Physiologically Based Pharmacokinetic/Pharmacodynamic Model for the Treatment of Dengue Infections Applied to the Broad Spectrum Antiviral Soraphen A

• DOI: 10.1021/acsptsci.1c00078
• Publication Date: 2021-08-30T17:59:10Z
• Authors: Katharina Rox; Maxi Heyner; Jana Krull; Kirsten Harmrolfs; Valtteri Rinne; Juho Hokkanen; Gemma Perez Vilaro; Juana Díez; Rolf Müller; Andrea Kröger; Yuichi Sugiyama; Mark Brönstrup
• Keywords: Viremia; Pharmacodynamics; Antiviral drug; Broad spectrum

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