Background/Purpose: Sarilumab, a fully human monoclonal antibody targeting interleukin-6 receptor alpha (IL-6Rα), is being evaluated for the treatment of rheumatoid arthritis (RA) based on the role of IL-6 in RA pathogenesis. This study aims to characterize the pharmacokinetic (PK) profile of single subcutaneous (SC) doses of sarilumab, and determine its relationship to markers of pharmacodynamic (PD) effects in patients (pts) with RA.

Methods: In this phase 1 parallel group study, pts with active RA (N=32) on background methotrexate (MTX) received a single SC dose of 50, 100, or 200 mg sarilumab or placebo (PBO). Blood samples were drawn at baseline and post-treatment days 1, 4, 8, 12, 15, 22, 29, 36, and 43.  The serum obtained was analyzed for concentrations of functional sarilumab, defined as antibody with 0 or 1 of the 2 binding sites occupied by soluble IL-6Rα, using a validated enzyme-linked immunosorbent assay (ELISA). Pharmacokinetic parameters were determined using non-compartmental methods. The PD markers IL-6, high sensitivity C-reactive protein (hsCRP), and serum amyloid A (SAA) were assessed in parallel. Safety and tolerability were evaluated based on incidence of adverse events (AEs) and clinical/laboratory assessments.

Results: All pts were white and female; age ranged from 45.5-55.4 years and RA duration from 7.9-10.3 years. PK is characterized as non-linear with target-mediated elimination. An initial absorption phase, followed by a saturating beta phase and a terminal target-mediated elimination phase were observed. Patients in the higher dose groups had higher concentrations of functional sarilumab, and these concentrations were detectable for a longer period (Table). A greater than dose-proportional increase in the area under the concentration-time profile (AUC) and maximum serum concentration (C_max) was observed. The beta phase was well defined in the 200 mg dose group. While no meaningful changes over time were observed in hsCRP, SAA, or IL-6 with PBO, changes in the sarilumab groups reflected both the dose and PK profile. Reductions in hsCRP and SAA and increases in IL-6 were greater and of longer duration at higher doses, and were statistically significant compared to placebo. The largest % changes were seen in the 200 mg group: hsCRP -91.7%, SAA -92.5%, and IL-6 +647%. The most commonly reported treatment-related AEs in the combined sarilumab groups were neutropenia, increased alanine aminotransferase, and increased aspartate aminotransferase, which were transient and not associated with clinical sequelae. One pt receiving sarilumab 50 mg had a serious AE of RA flare requiring hospitalization.

Conclusion: Sarilumab has a nonlinear PK profile with parallel linear and target-mediated elimination. PD effects were dose-dependent, consistent with the PK profile, and showed substantial reductions in acute phase reactants relative to placebo.