title: Disease-Drug Interaction of Sarilumab and Simvastatin in Patients with Rheumatoid Arthritis.
abstract: 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.
  
  
  
  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.
  
  
  
  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 Cmaxor half-life for either simvastatin or β-hydroxy-simvastatin acid after sarilumab administration.
  
  
  
  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.
  
  
  
  NCT02017639.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. leb7616@snu.ac.kr.
authors.forename: Eun Bong
authors.initials: EB
authors.lastname: Lee
authors.affiliation: Sanofi Genzyme, 55 Corporate Drive, Bridgewater, NJ, 08807, USA.
authors.forename: Nikki
authors.initials: N
authors.lastname: Daskalakis
authors.affiliation: Sanofi Genzyme, 55 Corporate Drive, Bridgewater, NJ, 08807, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Xu
authors.affiliation: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Paccaly
authors.affiliation: Sanofi Genzyme, 55 Corporate Drive, Bridgewater, NJ, 08807, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Miller
authors.affiliation: Metroplex Clinical Research Center, 8144 Walnut Hill Lane, No. 810, Dallas, 75231, TX, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Fleischmann
authors.affiliation: Arensia Exploratory Medicine GmbH, Moskauer Str. 25, 40227, Düsseldorf, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Bodrug
authors.affiliation: Altoona Center for Clinical Research, 175 Meadowbrook Lane, Duncansville, PA, 16635, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Kivitz
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000097:blood; D019821:Simvastatin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D000093242:Interleukin-6 Inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D051544:Cytochrome P-450 CYP3A; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D019821:Simvastatin; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C508603:IL6R protein, human; C483161:beta-hydroxy simvastatin acid; C000592401:sarilumab