Pharmacokinetics, pharmacodynamics and safety of a human anti-IL-6 monoclonal antibody (sirukumab) in healthy subjects in a first-in-human study |
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Authors: | Xu Zhenhua Bouman-Thio Esther Comisar Craig Frederick Bart Van Hartingsveldt Bart Marini Joseph C Davis Hugh M Zhou Honghui |
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Affiliation: | Centocor Research & Development, Inc., 200 Great Valley Parkway, Malvern, PA 19355, USA |
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Abstract: | AIMSTo assess the safety, tolerability, pharmacokinetics (PK) and immunogenicity of sirukumab (CNTO 136) following intravenous (i.v.) infusion in healthy subjects.METHODSForty-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.RESULTSAdverse 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.CONCLUSIONSSirukumab 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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Keywords: | first-in-human study interleukin-6 monoclonal antibody pharmacokinetics sirukumab |
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