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Background Sarilumab is a human monoclonal antibody blocking the interleukin-6 receptor alpha (IL-6Rɑ) approved for the treatment of moderately to severely active rheumatoid arthritis in adults with inadequate response or intolerance to other disease-modifying antirheumatic drugs. Objective The aim of the current analysis was to describe sarilumab exposure–response relationships. Methods Population pharmacokinetic/pharmacodynamic (PopPK/PD) models were developed describing the time course of the 28-joint disease activity score by C-reactive protein (DAS28-CRP) and absolute neutrophil count (ANC) using data from phase I–III studies (NCT01011959, NCT01061736, NCT01709578, NCT01768572) after subcutaneous sarilumab 50–150 mg every week or 100–200 mg every 2 weeks. Results The time course of DAS28-CRP and ANC after sarilumab administration was described by semi-mechanistic, indirect-response models. Drug effect was predicted to be numerically greater at median exposure for the 200 mg every 2 weeks regimen versus the 150 mg every 2 weeks regimen, for both DAS28-CRP (50% vs. 47%) and ANC reduction from baseline (39% vs. 31%), with the latter showing less fluctuations within a dosing interval. Four covariates were retained in the final models: body weight, baseline rheumatoid factor status, anti-cyclic citrullinated peptide status, and concomitant methotrexate. There was no clinically meaningful influence of investigated covariates for either model. Conclusion The PopPK/PD models showed numerically greater reductions in DAS28-CRP and ANC with sarilumab 200 mg every 2 weeks than with 150 mg every 2 weeks. There was no clinically meaningful influence of investigated covariates. These data contribute to the totality of evidence that supports a sarilumab subcutaneous starting dose of 200 mg every 2 weeks, with a subsequent reduction to 150 mg every 2 weeks in the event of laboratory abnormalities such as neutropenia.

Background and Objective Sarilumab binds to the interleukin-6 receptor with high affinity, inhibiting cis and trans signaling by interleukin-6. Sarilumab has demonstrated efficacy and safety in patients with rheumatoid arthritis. The objective of this study was to develop a population-pharmacokinetic model using data from 1770 patients with rheumatoid arthritis across phase I–III studies. Methods Potential covariates were identified using a stepwise forward-addition and backward-deletion strategy, and the final model was evaluated by visual predictive check and bootstrap methods. Results Sarilumab pharmacokinetics is described by a two-compartment model with first-order absorption and parallel linear and nonlinear Michaelis–Menten elimination. A subcutaneous dose of sarilumab 200 mg every 2 weeks resulted in more pronounced saturation of the nonlinear clearance pathway over the dosing interval than 150 mg every 2 weeks. Steady-state exposure (area under the plasma concentration–time curve from day 0 to day 14) increased twofold with dose escalation from 150 to 200 mg every 2 weeks. Body weight, anti-drug antibody status, sarilumab drug product, sex, creatinine clearance, albumin, and baseline C-reactive protein levels were identified as significant covariates according to the predefined statistical significance criteria in stepwise covariate searches. The main intrinsic source of pharmacokinetic variability in exposure was body weight. Compared with a typical 71-kg patient, the area under the plasma concentration–time curve from day 0 to day 14 was 20–23% lower for an 83-kg patient and 20–25% higher for a 62-kg patient. Conclusions These findings, combined with the safety and efficacy data, indicated limited clinical relevance of body-weight effect on sarilumab exposure. No adjustment in sarilumab dose is required for body weight or any other demographics assessed. Electronic supplementary material The online version of this article (10.1007/s40262-019-00765-1) contains supplementary material, which is available to authorized users.

Introduction Elevated interleukin (IL)-6 occurs in patients with active rheumatoid arthritis (RA), which has been shown to lead to a decrease in cytochrome P450 (CYP) enzyme activity and alterations in drug concentrations metabolized by CYP. IL-6 signaling blockade by IL-6 receptor (IL-6R) antagonists may reverse this effect of IL-6 and restore CYP activity. This study evaluated the pharmacokinetic profile of simvastatin (a CYP3A4 substrate) before and 1 week after a single dose of sarilumab (a human monoclonal antibody [mAb] blocking the IL-6Rα) in patients with RA, to assess potential interaction. Methods Nineteen patients with active RA received oral simvastatin 40 mg 1 day before and 7 days after subcutaneous injection of sarilumab 200 mg. The pharmacokinetic parameters of simvastatin and its primary metabolite, β-hydroxy-simvastatin acid, were calculated using noncompartmental analysis. Results Compared with simvastatin alone, single-dose simvastatin administration 7 days after single-dose sarilumab administration in patients with RA resulted in reduced simvastatin and β-hydroxy-simvastatin acid exposure in plasma. Mean effect ratios (90 % confidence interval) for simvastatin peak plasma concentration (C max) and area under the concentration–time curve extrapolated to infinity (AUC∞) were 54.1 % (42.2–69.4 %) and 54.7 % (47.2–63.3 %), respectively. No changes occurred in time to C max or half-life for either simvastatin or β-hydroxy-simvastatin acid after sarilumab administration. Conclusions Sarilumab treatment resulted in a reduction in exposure of simvastatin, consistent with reversal of IL-6-mediated CYP3A4 suppression in patients with active RA, as was reported for tocilizumab with simvastatin and for sirukumab with midazolam. Clinical trial registration number NCT02017639. Electronic supplementary material The online version of this article (doi:10.1007/s40262-016-0462-8) contains supplementary material, which is available to authorized users.