Pharmacokinetics, pharmacodynamics and safety of a human anti‐IL‐6 monoclonal antibody (sirukumab) in healthy subjects in a first‐in‐human study
Authors: Xu Zhenhua , Bouman‐Thio Esther , Comisar Craig , Frederick Bart , Van Hartingsveldt Bart , Marini Joseph C. , Davis Hugh M. , Zhou Honghui 
Published: March 2011

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 10 mg kg−1 in a dose‐escalating manner). All treated subjects were observed for 96 h 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 Cmax 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 (V1), the inter‐compartmental clearance (Q) and the peripheral volume of distribution (V2) were 0.364 l day−1, 3.28 l, 0.588 l day−1 and 4.97 l, 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 10 mg kg−1 in healthy subjects.