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

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

doi:10.1021/acsptsci.1c00078

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

ACS Pharmacol Transl Sci. 2021 Aug 30;4(5):1499-1513. doi: 10.1021/acsptsci.1c00078. eCollection 2021 Oct 8.

Authors

Katharina Rox^{1

2

3}, Maxi Heyner^{4

5}, Jana Krull¹, Kirsten Harmrolfs⁶, Valtteri Rinne⁷, Juho Hokkanen⁷, Gemma Perez Vilaro⁸, Juana Díez⁸, Rolf Müller^{2

6}, Andrea Kröger^{4

5}, Yuichi Sugiyama³, Mark Brönstrup^{1

2}

Affiliations

¹ Department of Chemical Biology, Helmholtz Centre for Infection Research (HZI), Inhoffenstrasse 7, 38124 Braunschweig, Germany.
² German Centre for Infection Research (DZIF), Partner-Site Hannover-Braunschweig, 38124 Braunschweig, Germany.
³ Sugiyama Laboratory, RIKEN Baton Zone Program, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
⁴ Research Group Innate Immunity and Infection, Helmholtz Centre for Infection Research (HZI), Inhoffenstrasse 7, 38124 Braunschweig, Germany.
⁵ Institute for Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
⁶ Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research (HZI), Campus E 8.1, 66123 Saarbrücken, Germany.
⁷ Admesope Ltd, Typpitie 1, 90620 Oulu, Finland.
⁸ Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Dr. Aiguader, 88, 08003 Barcelona, Spain.

Abstract

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.