Background/Purpose: The in vitro binding affinity of sarilumab (K_D 61.9 pM) for the human interleukin-6 receptor (IL-6R) is 15–22-fold higher than that of tocilizumab. This study evaluated the relationship between IL-6R receptor occupancy (RO), pharmacodynamic (PD) variables (eg CRP), and the potential clinical relevance of the differences between sarilumab and tocilizumab.

Methods: Binding to 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. PK/PD models simulated sIL-6R RO over time for: sarilumab 200 and 150 mg subcutaneously (SC) once every 2 weeks (q2w); tocilizumab 162 mg SC q2w and once every week (qw); and tocilizumab 4 and 8 mg/kg intravenously (IV) once every 4 weeks (q4w). RO profiles were compared with changes in CRP levels following administration of sarilumab SC and tocilizumab IV in patients with RA (ASCERTAIN; NCT01768572); during the study period, 60.8% of patients receiving tocilizumab required a dose increase from 4 to 8 mg/kg IV q4w, based on clinical response.

Results: Sarilumab 200 mg SC q2w achieved >90% RO after the first dose, which was maintained over the dosing interval throughout the 24-week treatment period; at 150 mg SC q2w, RO was >90% from the second dose onwards. Tocilizumab 162 mg SC q2w achieved RO >90% after the first dose but this decreased to < 50% before the second dose. The RO for tocilizumab 4 mg/kg IV q4w was >99% after the first dose at Week 1 but decreased over the dosing interval to < 50% before the second dose. At trough steady state (Week 24), RO was greater with sarilumab 200 mg SC q2w (98%) and 150 mg SC q2w (94%) versus tocilizumab 162 mg SC q2w (84%) and 4 mg/kg IV q4w (60%). At the higher dose (8 mg/kg IV q4w) or dosing frequency (162 mg SC qw), tocilizumab maintained RO ≥99% at steady state, similar to sarilumab 200 mg SC q2w. CRP levels were inversely associated with RO at trough in patients with RA; the greatest suppression in CRP levels occurred with sarilumab SC (either dose) or with the tocilizumab 8 mg/kg IV q4w (Figure). Proportionally smaller CRP reductions were observed with tocilizumab 4 mg/kg IV q4w, consistent with the lower RO of tocilizumab at this dose.

Conclusion: The higher IL-6R binding affinity of sarilumab translated into higher RO and greater reduction in CRP levels when compared with tocilizumab. Sarilumab 200 mg SC q2w led to a rapid and sustained suppression of CRP over the 24-week treatment course; the higher dose (IV) or increased dosing frequency (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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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sarilumab-and-tocilizumab-receptor-occupancy-ro-and-effects-on-c-reactive-protein-crp-levels-in-patients-with-rheumatoid-arthritis-ra/