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Aim To assess the potential of interleukin-6 (IL-6) signaling blockade in the lung to treat SARS-CoV-2 infection via model-based simulation by exploring soluble IL-6 receptor (sIL-6R) sequestration by tocilizumab (TCZ) and IL-6 sequestration by siltuximab (SIL). Methods Literature values of IL-6, IL-6 antagonist SIL, sIL-6R, IL-6R antagonist TCZ, and their respective binding constants were used to develop a model to predict the impact of treatment on IL-6 signaling. Models were used to generate simulated bronchoalveolar lavage fluid (BALF) concentrations for normal subjects, subjects at risk of developing acute respiratory distress syndrome (ARDS), and subjects with ARDS under four conditions: without treatment, treatment with TCZ, treatment with SIL, and treatment with TCZ + SIL. Results With TCZ intervention, IL-6 levels are unaffected and sIL-6R is reduced somewhat below the Normal case. IL-6:sIL-6R complex only slightly decreased relative to the no-intervention case. With SIL intervention, sIL-6R levels are unaffected and IL-6 is greatly reduced below the Normal case. IL-6:sIL-6R complex is greatly decreased relative to the no-intervention case. With TCZ + SIL intervention, IL-6 and sIL-6R levels are reduced below the Normal case and achieve suppression equivalent to monotherapy results for their respective targets. IL-6:sIL-6R complex reduction is predicted to be greater than that achieved with monotherapy. This reflects sequestration of both components of the complex and the nonlinear binding equilibrium. Conclusion Co-administration of both IL-6 and IL-6R sequestering products such as SIL and TCZ may be necessary to effectively treat COVID-19 patients who have or are at risk of developing ARDS.

During a pandemic caused by a novel pathogen (NP), drug repurposing offers the potential of a rapid treatment response via a repurposed drug (RD) while more targeted treatments are developed. Five steps of model-informed drug repurposing (MIDR) are discussed: (i) utilize RD product label and in vitro NP data to determine initial proof of potential, (ii) optimize potential posology using clinical pharmacokinetics (PK) considering both efficacy and safety, (iii) link events in the viral life cycle to RD PK, (iv) link RD PK to clinical and virologic outcomes, and optimize clinical trial design, and (v) assess RD treatment effects from trials using model-based meta-analysis. Activities which fall under these five steps are categorized into three stages: what can be accomplished prior to an NP emergence (preparatory stage), during the NP pandemic (responsive stage) and once the crisis has subsided (retrospective stage). MIDR allows for extraction of a greater amount of information from emerging data and integration of disparate data into actionable insight.