Tarunendu Mapder1; Juliano F Gianlupi2,3; Sara K Quinney1,4; James A Glazier2,3; Robert E Stratford1
1Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; 2Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA; 3Biocomplexity Institute, Indiana University, Bloomington, IN, USA; 4Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Objective: Developing antiviral drugs and neutralizing antibodies to treat SARS-CoV-2 infection are currently emerging, and several clinical trials are ongoing to counter the pandemic outbreak. Although clinical trials on COVID-19 therapeutics have advantages that are not usual, defining optimal dosing strategies can be facilitated using in vitro cell culture and tissue culture models. To aid this approach, a clear understanding of viral dynamics and interaction with the multilayered immune system is crucial. The two main aim of this study are: (1) to explore how good the antiviral needs to be in order to contain viral spread if the tissue infection, viral release and cytokines secretion are spatially inhomogeneous; and (2) clinical trials and scientific studies show that remdesivir does not have clear survival benefit over standard clinical care. The dosing schedule of this widely used drug might be a reason for this questionable benefit.
Methods: We studied the dynamics of viral infection and local-tissue immune cells (dendritic cells and CD8+ T-cells) on a 2.5-dimensional small (900 cells) lung tissue patch, simulated as a cellular potts model in CompuCell3D. The rest of the systemic immune response and underlying lymph node kinetics (activation and proliferation of CD4+, CD8+ T-cells, B-cells) were considered as a connected continuum model with adaptive immune response feedback through emergence of immune cells migration, antibody and cytokines into the tissue environment. We did not include the inflammatory response or other downstream events, but considered the viral burden and cytokines levels as measures of severity of symptoms. In this study we expanded the Sego model1 with antiviral (Remdesivir2) treatments, developed in separate minimalized physiologically-based pharmacokinetic (mPBPK) model, that in turn were connected with the aforesaid virtual tissue model using microdosimetry principles. The effect of Remdesivir was implemented as an inhibitor of intracellular viral RNA.
Results: This multiscale hybrid model efficiently mimics physiological scenarios via manifestation of viral infection and also suggests optimal regimens of treatment. Initially, we estimated the variability in the viral infection period based on the initial number of infected epithelial cells. This intervention-less study suggests up to 10 initial infected cells per tissue patch produces feasible range of viral clearance. With this calibrated framework, we experimented the effects of frequency, potency and delay in the remdesivir treatment. Based on the virus clearance, we have classified the treatment regimens in four classes: rapid clearance, slow clearance, persistent infection and runaway virus. The rapid and slow clearances are actually yield recovery of the tissue section while the other two classes leads to long infection and damage. Our study infers that treatment starting by 3 days of infection (earliest symptom onset), a dosing interval of 12 hours and an IC50 multiplier of 0.05 provides a tradeoff between complete infection and a containment of infection.
Conclusions: This integrated modelling framework enabled us to examine COVID-19 treatments in a unique way, including tissue level mechanistic insight of new therapeutics. The approach suggests possible improvements to current treatment regimens.
1. Sego, T.J., Aponte-Serrano, J.O., Gianlupi, J.F., Heaps, S.R., Breithaupt, K., Brusch, L., Crawshaw, J., Osborne, J.M., Quardokus, E.M., Plemper, R.K., Glazier, J.A., 2020. A modular framework for multiscale, multicellular, spatiotemporal modeling of acute primary viral infection and immune response in epithelial tissues and its application to drug therapy timing and effectiveness. PLOS Comput. Biol. 16, e1008451.
2. Humeniuk, R., Mathias, A., Cao, H., Osinusi, A., Shen, G., Chng, E., Ling, J., Vu, A., German, P., 2020. Safety, Tolerability, and Pharmacokinetics of Remdesivir, An Antiviral for Treatment of COVID-19, in Healthy Subjects. Clin. Transl. Sci. 13, 896–906.
Reference: PAGE 29 (2021) Abstr 9700 [www.page-meeting.org/?abstract=9700]
Poster: Drug/Disease Modelling - COVID-19