Disease–Drug Interaction of Sarilumab and Simvastatin in Patients with Rheumatoid Arthritis

Abstract

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 (Cmax) 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 Cmax 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.