Tocilizumab is a recombinant humanized antihuman interleukin-6 receptor 
monoclonal antibody, which inhibits binding of IL-6 to its soluble (sIL-6R) and 
membrane-expressed (mIL-6R) receptors. The work investigated whether the 
observed decline in peripheral neutrophil and platelet counts after tocilizumab 
administration can be directly explained by tocilizumab IL-6R blockade, thus 
demonstrating the mechanism of tocilizumab action. Tocilizumab and total sIL-6R 
concentrations, neutrophil and platelet counts from 4 phase 3 studies in 
rheumatoid arthritis patients were available. Patients received 4 or 8 mg/kg 
tocilizumab intravenous infusions every 4 weeks for a total of 6 doses. A 
population approach was applied to describe the relationship between tocilizumab 
and sIL-6R concentrations and subsequent changes in neutrophil and platelet 
counts. Following tocilizumab administration, concentrations of total sIL-6R 
increased, while neutrophil and platelet counts declined. These changes were 
transient, with counts returning to their respective baseline levels soon after 
tocilizumab is eliminated from the body. Tocilizumab concentrations were 
described by a two compartment model with parallel linear and Michaelis-Menten 
elimination. The quasi-steady-state target-mediated drug disposition model 
described tocilizumab relationships to total sIL-6R, which allowed computation 
of unobserved unbound sIL-6R concentrations. The neutrophil counts were 
described as a direct function of unbound sIL-6R concentrations. The platelet 
counts were described by the transit-compartment life-span model with inhibition 
of production that depended on the unbound sIL-6R concentrations. Thus, the 
observed changes in sIL-6R, neutrophil, and platelet data are consistent with 
the tocilizumab mechanism of action and can be fully explained by tocilizumab 
binding to sIL-6R and mIL-6R.