title: Evaluation of disease-mediated therapeutic protein-drug interactions between an anti-interleukin-6 monoclonal antibody (sirukumab) and cytochrome P450 activities in a phase 1 study in patients with rheumatoid arthritis using a cocktail approach.
abstract: This therapeutic protein-drug interaction study evaluated the disease-mediated effect of sirukumab (anti-interleukin 6 [anti-IL-6] monoclonal antibody) on the pharmacokinetics of the cytochrome P450 (CYP) probe substrates midazolam (CYP3A), omeprazole (CYP2C19), warfarin (CYP2C9), and caffeine (CYP1A2) in patients with active rheumatoid arthritis (RA). Twelve patients with C-reactive protein (CRP) ≥ 8.0 mg/L at screening received oral administration of a CYP probe cocktail consisting of 0.03 mg/kg midazolam, 10 mg warfarin + 10 mg vitamin K (equivalent to 5 mg S-warfarin), 20 mg omeprazole, and 100 mg caffeine 1 week before and 1, 3, and 6 weeks after a single subcutaneous dose of 300 mg sirukumab. The results showed that the pharmacokinetics of midazolam, omeprazole, and S-warfarin were nonequivalent before and after the administration of a single dose of 300 mg sirukumab. Area under the plasma concentration-time curve (AUC0- ∞ ) for midazolam, omeprazole, and S-warfarin was reduced by 30%-35%, 37%-45%, and 18%-19%, respectively, after sirukumab administration. Caffeine AUC0-∞ was increased by 20%-34% after sirukumab administration. The effect of sirukumab on CYP substrates was sustained for at least 6 weeks. No new adverse drug reactions related to the administration of sirukumab were observed in this study. These results suggest that sirukumab may reverse IL-6-mediated suppression of CYP3A, CYP2C9, and CYP2C19 activities in patients with active RA.
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA, USA.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Janssen Biologics B.V., Leiden, The Netherlands.
authors.forename: Dick E
authors.initials: DE
authors.lastname: de Vries
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA, USA.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Marciniak
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA, USA.
authors.forename: Dion
authors.initials: D
authors.lastname: Chen
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Leon
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA, USA.
authors.forename: Hugh M
authors.initials: HM
authors.lastname: Davis
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA, USA.
authors.forename: Honghui
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D002110:Caffeine / Q000097:blood / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology*; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015850:Interleukin-6; D002110:Caffeine; D014859:Warfarin; C568922:sirukumab; D003577:Cytochrome P-450 Enzyme System; D009853:Omeprazole; D008874:Midazolam
keywords: cocktail; human anti-IL-6 monoclonal antibody; sirukumab; therapeutic protein-drug interaction