Bridging Clinical Outcomes of Canakinumab Treatment in Patients With Rheumatoid Arthritis With a Population Model of IL-1β Kinetics

Canakinumab, an anti-interleukin-1β (IL-1β) monoclonal antibody, is approved for cryopyrin-associated periodic syndromes and is under investigation for the management of other inflammatory disorders. In this study, population-based pharmacokinetic–pharmacodynamic models were developed to understand responses to canakinumab in patients with rheumatoid arthritis (RA). Total canakinumab and total IL-1β concentrations were obtained from four clinical trials (n = 472). In contrast to traditional models, free IL-1β concentrations were calculated and used to link canakinumab to changes in C-reactive protein (CRP) concentrations and American College of Rheumatology (ACR) scores of 20, 50, and 70% improvement. Temporal patterns of total canakinumab, total IL-1β, CRP, and ACR scores were all well described. Simulations confirmed that 150 mg every 4 weeks improved ACR scores in patients with RA, but no additional benefit was provided by higher doses or more frequent administration. Integrating predicted endogenous free ligand concentrations with biomarkers and clinical outcomes could be extended to new therapies of anti-inflammatory diseases.