Abstract
Aims: To assess the potential of interleukin-6 (IL-6) signalling 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 signalling. Models were used to generate simulated bronchoalveolar lavage fluid concentrations for normal subjects, subjects at risk of developing acute respiratory distress syndrome (ARDS), and subjects with ARDS under 4 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: Coadministration 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.
Keywords: COVID-19; IL-6; acute respiratory distress syndrome; modelling; siltuximab; simulation; tocilizumab.
【저자키워드】 COVID-19, acute respiratory distress syndrome, IL-6, modelling, tocilizumab., Simulation, siltuximab, 【초록키워드】 Treatment, ARDS, Tocilizumab, SARS-COV-2 infection, interleukin-6, lung, risk, Intervention, Bronchoalveolar lavage fluid, Model, targets, literature, monotherapy, predict, binding, acute respiratory distress, Concentration, COVID-19 patient, IL-6 receptor, IL-6 antagonist, reduction, subject, complex, syndrome, IL-6R, treat, blockade, component, sIL-6R, sequestering, normal, greater, predicted, develop, generate, reduced, were used, subjects, reflect, binding constant, IL-6 level, TCZ, 【제목키워드】 Tocilizumab, combination therapy, acute respiratory distress, Effect,