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 (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.

Conflict of interest statement

Funding

This study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Andrea Eckhart, PhD, an employee of MedThink SciCom, provided editorial assistance, which was funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc.

Conflicts of interest

Eun Bong Lee has acted as a consultant to Pfizer. Nikki Daskalakis, Christine Xu, and Barry Miller are employees of Sanofi Genzyme and may hold stock and/or stock options in the company. Anne Paccaly is an employee of Regeneron Pharmaceuticals, Inc. and may hold stock and/or stock options in the company. Roy Fleischmann has received research grants from AbbVie, Amgen, Ardea, AstraZeneca, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Pfizer, Roche, Sanofi, and UCB; and has received consulting fees from AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, Eli Lilly, Pfizer, Roche, and UCB. Inga Bodrug was an investigator for this study. Alan Kivitz has received research grants from, and holds stock in, Sanofi and Regeneron Pharmaceuticals, Inc.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in this study.

Figures

Fig. 1

Study design. PD pharmacodynamics, PK pharmacokinetics, PO oral, SC subcutaneous

Fig. 2

Mean [+SD] a simvastatin and b β-hydroxy-simvastatin acid plasma concentration–time profiles after administration of simvastatin 40 mg 1 day before and 7 days after subcutaneous injection of sarilumab 200 mg (N = 19). Pharmacokinetic parameters for two patients were not calculated because of sample stability issues during bioanalysis. SD standard deviation

Fig. 3

Pharmacodynamic response data corresponding to baseline, 1 week after sarilumab administration alone (day 8), and approximately 2 weeks after sarilumab administration and 1 week after simvastatin administration (day 15) for a sIL-6R, b IL-6, and c CRP. N = 19, N = 17, and N = 19 for baseline, sarilumab, and sarilumab plus simvastatin, respectively. Data are expressed as mean ± SEM. CRP C-reactive protein, IL-6 interleukin 6, SEM standard error of the mean, sIL-6R soluble IL-6 receptor