Physiologically Based Pharmacokinetic/Pharmacodynamic Model for the Treatment of Dengue Infections Applied to the Broad Spectrum Antiviral Soraphen A,ACS Pharmacology & Translational Science

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Physiologically Based Pharmacokinetic/Pharmacodynamic Model for the Treatment of Dengue Infections Applied to the Broad Spectrum Antiviral Soraphen A
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2021-08-30 , DOI: 10.1021/acsptsci.1c00078
Katharina Rox _{1,

2,

3} , Maxi Heyner _{4,

5} , Jana Krull ₁ , Kirsten Harmrolfs ₆ , Valtteri Rinne ₇ , Juho Hokkanen ₇ , Gemma Perez Vilaro ₈ , Juana Díez ₈ , Rolf Müller _{2,

6} , Andrea Kröger _{4,

5} , Yuichi Sugiyama ₃ , Mark Brönstrup _{1,

2}

Affiliation

While a drug treatment is unavailable, the global incidence of Dengue virus (DENV) infections and its associated severe manifestations continues to rise. We report the construction of the first physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model that predicts viremia levels in relevant target organs based on preclinical data with the broad spectrum antiviral soraphen A (SorA), an inhibitor of the host cell target acetyl-CoA-carboxylase. SorA was highly effective against DENV in vitro (EC₅₀ = 4.7 nM) and showed in vivo efficacy by inducing a significant reduction of viral load in the spleen and liver of IFNAR^–/– mice infected with DENV-2. PBPK/PD predictions for SorA matched well with the experimental infection data. Transfer to a human PBPK/PD model for DENV to mimic a clinical scenario predicted a reduction in viremia by more than one log₁₀ unit for an intravenous infusion regimen of SorA. The PBPK/PD model is applicable to any DENV drug lead and, thus, represents a valuable tool to accelerate and facilitate DENV drug discovery and development.

中文翻译：

用于治疗登革热感染的生理学药代动力学/药效学模型应用于广谱抗病毒药物 Soraphen A

虽然无法获得药物治疗，但登革热病毒 (DENV) 感染及其相关严重表现的全球发病率继续上升。我们报告了第一个基于生理学的药代动力学/药效学 (PBPK/PD) 模型的构建，该模型基于广谱抗病毒药物 soraphen A (SorA) 的临床前数据预测相关靶器官中的病毒血症水平，SorA 是宿主细胞靶乙酰-的抑制剂。 CoA-羧化酶。SorA在体外对 DENV 非常有效(EC ₅₀ = 4.7 nM)，并通过诱导 IFNAR 在脾脏和肝脏中的病毒载量显着降低而显示出体内功效^–/–感染 DENV-2 的小鼠。SorA 的 PBPK/PD 预测与实验感染数据非常吻合。转移到 DENV 的人类 PBPK/PD 模型以模拟临床情况，预测SorA 静脉输注方案的病毒血症减少超过一个 log _10单位。PBPK/PD 模型适用于任何 DENV 药物先导，因此是加速和促进 DENV 药物发现和开发的宝贵工具。

更新日期：2021-10-08

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