Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single‐Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate

Abstract

We assessed pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of interleukin-6 (IL-6), soluble IL-6 receptor, and C-reactive protein (CRP) in serum, and absolute neutrophil count (ANC) in blood following single doses of subcutaneous sarilumab versus intravenous tocilizumab (NCT02097524) from patients with rheumatoid arthritis (RA) who are inadequate responders to methotrexate (MTX) and on a stable dose of MTX. Patients with RA randomized (1:1:1:1) to single-dose sarilumab (150 or 200 mg subcutaneously) or tocilizumab (4 or 8 mg/kg intravenously) were included (n = 101), and PK, PD, and PK/PD relationships and safety were assessed over 6 weeks postdose. PK profiles for both drugs are described by parallel linear and nonlinear target-mediated clearance pathways. PD markers showed similar onset of effect during the first week postdose, regardless of dose or route of administration. CRP and ANC decreased, with median postdose nadirs at 7-15 days for CRP and 3-5 days for ANC. Both drugs at low and high doses achieved the same nadir for ANC and a similar return toward baseline within 2 weeks postdose, suggesting a saturation of effect. Safety profiles of sarilumab and tocilizumab were generally similar. In conclusion, despite differences in PK, the onset of the decrease in CRP (efficacy) and ANC (safety) after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab. PD effects and safety were consistent with previous studies.

Effects of the Interleukin-6 Receptor Blocker Sarilumab on Metabolic Activity and Differentiation Capacity of Primary Human Osteoblasts

“…This dosing regime was associated with a significant improvement in symptoms in RA patients [ 18 ]. The concentration in the cell culture experiments was based on the maximum concentration (Cmax) in serum as measured in pharmacokinetic studies of sarilumab-treated patients [ 19 , 20 ]. However, in vitro inhibition of IL-6 signaling was already achieved by much lower concentrations of sarilumab.…”

Blood Biomarkers for Monitoring and Prognosis of Large Vessel Vasculitides

“…However, anti-IL-6 receptor therapies directly attenuate the levels of downstream molecules including CRP. In this specific setting, measuring IL-6 rather than CRP might be rationale, even though IL-6 levels usually rise after the first infusions of IL-6 receptor antagonists [83,84]. A recent paper showed that persistently high levels of IL-6 despite treatment with tocilizumab may predict future relapses [85].…”

Optimisation of anti-interleukin-6 therapy: Precision medicine through mathematical modelling

“…This could, in part, also be due to differences in their modes of action. Our results imply that 100 μg/ml tocilizumab (the concentration in plasma following the usual dose in humans ( 24 )) can block IL-6 concentrations of no more than 1 ng/ml. Importantly, anti-IL-6 and anti-IL-6R mAbs have been found to reduce systemic CRP levels to less than 4 and 1 mg/l ( 23 , 26 ), respectively, which does not indicate full inhibition of IL-6 bioactivity.…”

“…Given previous estimates indicating weak diffusion of plasma mAb into lymph nodes and interstitial lung tissue (8.46% and 14.9% of that in plasma, respectively) ( 21 , 22 ) and the established pharmacokinetics/pharmacodynamics of siltuximab ( 23 ) and tocilizumab ( 24 ), we assumed the mAb concentration in lymph nodes (iMCD scenario) or BAF (COVID-19 scenario) to be 10% of that in plasma. Because of uncertainty around mAb biodistribution, particularly into BAF (unknown but expected to be low: ~0.1–0.3% of that in plasma; see Supplementary Methods ), we also include results with mAb penetration into lymph nodes and BAF of 100% and 1% of the concentration in plasma as Supplementary Data .…”