为 = 0.72 和 = 0.67），血浆浓度为 1μg/ml 时，真菌负荷降低约 5logCFU/g。在最高的负荷剂量-维持剂量方案中，在真菌负荷组的一半小鼠和生存组的四分之一小鼠中，在最后一次给药后 20 天，真菌负荷无法检测到。这些数据支持负荷剂量-维持剂量策略，以快速达到治疗隐球菌性脑膜炎的高效 VT-1129 浓度。
