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