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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 6/2017

Open Access 01-06-2017 | Original Research Article

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

Authors: Eun Bong Lee, Nikki Daskalakis, Christine Xu, Anne Paccaly, Barry Miller, Roy Fleischmann, Inga Bodrug, Alan Kivitz

Published in: Clinical Pharmacokinetics | Issue 6/2017

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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.
Appendix
Available only for authorised users
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Metadata
Title
Disease–Drug Interaction of Sarilumab and Simvastatin in Patients with Rheumatoid Arthritis
Authors
Eun Bong Lee
Nikki Daskalakis
Christine Xu
Anne Paccaly
Barry Miller
Roy Fleischmann
Inga Bodrug
Alan Kivitz
Publication date
01-06-2017
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 6/2017
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-016-0462-8

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