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: 0301 basic medicine; 03 medical and health sciences; 3. Good health

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.