COVID-19 acute respiratory distress syndrome : A simulation study of the effects of combination therapy with tocilizumab and siltuximab
© 2021 British Pharmacological Society..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:88 |
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| Enthalten in: |
British journal of clinical pharmacology - 88(2022), 3 vom: 27. März, Seite 1043-1053 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Doyle, Eileen B [VerfasserIn] |
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| Links: |
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| Themen: |
Acute respiratory distress syndrome |
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| Anmerkungen: |
Date Completed 24.02.2022 Date Revised 07.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bcp.15009 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM328632163 |
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| 100 | 1 | |a Doyle, Eileen B |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a COVID-19 acute respiratory distress syndrome |b A simulation study of the effects of combination therapy with tocilizumab and siltuximab |
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| 500 | |a Date Completed 24.02.2022 | ||
| 500 | |a Date Revised 07.12.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 British Pharmacological Society. | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a COVID-19 | |
| 650 | 4 | |a IL-6 | |
| 650 | 4 | |a acute respiratory distress syndrome | |
| 650 | 4 | |a modelling | |
| 650 | 4 | |a siltuximab | |
| 650 | 4 | |a simulation | |
| 650 | 4 | |a tocilizumab | |
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| 700 | 1 | |a Dodds, Michael G |e verfasserin |4 aut | |
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