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

Centocor Research & Development, Inc., 200 Great Valley Parkway, Malvern, PA 19355, USA.
British Journal of Clinical Pharmacology (Impact Factor: 3.69). 03/2011; 72(2):270-81. DOI: 10.1111/j.1365-2125.2011.03964.x
Source: PubMed

ABSTRACT 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 C(max) and AUC(0,infinity) 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 0.364 l day(-1), 3.28 l, 0.588 l day(-1) and 4.971, 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.

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