title: Linking interleukin-6 receptor blockade with tocilizumab and its hematological effects using a modeling approach.
abstract: 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.
authors.affiliation: QuantPharm LLC, 49 Flints Grove Drive, North Potomac, MD 20878, USA. lgibiansky@quantpharm.com
authors.forename: Leonid
authors.initials: L
authors.lastname: Gibiansky
authors.forename: Nicolas
authors.initials: N
authors.lastname: Frey
mesh_terms: D000465:Algorithms; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D003198:Computer Simulation; D004311:Double-Blind Method; D006801:Humans; D007958:Leukocyte Count; D008954:Models, Biological; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D010976:Platelet Count; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D019947:Receptors, Interleukin-6; C502936:tocilizumab
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