caa a22 4500 605533911 CHVBK 20210128100840.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s10928-015-9415-3 doi (NATIONALLICENCE)springer-10.1007/s10928-015-9415-3 Model-based assessment of erlotinib effect in vitro measured by real-time cell analysis [Elektronische Daten] [Stephan Benay, Christophe Meille, Stefan Kustermann, Isabelle Walter, Antje Walz, P. Gonsard, Elina Pietilae, Nicole Kratochwil, Athanassios Iliadis, Adrian Roth, Thierry Lave] Real time cell analysis (RTCA) is an impedance-based technology which tracks various living cell characteristics over time, such as their number, morphology or adhesion to the extra cellular matrix. However, there is no consensus about how RTCA data should be used to quantitatively evaluate pharmacodynamic parameters which describe drug efficacy or toxicity. The purpose of this work was to determine how RTCA data can be analyzed with mathematical modeling to explore and quantify drug effect in vitro. The pharmacokinetic-pharmacodynamic erlotinib concentration profile predicted by the model and its effect on the human epidermoïd carcinoma cell line A431 in vitro was measured through RTCA output, designated as cell index. A population approach was used to estimate model parameter values, considering a plate well as the statistical unit. The model related the cell index to the number of cells by means of a proportionality factor. Cell growth was described by an exponential model. A delay between erlotinib pharmacokinetics and cell killing was described by a transit compartment model, and the effect potency, by an E max function of erlotinib concentration. The modeling analysis performed on RTCA data distinguished drug effects in vitro on cell number from other effects likely to modify the relationship between cell index and cell number. It also revealed a time-dependent decrease of erlotinib concentration over time, described by a mono-exponential pharmacokinetic model with nonspecific binding. Springer Science+Business Media New York, 2015 Real time cell analysis nationallicence Pharmacokinetic nationallicence Pharmacodynamic nationallicence Cell growth inhibition nationallicence Impedance nationallicence In vitro nationallicence Benay Stephan Pharmacokinetics Unit, SMARTc, Inserm CRO2 UMR S 911, Aix-Marseille University, 13385, Marseille, France aut Meille Christophe Modeling and Simulation, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut Kustermann Stefan Mechanistic Safety, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut Walter Isabelle ADME, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut Walz Antje Modeling and Simulation, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut Gonsard P. ADME, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut Pietilae Elina Mechanistic Safety, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut Kratochwil Nicole ADME, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut Iliadis Athanassios Pharmacokinetics Unit, SMARTc, Inserm CRO2 UMR S 911, Aix-Marseille University, 13385, Marseille, France aut Roth Adrian Mechanistic Safety, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut Lave Thierry Modeling and Simulation, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/3(2015-06-01), 275-285 1567-567X 42:3<275 2015 42 10928 https://doi.org/10.1007/s10928-015-9415-3 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-015-9415-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Benay Stephan Pharmacokinetics Unit, SMARTc, Inserm CRO2 UMR S 911, Aix-Marseille University, 13385, Marseille, France aut NATIONALLICENCE 700 1- Meille Christophe Modeling and Simulation, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut NATIONALLICENCE 700 1- Kustermann Stefan Mechanistic Safety, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut NATIONALLICENCE 700 1- Walter Isabelle ADME, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut NATIONALLICENCE 700 1- Walz Antje Modeling and Simulation, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut NATIONALLICENCE 700 1- Gonsard P. ADME, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut NATIONALLICENCE 700 1- Pietilae Elina Mechanistic Safety, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut NATIONALLICENCE 700 1- Kratochwil Nicole ADME, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut NATIONALLICENCE 700 1- Iliadis Athanassios Pharmacokinetics Unit, SMARTc, Inserm CRO2 UMR S 911, Aix-Marseille University, 13385, Marseille, France aut NATIONALLICENCE 700 1- Roth Adrian Mechanistic Safety, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut NATIONALLICENCE 700 1- Lave Thierry Modeling and Simulation, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/3(2015-06-01), 275-285 1567-567X 42:3<275 2015 42 10928