Background Elevated IL-6 levels occur in rheumatoid arthritis (RA) and can lead to modulation of cytochrome P450 (CYP) enzyme activity and changes in drug levels (CYP substrates) compared with individuals without RA. Conversely, blockade of IL-6 signaling by IL-6 receptor (IL-6R) antagonists may reverse this effect of IL-6 and restore CYP activity. Hence, IL-6 is expected to inhibit CYP3A4 activity, while IL-6 inhibitors, such as sarilumab, are expected to restore elevated simvastatin (a CYP3A4 substrate) concentrations in patients with RA back to those observed in healthy individuals.
Objectives This study (NCT02017639) evaluated the pharmacokinetic profile of simvastatin, a CYP3A4 substrate, before and after a single dose of sarilumab, an investigational anti–IL-6R monoclonal antibody, in patients with active RA to assess disease-drug interaction of sarilumab on simvastatin.
Methods Nineteen adult patients with moderate-to-severe RA with CRP >6.0 mg/L at baseline received simvastatin 40 mg 1 day before and 7 days after subcutaneous injection of sarilumab 200 mg. A series of plasma samples were collected over 24 hours and analyzed for concentrations of simvastatin and its major metabolite, β-hydroxy-simvastatin acid, using a validated LC-MS/MS method. Pharmacokinetic parameters of plasma simvastatin and β-hydroxy-simvastatin acid were calculated using noncompartmental analysis. The geometric mean ratios (with vs without sarilumab) and 90% CIs for peak plasma concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUC0–∞) were calculated. C-reactive protein was also analyzed.
Results The majority of patients were female (78.9%) and Caucasian (63.2%). All patients had moderate-to-severe disease activity per study inclusion criteria with a mean CRP (± SD) of 22.1±24.4 mg/L. Administration of a single dose of sarilumab along with simvastatin to patients with RA resulted in reduced exposure to simvastatin by 45% and to β-hydroxy-simvastatin acid by 36% compared with simvastatin alone. Mean effect ratios (90% CI) for simvastatin Cmax and AUC0-∞ were 54.1% (42.2%>69.4%) and 54.7% (47.2%>63.3%), respectively (Table). There were no changes in time to Cmax (tmax) or half-life (t1/2) for either simvastatin or β-hydroxy-simvastatin acid following sarilumab exposure (Table). Levels of CRP decreased from 22.1±24.4 mg/L at baseline to reach a nadir of 1.9±0.9 mg/L at 1 wk after sarilumab administration and remained low thereafter. Consistent with the anticipated effects of IL-6 inhibition and the known safety profile of sarilumab, the most frequently reported TEAE across all study treatments was neutropenia, followed by increased alanine aminotransferase level.
Conclusions Sarilumab reverses IL-6–mediated suppression of CYP3A4 activity in patients with active RA. The observed reduction of simvastatin exposure is consistent with similar studies conducted with tocilizumab and sirukumab, in agreement with IL-6–mediated disease-drug interaction effect.
Acknowledgement This study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Editorial assistance was provided by Andrea Eckhart, PhD, MedThink SciCom, and funded by Sanofi and Regeneron Pharmaceuticals, Inc.
Disclosure of Interest E. Lee Consultant for: Pfizer, N. Daskalakis Shareholder of: Sanofi, Employee of: Sanofi, C. Xu Shareholder of: Sanofi, Employee of: Sanofi, A. Paccaly Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, B. Miller Shareholder of: Sanofi, Employee of: Sanofi, R. Fleischmann Grant/research support from: has received research grants from AbbVie, Amgen, Ardea, AstraZeneca, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Pfizer, Roche, Sanofi, and UCB, Consultant for: has received consulting fees from AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, Eli Lilly, Pfizer, Roche, and UCB, I. Bodrug: None declared, A. Kivitz Shareholder of: has received research grants from and holds stock in Sanofi and Regeneron Pharmaceuticals, Inc., Grant/research support from: has received research grants from and holds stock in Sanofi and Regeneron Pharmaceuticals, Inc.