Pharmacokinetics, pharmacodynamics and safety of a human anti-IL-6 monoclonal antibody (sirukumab) in healthy subjects in a first-in-human study

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT •Interleukin (IL)-6 is a cytokine known for pleiotropic and pro-inflammatory functions. IL-6 is involved in various disease processes including lupus erythematosus, rheumatoid arthritis, insulin resistance and malignancy. •Anti-IL-6 receptor therapy has recently been demonstrated to be effective in the treatment of patients with rheumatoid arthritis. WHAT THIS STUDY ADDS •Sirukumab, a human monoclonal antibody against soluble IL-6, has been found to bind to human IL-6 with high affinity and specificity and thus suppress the biological activity of IL-6. Preclinical studies have demonstrated the safety of sirukumab in cynomolgus monkeys, a toxicologically relevant animal species, following repeated intravenous and subcutaneous administrations. •This study shows that sirukumab has desirable pharmacokinetic characteristics (linear pharmacokinetics with long half-life), a low incidence of immunogenicity and a well-tolerated safety profile in healthy subjects, supporting further development of sirukumab as a potentially valuable therapeutic agent. AIMS To assess the safety, tolerability, pharmacokinetics (PK) and immunogenicity of sirukumab (CNTO 136) following intravenous (i.v.) infusion in healthy subjects. METHODS Forty-five healthy adult subjects (38 men and seven women) were randomly assigned to receive a single i.v. dose of placebo or sirukumab (0.3, 1, 3, 6 or 10mgkg -1 in a dose-escalating manner). All treated subjects were observed for 96h post infusion and underwent 20-week follow-up evaluations. Serum samples were collected to measure sirukumab concentrations, pharmacodynamic biomarkers and antibodies to sirukumab. Non-compartmental analysis and population PK modelling were conducted to characterize the PK of sirukumab. RESULTS Adverse events were generally brief in duration, mild or moderate in intensity and non-dose-dependent. No serious adverse events were observed in the sirukumab-treated subjects. Both C max and AUC(0,∞) increased in an approximately dose-proportional manner. Median terminal half-life ranged from 18.5 to 29.6 days. A two-compartment model adequately described the PK of sirukumab following i.v. administration. Population estimates for the clearance (CL), the central volume of distribution (V 1), the inter-compartmental clearance (Q) and the peripheral volume of distribution (V 2) were 0.364lday -1, 3.28l, 0.588l day -1 and 4.97l, respectively. Compared with placebo subjects, a sustained decrease from baseline in C-reactive protein was observed in all sirukumab-treated dose groups, although no clear dose-response relationship was observed. No subjects were positive for antibodies to sirukumab. CONCLUSIONS Sirukumab had a well-tolerated safety profile, desirable PK characteristics and a low incidence of immunogenicity following an i.v. infusion of 0.3 to 10mgkg -1 in healthy subjects. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.