Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing
Modeling study analyzing timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide. The greatest benefits were seen when treatments were given immediately at the time of diagnosis. Authors state that "For IVM, no results of clinical trials regarding its effectiveness in COVID-19 have been published yet", which is inaccurate - there were 19 peer-reviewed trials published as of Mar 10, 2021 (43 including preprints).
Kern et al., 10 Mar 2021, peer-reviewed, 4 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: METHODS
published: 10 March 2021
doi: 10.3389/fphar.2021.625678
Modeling of SARS-CoV-2 Treatment
Effects for Informed Drug
Repurposing
Charlotte Kern 1,2†, Verena Schöning 1†, Carlos Chaccour 3,4,5 and Felix Hammann 1*
1
Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital (Bern University Hospital), University
of Bern, Bern, Switzerland, 2Graduate School for Health Sciences, University of Bern, Bern, Switzerland, 3ISGlobal, Hospital
Clínic-Universitat de Barcelona, Barcelona, Spain, 4Clínica Universidad de Navarra, Pamplona, Spain, 5Ifakara Health Institute,
Ifakara, Tanzania
Edited by:
Lei Xi,
Virginia Commonwealth University,
United States
Reviewed by:
Arnab K Chatterjee,
Calibr at Scripps Research,
United States
Kirill Gorshkov,
National Center for Advancing
Translational Sciences (NCATS),
United States
Daniel F Alonso,
National University of Quilmes,
Argentina
*Correspondence:
Felix Hammann
Felix.Hammann@insel.ch
†
Several repurposed drugs are currently under investigation in the fight against coronavirus
disease 2019 (COVID-19). Candidates are often selected solely by their effective
concentrations in vitro, an approach that has largely not lived up to expectations in
COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung
tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo, host
response, and concentration-time profiles must also be considered. Here we address the
latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired
immune response to investigate the dynamic impact of timing and dosing regimens of
hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide. We
observed greatest benefits when treatments were given immediately at the time of
diagnosis. Even interventions with minor antiviral effect may reduce host exposure if
timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak
viral load dropped by 0.3–0.6 log units and exposure by 8.8–22.3%. The other drugs had
little to no appreciable effect. Given how well previous clinical trial results for
hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here,
similar strategies should be considered in future drug candidate prioritization efforts.
Keywords: COVID-19, disease modeling, drug repurposing, viral kinetics, pharmacometrics
These authors have contributed
equally to this work
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