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Differential binding of sarilumab and tocilizumab to IL-6Rα and effects of receptor occupancy on clinical parameters

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dc.contributor.author Xu, Christine
dc.contributor.author Rafique, Ashique
dc.contributor.author Potocky, Terra
dc.contributor.author Paccaly, Anne
dc.contributor.author Nolain, Patrick
dc.contributor.author Lu, Qiang
dc.contributor.author Iglesias-Rodriguez, Melitza
dc.contributor.author John, Gregory St
dc.contributor.author Nivens, Michael C.
dc.contributor.author Kanamaluru, Vanaja
dc.contributor.author Fairhurst, Jeanette
dc.contributor.author Ishii, Tomonori
dc.contributor.author Maldonado, Rafael, 1961-
dc.contributor.author Choy, Ernest
dc.contributor.author Emery, Paul
dc.date.accessioned 2023-03-23T07:04:16Z
dc.date.available 2023-03-23T07:04:16Z
dc.date.issued 2020
dc.identifier.citation Xu C, Rafique A, Potocky T, Paccaly A, Nolain P, Lu Q, Iglesias-Rodriguez M, St John G, Nivens MC, Kanamaluru V, Fairhurst J, Ishii T, Maldonado R, Choy E, Emery P. Differential binding of sarilumab and tocilizumab to IL-6Rα and effects of receptor occupancy on clinical parameters. J Clin Pharmacol. 2021 May;61(5):714-24. DOI: 10.1002/jcph.1795
dc.identifier.issn 0091-2700
dc.identifier.uri http://hdl.handle.net/10230/56325
dc.description.abstract We evaluated interleukin-6 (IL-6) receptor-α subunit (IL-6Rα) signaling inhibition with sarilumab and tocilizumab, the association between IL-6Rα receptor occupancy (RO) and C-reactive protein (CRP), and the potential clinical relevance of any differences. For this, we measured IL-6Rα binding and signaling inhibition with sarilumab and tocilizumab in vitro, simulated soluble IL-6Rα RO over time for approved sarilumab subcutaneous (SC) and tocilizumab intravenous (IV) and SC doses, and assessed associations between calculated RO and CRP reduction, 28-joint Disease Activity Score based on CRP, and 20%/50%/70% improvement in American College of Rheumatology responses from clinical data. Sarilumab binds IL-6Rα in vitro with 15- to 22-fold higher affinity than tocilizumab, and inhibits IL-6-mediated classical and trans signaling via membrane-bound and soluble IL-6Rα. Sarilumab 200 and 150 mg SC every 2 weeks achieved >90% RO after first and second doses, respectively, maintained throughout the treatment period. At steady-state trough, RO was greater with sarilumab 200 mg (98%) and 150 mg SC every 2 weeks (94%), and tocilizumab 162 mg SC weekly (>99%) and 8 mg/kg IV every 4 weeks (99%), vs tocilizumab 162 mg SC every 2 weeks (84%) and 4 mg/kg IV every 4 weeks (60%). Higher RO was associated with greater CRP reduction and 28-joint Disease Activity Score based on CRP reduction, and more sarilumab patients achieving 20%/50%/70% improvement in American College of Rheumatology responses. The greatest reduction in CRP levels was observed with sarilumab (both doses) and tocilizumab 8 mg/kg IV every 4 weeks (reductions proportionally smaller with 4 mg/kg IV every 4 weeks). Higher IL-6Rα binding affinity translated into higher RO with sarilumab vs tocilizumab 4 mg/kg every 4 weeks or 162 mg every 2 weeks; tocilizumab required the higher dose or increased frequency to maintain the same degree of RO and CRP reduction. Higher RO was associated with clinical parameter improvements.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Wiley
dc.relation.ispartof J Clin Pharmacol. 2021 May;61(5):714-24
dc.rights This is the peer reviewed version of the following article: Xu C, Rafique A, Potocky T, Paccaly A, Nolain P, Lu Q, Iglesias-Rodriguez M, St John G, Nivens MC, Kanamaluru V, Fairhurst J, Ishii T, Maldonado R, Choy E, Emery P. Differential binding of sarilumab and tocilizumab to IL-6Rα and effects of receptor occupancy on clinical parameters. J Clin Pharmacol. 2021 May;61(5):714-24. DOI: 10.1002/jcph.1795, which has been published in final form at http://dx.doi.org/10.1002/jcph.1795. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
dc.title Differential binding of sarilumab and tocilizumab to IL-6Rα and effects of receptor occupancy on clinical parameters
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1002/jcph.1795
dc.subject.keyword C-reactive protein
dc.subject.keyword Interleukin-6
dc.subject.keyword Receptors
dc.subject.keyword Rheumatoid arthritis
dc.subject.keyword Sarilumab
dc.subject.keyword Tocilizumab
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/acceptedVersion

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