{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,8,4]],"date-time":"2024-08-04T22:38:59Z","timestamp":1722811139053},"reference-count":22,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2018,6,14]],"date-time":"2018-06-14T00:00:00Z","timestamp":1528934400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005205","name":"Janssen Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005205","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>To characterize the dose\u2010exposure\u2013response relationship of sirukumab, an anti\u2013interleukin 6 human monoclonal antibody, in the treatment of moderately to severely active rheumatoid arthritis (RA), we conducted exposure\u2010response (E\u2010R) modeling analyses based on data from two pivotal phase 3 placebo\u2010controlled trials of sirukumab in patients with RA who were inadequate responders to nonbiologic disease\u2010modifying antirheumatic drugs or anti\u2010tumor necrosis factor \u03b1 agents. A total of 2176 patients were included for the analyses and received subcutaneous administration of either placebo or sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. The clinical endpoints were 20%, 50%, and 70% improvement in the American College of Rheumatology response criteria (ie, ACR20, ACR50, and ACR70), and 28\u2010joint Disease Activity Index Score (DAS28) using C\u2010reactive protein. To provide a thorough assessment of the sirukumab E\u2010R relationship, 2 pharmacokinetic\/pharmacodynamic modeling approaches were implemented, including joint longitudinal modeling (ie, indirect response modeling of the time course of the 2 clinical endpoints) and landmark analyses (ie, direct linking of selected pharmacokinetic parameters to response at week 16 or 24). Results from both modeling analyses were generally consistent, and collectively suggested that the sirukumab subcutaneous dose of 50 mg every 4 weeks would produce near\u2010maximal efficacy. No covariates identified in the E\u2010R modeling analyses would have a significant impact on dose\u2010response. Despite body weight and comorbid diabetes having significant effect on sirukumab exposure, simulations suggested that their effect on efficacy was small. Our work provides a comprehensive evaluation of sirukumab E\u2010R to support dose recommendations in patients with RA.<\/jats:p>","DOI":"10.1002\/jcph.1272","type":"journal-article","created":{"date-parts":[[2018,6,14]],"date-time":"2018-06-14T13:41:03Z","timestamp":1528983663000},"page":"1501-1515","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exposure\u2010Response Modeling Analyses for Sirukumab, a Human Monoclonal Antibody Targeting Interleukin 6, in Patients With Moderately to Severely Active Rheumatoid Arthritis"],"prefix":"10.1002","volume":"58","author":[{"given":"Yan","family":"Xu","sequence":"first","affiliation":[{"name":"Global Clinical Pharmacology Janssen Research &amp; Development LLC.  Spring House PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuanpu","family":"Hu","sequence":"additional","affiliation":[{"name":"Global Clinical Pharmacology Janssen Research &amp; Development LLC.  Spring House PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanli","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Global Clinical Pharmacology Janssen Research &amp; Development LLC.  Spring House PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Hsu","sequence":"additional","affiliation":[{"name":"Immunology Clinical Development Janssen Research &amp; Development LLC.  Spring House PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenhua","family":"Xu","sequence":"additional","affiliation":[{"name":"Global Clinical Pharmacology Janssen Research &amp; Development LLC.  Spring House PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amarnath","family":"Sharma","sequence":"additional","affiliation":[{"name":"Global Clinical Pharmacology Janssen Research &amp; Development LLC.  Spring House PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honghui","family":"Zhou","sequence":"additional","affiliation":[{"name":"Global Clinical Pharmacology Janssen Research &amp; Development LLC.  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