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COVID-19: Simulation Study of Tocilizumab and Siltuximab Interventions in the Context of Acute Respiratory Distress Syndrome
  • Eileen Doyle,
  • Darren Bentley,
  • Michael Dodds
Eileen Doyle
Certara LP
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Darren Bentley
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Michael Dodds
Certara LP
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Abstract

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, the IL-6 antagonist SIL, sIL-6R, the 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 (BAL) concentrations for normal subjects, subjects at risk of developing acute respiratory distress syndrome (ARDS), and subjects with ARDS were simulated 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 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.

Peer review status:IN REVISION

10 Jun 2020Submitted to British Journal of Clinical Pharmacology
11 Jun 2020Assigned to Editor
11 Jun 2020Submission Checks Completed
22 Jun 2020Reviewer(s) Assigned
09 Jul 2020Review(s) Completed, Editorial Evaluation Pending
27 Jul 2020Editorial Decision: Revise Major