Exposure-Response Modeling Analyses for Sirukumab, a Human Monoclonal Antibody Targeting Interleukin 6, in Patients With Moderately to Severely Active Rheumatoid Arthritis.

Autor: Xu Y; Global Clinical Pharmacology, Janssen Research & Development, LLC., Spring House, PA, USA., Hu C; Global Clinical Pharmacology, Janssen Research & Development, LLC., Spring House, PA, USA., Zhuang Y; Global Clinical Pharmacology, Janssen Research & Development, LLC., Spring House, PA, USA., Hsu B; Immunology Clinical Development, Janssen Research & Development, LLC., Spring House, PA, USA., Xu Z; Global Clinical Pharmacology, Janssen Research & Development, LLC., Spring House, PA, USA., Sharma A; Global Clinical Pharmacology, Janssen Research & Development, LLC., Spring House, PA, USA., Zhou H; Global Clinical Pharmacology, Janssen Research & Development, LLC., Spring House, PA, USA.
Jazyk: angličtina
Zdroj: Journal of clinical pharmacology [J Clin Pharmacol] 2018 Nov; Vol. 58 (11), pp. 1501-1515. Date of Electronic Publication: 2018 Jun 14.
DOI: 10.1002/jcph.1272
Abstrakt: To characterize the dose-exposure-response relationship of sirukumab, an anti-interleukin 6 human monoclonal antibody, in the treatment of moderately to severely active rheumatoid arthritis (RA), we conducted exposure-response (E-R) modeling analyses based on data from two pivotal phase 3 placebo-controlled trials of sirukumab in patients with RA who were inadequate responders to nonbiologic disease-modifying antirheumatic drugs or anti-tumor necrosis factor α 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-joint Disease Activity Index Score (DAS28) using C-reactive protein. To provide a thorough assessment of the sirukumab E-R 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-maximal efficacy. No covariates identified in the E-R modeling analyses would have a significant impact on dose-response. 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-R to support dose recommendations in patients with RA.
(© 2018, The American College of Clinical Pharmacology.)
Databáze: MEDLINE
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