Open AccessPhysiologically Based Pharmacokinetic/Pharmacodynamic Model for the Treatment of Dengue Infections Applied to the Broad Spectrum Antiviral Soraphen A
Author(s) -
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
Publication year - 2021
Publication title -
acs pharmacology and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.271
H-Index - 10
ISSN - 2575-9108
DOI - 10.1021/acsptsci.1c00078
Subject(s) - physiologically based pharmacokinetic modelling , viremia , dengue fever , pharmacology , pharmacodynamics , pharmacokinetics , dengue virus , in vivo , antiviral drug , drug , broad spectrum , virology , medicine , biology , chemistry , virus , microbiology and biotechnology , combinatorial chemistry
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 (EC 50 = 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 log 10 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.