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Lewis Sheiner


2019
Stockholm, Sweden



2018
Montreux, Switzerland

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
Verona, Italy

2002
Paris, France

2001
Basel, Switzerland

2000
Salamanca, Spain

1999
Saintes, France

1998
Wuppertal, Germany

1997
Glasgow, Scotland

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 14 (2005) Abstr 771 [www.page-meeting.org/?abstract=771]


oral presentation


Sophie Glatt Preclinical Population PK/PD of TGF beta RI Kinase inhibitor for Cancer

S. Glatt(1), C Pitou (1), J. Yingling (1), L. Bueno (2), D. de Alwis (1), I.F Troconiz (2)

(1) Eli Lilly Global PK/PD trial Simulation, Erlwood Manor, UK; (2) Department of Pharmacy, School of pharmacy, University of Navarra, Pamplona, Spain

Objectives: The primary objective of PK/PD modeling in preparation for the First Human Dose study was to estimate a pharmacologically effective dose range in humans based on preclinical data

Methods: Data from tumor growth kinetics Xenograft model in mice and from in vivo target inhibition (IVTI) in rats and in mice were incorporated in our PK/PD analysis. The PK/PD model in mice integrated the time course of the pharmacokinetics of the compound, the inhibition of SMAD phosphorylation (biomarker) and the tumor growth data in terms of pharmacodynamics. An indirect response model was used to relate the predicted plasma concentrations with the observed pSMAD data The model assumed the existence of factors within the tumor cell responsible for the synthesis and degration of pSMAD. A Gompertz model was applied to describe the tumor growth curve. This model can be extended to further understand the relationship between the time course of the tumor growth and the time course of TGF beta RI kinase inhibitor A PK/PD model in rats based on SMAD phosphorylation was also built. This model incorporated the pharmacokinetics and the inhibition of the pSMAD from the IVTI studies This model supported an understanding of TGF beta RI kinase inhibitor concentrations and the relationship to the inhibition of the SMAD phosphorylation. Both models enabled prediction of the targeted inhibition of SMAD phosphorylation under different dosing regimens

Results and Conclusions: In both models, the variability of the biomarker was incorporated to assess the variability in the response, in order to simulate profiles in humans. Simulations were performed in order to assist the dose range selection for the First Human Dose (FHD) study. Potentially with these two approaches, the relationship between the time course of TGF beta RI kinase inhibitor concentrations and the clinical tumor response was defined The PK/PD modeling would provide guidance for the design of future studies, as these models will be updated as new data become available from the FHD study