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Lewis Sheiner


2017
Budapest, Hungary



2016
Lisboa, Portugal

2015
Hersonissos, Crete, Greece

2014
Alicante, Spain

2013
Glasgow, Scotland

2012
Venice, Italy

2011
Athens, Greece

2010
Berlin, Germany

2009
St. Petersburg, Russia

2008
Marseille, France

2007
KÝbenhavn, Denmark

2006
Brugge/Bruges, Belgium

2005
Pamplona, Spain

2004
Uppsala, Sweden

2003
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2002
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2001
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2000
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1999
Saintes, France

1998
Wuppertal, Germany

1997
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1996
Sandwich, UK

1995
Frankfurt, Germany

1994
Greenford, UK

1993
Paris, France

1992
Basel, Switzerland



Printable version

PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
ISSN 1871-6032

Reference:
PAGE 20 (2011) Abstr 1965 [www.page-meeting.org/?abstract=1965]


PDF poster/presentation:
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Poster: Inflammation


II-24 Leonid Gibiansky Mechanistic Modeling of the Link between Interleukin 6 Receptor Blockade with Tocilizumab and Its Hematological Effects

Leonid Gibiansky (1) and Nicholas Frey (2)

(1) QuantPharm LLC, North Potomac, MD, USA; (2) F. Hoffmann-La Roche Ltd, Basel, Switzerland

Objectives: Tocilizumab (TZ) is a recombinant humanized IL-6 receptor monoclonal antibody that inhibits binding of IL-6 to its soluble (sIL-6R) and membrane-expressed (mIL-6R) receptors. Elevated serum IL-6 levels have been reported in rheumatoid arthritis (RA) patients and have been shown to be associated with disease activity. The aim of this study was to investigate whether the decline in peripheral neutrophil and platelet counts after TZ administration can be directly explained by IL-6R blockade, thus demonstrating its mechanism of action.

Methods: Serum concentrations of TZ, total sIL-6R (bound and unbound to TZ), and neutrophil and platelet counts from 4 phase 3 studies in patients with moderate to severe active RA who received 4 or 8 mg/kg TZ infusions every 4 weeks (total of 6 doses) were used. Mechanistic population PK/PD models were dev eloped to describe the relationship between TZ and sIL-6R concentrations and subsequent changes in neutrophil and platelet counts.

Results: Following TZ administration, concentrations of total sIL-6R increased, while neutrophil and platelet counts declined. These changes were transient, with counts starting to return to baseline levels after TZ infusion. The nadir of cell counts was similar for 4 and 8 mg/kg dose groups. However, the rate of rebound was dose-dependent, with cell counts returning to baseline approximately 4 weeks later for 8 mg/kg compared to the 4 mg/kg dose. A 2-compartment model with parallel linear and Michaelis-Menten (MM) elimination described the TZ time course. Quasi-steady-state (QSS) approximation of the target-mediated drug disposition model described the relationship between TZ and total sIL-6R, allowing computation of unbound sIL-6R concentrations. Interestingly, MM and QSS constants were found to be similar to the in-vitro values for TZ binding to mIL-6R and sIL-6R, respectively. The observed neutrophil changes were described as a direct function of the unbound sIL-6R concentrations. The observed platelet counts were described by the transit-compartment lifespan model with inhibition of production that depended on the unbound sIL-6R concentrations. Diagnostic plots and predictive check simulations indicated excellent agreement of model predictions with the observed data.

Conclusions:The observed changes in sIL-6R, neutrophil and platelet data are consistent with the TZ mechanism of action and can be fully explained by TZ binding to both soluble and membrane-expressed IL-6R.