Objectives The in vitro binding affinity of sarilumab (KD 61.9 pM) for the human interleukin-6 receptor (IL-6R) is 15- to 22-fold higher than tocilizumab.1 We explored the relationship between IL-6R RO, relevant pharmacodynamic (PD) variables (eg CRP), and potential clinical relevance of the differences between sarilumab and tocilizumab.
Methods Binding to total soluble IL-6R (sIL-6R) in vivo translates into the quasi-steady-state target-mediated drug disposition pharmacokinetics (PK) and indirect-response PD model with inhibition of elimination of sIL–6R and unbound sIL-6R concentration for both sarilumab and tocilizumab.2–5 PK/PD models were used to simulate sIL-6R RO dynamic profiles (% RO over time) for: sarilumab after subcutaneous (SC) doses of 200 and 150 mg once every 2 wks (q2w); tocilizumab after SC doses of 162 mg q2w and once every wk (qw); and tocilizumab after intravenous (IV) doses of 4 and 8 mg/kg once every 4 wks (q4w). In addition, RO profiles were compared with changes in observed CRP levels in patients with RA following administration of sarilumab SC and tocilizumab IV (ASCERTAIN study; NCT01768572). In this study, 60.8% of patients required an increase in tocilizumab dose from 4 to 8 mg/kg IV during the study period, based on clinical response.
Results Sarilumab SC 200 mg q2w achieved >90% RO after the first dose, which was maintained over the dosing interval throughout the 24-wk treatment course; at the lower dose of 150 mg q2w, RO was >90% from the second dose onwards. RO for tocilizumab SC, at 162 mg q2w, was >90% immediately after the first dose but dropped below 50% prior to the second dose. Similarly, for tocilizumab IV at 4 mg/kg q4w, the RO was high immediately after the first dose (>99% at Wk 1) but decreased over the dosing interval. At trough steady-state (Wk 24), RO was greater with sarilumab SC 200 mg q2w (98%) and 150 mg q2w (94%) compared with tocilizumab SC 162 mg q2w (84%) and IV 4 mg/kg q4w (60%). The higher doses of tocilizumab SC 162 mg qw and tocilizumab IV 8 mg/kg q4w were able to maintain RO ≥99% at steady state, similar to sarilumab SC 200 mg at steady state. CRP levels in patients with RA were inversely associated with RO at trough; the greatest suppression in CRP was seen in patients who received sarilumab SC (at either dose) or the higher IV tocilizumab dose (Fig). However, proportionally smaller reductions in CRP levels were observed with the lower IV tocilizumab dose (4 mg/kg q4w), consistent with the lower RO of tocilizumab.
Conclusion The higher binding affinity of sarilumab to IL-6R compared with tocilizumab translated into higher RO and greater reduction in CRP levels for sarilumab than tocilizumab, confirming the expected association between RO and PD effect. Sarilumab SC 200 mg q2w led to a rapid and sustained suppression of CRP over the 24-wk interval investigated; however, a higher dose (IV) or frequency of administration (SC) of tocilizumab was required to maintain the same degree of RO and CRP suppression. CRP may be a useful tool in clinical practice for patients treated with an IL-6R blocker.
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Acknowledgement Study funding and editorial support (Helen Johns, Adelphi) provided by Sanofi and Regeneron Pharmaceuticals, Inc.
Disclosure of Interests Christine Xu Shareholder of: Sanofi, Employee of: Sanofi, Patrick Nolain Shareholder of: Sanofi, Employee of: Sanofi, Qiang Lu Shareholder of: Sanofi, Employee of: Sanofi, Anne Paccaly Shareholder of: Regeneron, Amgen, Employee of: Regeneron, Sanofi, Amgen, Melitza Iglesias-Rodriguez Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Gregory St John Shareholder of: Regeneron Pharmaceuticals Inc, Employee of: Regeneron Pharmaceuticals Inc, Chad Nivens Shareholder of: Regeneron, Employee of: Regeneron, Rafael Maldonado Grant/research support from: Sanofi, Esteve, Almirall, GSK, Boehringer, Lundbeck, Grünenthal, UPSA, Uphjon, Uriach, Ferrer, Janus, Aelis, Spherium, Pharmaleads, BRAINco, Phytoplant, Rhodes and GW Pharma., Consultant for: Sanofi, Esteve, Almirall, GSK, Boehringer, Lundbeck, Grünenthal, UPSA, Uphjon, Uriach, Ferrer, Janus, Aelis, Spherium, Pharmaleads, BRAINco, Phytoplant, Rhodes and GW Pharma., Tomonori Ishii Grant/research support from: GSK, Janssen, Consultant for: GSK, Janssen, Speakers bureau: Mitsubishi-Tanabe, Janssen, Chugai, Ono, Sanofi, Abbvie, Eisai, Astellas, UCB, Teijin, Daiichi-Sankyo, Pfizer, Takeda, Asahi, and Kasei Pharma, Ernest Choy Grant/research support from: Amgen, Bio-Cancer, Chugai Pharma, Ferring Pharmaceuticals, Novimmune, Pfizer, Roche, and Union Chimique Belge, Consultant for: Abbvie, Amgen, AstraZeneca, Biogen, BMS, Boehringer Ingelheim, Celgene, Chelsea Therapeutics, Chugai Pharma, Daiichi Sankyo, Eli Lilly, Ferring Pharmacuetical, GlaxoSmithKline, Hospita, ISIS, Jazz Pharmaceuticals, Janssen, MedImmune, Merrimack Pharmaceutical, Merck Sharp & Dohme, Napp, Novimmune, Novartis, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, SynAct Pharma, Sanofi-Genzyme, Tonix and Union Chimique Belge, Speakers bureau: Amgen, BMS, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Hospira, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis, and Union Chimique Belge, Vanaja Kanamaluru Shareholder of: Sanofi, Employee of: Sanofi
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