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Thierry Lavé received his RharmD and RhD in pharmaceutical sciences from the University of Strasbourg in 1992 and 1993. He also received a statistical degree from the University of Raris in 1992 and did an internship in hospital pharmacy from 1988 to 1992 in Strasbourg. Thierry Lavé joined Roche's Department of Rreclinical Rharmacokinetics and Drug Metabolism in 1992 and worked in this department as a postdoctoral fellow for 2 years. Thierry Lavé is currently a Scientific Expert at Hoffmann-La Roche and took responsbility for the global modeling and simulation group in preclinical research in 2002. His main area of research is in preclinical modeling of safety, pharmacokinetics, and formulation, physiologically-based pharmacokinetics, interspecies scaling, drug-drug interaction, and all aspects related to early predictions of pharmacokinetics/pharmacodynamics in humans during drug discovery and early drug development. He has published a number of papers in these areas. Thierry Lavée also teaches pharmacokinetics at the Universities of Rharmacy in Basel, Strasbourg, Helsinki, and Besancon.

Neil Parrott graduated in physics from the University of Bristol, UK, then specialized in information technology and medical imaging at the University of Aberdeen, UK. In 1988, he started work with Sandoz Pharma as a developer of chemistry and biology databases and search algorithms. Later with Sandoz he joined the combinatorial chemistry group developing software and automation for high-throughput solid-phase synthesis. In 1998' he joined the Informatics group in Roche Pharma Research where he developed data analysis tools for pharmacokinetic data and led a project to integrate DMPK data into the Roche Research global data warehouse. While working in the DMPK area he became interested in physiologically-based pharmacokinetics and transferred to the Research Modeling and Simulation group where he is now involved in preclinical project support with pharmacokinetic and absorption modeling.

Hannah Jones is a Research Scientist within the DMPK department at F Hoffmann-La Roche, where she is responsible for the simulation of human pharmacokinetics for discovery and early development compounds before entry into human. She received a BSc (Hons) in pharmacology and a PhD in drug metabolism from the School of Biological Sciences and the School of Pharmacy at the University of Manchester, UK, respectively. Hannah is interested in the prediction of human pharmacokinetics, including metabolism, distribution, absorption, drug-drug interactions, and the incorporation of variability and uncertainty. She has several research publications in this area.

© 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II

No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6 in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers ISBN (Volume 5) 0-08-044518-7; pp. 867-884

5.38 Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling for the Prediction of In Vivo Drug Concentration-Effect Relationships - Application in Drug Candidate Selection and Lead Optimization

M Danhof, Leiden University, Leiden, The Netherlands

P H Van der Graaf, Pfizer Global Research and Development, Sandwich, UK

D M Jonker, Novo Nordisk A/S, Bagsv^rd, Denmark

SAG Visser, AstraZeneca R&D, Sodertalje, Sweden

K P Zuideveld, F. Hoffmann-La Roche Ltd, Basel, Switzerland

© 2007 Elsevier Ltd. All Rights Reserved.

5.38.1 Introduction 885

5.38.2 Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling: Concepts 886 Pharmacokinetic Considerations: The Rationale of Obtaining Drug Concentrations in In Vivo Pharmacodynamic Investigations 886 Target Site Distribution: The Estimation of Drug Concentrations in the

Biophase In Vivo 887 Target Site Interaction and Activation: The Pharmacodynamic Basis of Predicting In Vivo Drug Concentration-Effect Relationships 888 Full parametric approach to the incorporation of receptor theory: the operational model of agonism 889 Semiparametric approach to the incorporation of receptor theory 889 Transduction: The Modeling of Time-Dependent Pharmacodynamics to

Derive In Vivo Drug Concentration-Effect Relationships 890 Functional Adaptation: Modeling of Homeostatic Feedback to Derive In Vivo Concentration-Effect Relationships 891 Disease: Modeling of Disease Processes to Derive In Vivo Drug Concentration-Effect Relationships 891

5.38.3 Application of Pharmacokinetic-Pharmacodynamic Modeling in

Drug Design and Lead Optimization 892 Adenosine A1 Receptor Agonists 892 m Opioid Receptor Agonists 893 GABAa Receptor Agonists 895 Serotonin (5HT1A) Receptor Agonists 898 Drug-Induced QT Interval Prolongation 901

5.38.4 Conclusion 903 References 904

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