COVID-19 acute respiratory distress syndrome: A simulation study of the effects of combination therapy with tocilizumab and siltuximab.

Abstract

AimsTo 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).MethodsLiterature 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.ResultsWith 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.ConclusionCoadministration 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.