Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

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1 Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

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3 H. Gerhard Vogel Jochen Maas Franz J. Hock Dieter Mayer Editors Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays Second Edition With 243 Figures and 157 Tables

4 Editors H. Gerhard Vogel Deceased Jochen Maas Sanofi Pharma Deutschland GmbH A company of the Sanofi-Aventis Group Industriepark Hoechst Frankfurt am Main, Germany Franz J. Hock Dieburg, Germany Dieter Mayer Idstein, Germany ISBN ISBN (ebook) ISBN (print and electronic bundle) DOI / Springer Heidelberg Dordrecht London New York Library of Congress Control Number: # Springer-Verlag Berlin Heidelberg 2006, 2013 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer ScienceþBusiness Media (

5 In Memory of Hans Gerhard Vogel

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7 Preface to the Second Edition Both safety and pharmacokinetic aspects are important factors in the Research & Development of pharmaceuticals: safety pharmacology, toxicology and pharmacokinetics are the cornerstone disciplines of preclinical development, but the scope has widened both towards Research and towards Development over the last few years. In this book, all in-silico approaches, in-vitro, ex-vivo, in-vivo animal and clinical studies had to be taken into consideration. These studies are used to generate a lot of data which must be evaluated carefully. It was therefore necessary to include the conduct of studies but also the technologies to generate these data in a textbook like this. Since toxicology and safety pharmacology depend directly on exposure, it was also mandatory to cover PK aspects and technologies. All these aspects were included in the first edition of Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Some of the methods described in the first edition have been introduced into the scientific community over the years and decades for instance specific chromatography technologies like gas chromatography and there were no novel tendencies to be observed between the dates of the first and second editions. These chapters were not modified since all the information included can still be regarded as "state of the art". But there are other topics which have shown considerable development with many new insights and technologies. Transporters and their biology are the best example of these areas: these chapters have been completely modified since the first edition. A third group of chapters had to consider some new aspects without it being necessary to modify them completely. These were amended by adding new results and experiences. And last but not least, I want to thank again all the authors who contributed despite their very busy daily lives in the pharmaceuticals industry. And a special thank you to Hans Gerhard Vogel who was the Editor-in-Chief of the first edition and all of the Drug Discovery and Evaluation titles at Springer consisting of Pharmacological Assays, Safety and Pharmacokinetic Assays and Methods in Clinical Pharmacology. Gerhard Vogel passed away in He initiated the second edition of this title. Without him neither this second edition nor any of the other titles of Drug Discovery and Evaluation would ever have been completed. Frankfurt, Germany 2013 Jochen Maas vii

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9 Preface to the First Edition Drug discovery and evaluation has been a sequential process for a long period of time. It started with the selection of the most active compound from a series of newly synthesized compounds with the help of special pharmacological assays. Safety aspects were considered by testing the selected compound in high doses in tests directed to indications other than the intended indication of the new compound. These tests were followed by pharmacokinetic studies, which were mainly aimed at confirmation of a suitable half-life time and of oral activity. Safety relied on acute and subacute toxicity studies, which gave information more on organ structure than on organ function.toxicological and pharmacokinetic studies were adapted to the progress of studies in clinical pharmacology and clinical trials. This strategy has been changed during the last 15 years for several reasons: Some negative effects on organ function, e.g., ventricular tachy-arrhythmia were detected too late. On the other hand, negative findings in chronic toxicity studies in animals turned out to be irrelevant for human beings. New scientific approaches, e.g. combinatorial chemistry, high-throughput screening, in silico models, pharmaco-genomics and pharmaco-proteomics offered new possibilities. The success rate in the pharmaceuticals industry and the introduction of new chemical entities to the market per year dropped dramatically, whereas the development time for new compounds increased, sometimes exceeding the patent protection. This forced a change of strategy: Parallel instead of sequential involvement of the various disciplines. The term Safety Pharmacology was coined. An International Conference on Harmonization (ICH) Safety Pharmacolog working group was founded. Easily accessible and most informative tests must be selected. Exposure of drug to the body by pharmacokinetic studies on absorption, distribution, metabolism and excretion must be investigated at an early stage of development and can contribute to the selection of a compound for development. Toxicology experienced major improvements by the introduction of new methods, e.g., in silico methods, toxicogenomics and toxicoproteomics. These aspects stimulated our decision to publish this volume as a counterpart to Drug Discovery and Evaluation. Pharmacological Assays (Second Edition Springer-Verlag 2002). The current book contains three sections. Dr. Franz Jakob Hock shares with me the responsibility for the section Safety Pharmacology ; Dr. Jochen Maas took over the responsibility for the section Safety Pharmacokinetics and Prof. Dr. Dieter Mayer for the section Safety Toxicology. ix

10 x Preface to the First Edition As with the book on pharmacological assays, this book is intended to aid both scientists and students. The reader can find methods for selecting candidates for drug development at early stages, such as screening methods based on the stage of development, or methods up to advanced stages of development and which are considered necessary for international approval from the scientific and regulatory point of view. Juni 2006 H. Gerhard Vogel

11 Acknowledgments "I want to thank all authors of the PK-part for their tremendous work. It was often not easy to complete their individual chapters in addition to their busy daily activities in their respective companies. A special thanks goes to Dr. Roland Wesch who supported me in an optimal way to collect, review and edit all information received from the different authors" Jochen Maas xi

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13 About the Editors Jochen Maas Jochen Maas is appointed General Manager, Research & Development (R&D) at Sanofi Deutschland GmbH, as of October 1st, 2010, based in Frankfurt. He is a member of the Global R&D Management Board and of the German Management Board. He was appointed as head of the German hub R&D organization in Jochen has huge experience in all phases of the R&D value chain. He started his career in PK, then he expanded his responsibilities to preclinical Development, preclinical and clinical Development and Research & Development. Afterwards, he was responsible for Global Research & Development in the Diabetes Division and acted as Vice President R&D Europe at sanofi-aventis. Jochen also lectures in pharmacokinetics and administering medication as a professor at Gießen-Friedberg University of Applied Sciences. He is a biologist and veterinarian. He has a doctorate in veterinary medicine including a specification in Radiology. He studied at the Universities of Zurich, Heidelberg and Munich. After joining the Group in 1992 as head of the pharmacokinetics laboratory, he held various R&D management positions in Germany and France. xiii

14 xiv About the Editors Franz J. Hock Since retiring from Aventis in 2002, Dr. Hock has leveraged his experience as a freelance consultant specializing in Safety Pharmacology. Dr. Hock was a research scientist at Hoechst, Hoechst Marion Roussel and Aventis from He initially worked on methods in general pharmacology and nephrology, before becoming Head of a Laboratory devoted to pharmacological methods for drugs influencing memory and learning. He was ultimately Head of Laboratory for General/Safety Pharmacology at the Frankfurt site of Aventis Pharma Deutschland GmbH. Dr. Hock received his MSc in Neurobiology from the Technical University Darmstadt and his DSc in Zoology form the University Kassel, Department of Biology, Institute of Neuroethology and Biocybernetics. He received the degree of Fachpharmakologe DGPT ("certified expert pharmacology") in In 1983 he spent a sabbatical year at the University of California, Irvine, at the Center for the Neurobiology of Learning and Memory (Director Prof. Dr. James L. McGaugh). He lectured for several years to students in Biology at the University of Kassel und the Technical University of Darmstadt. He has published over 100 original papers on methods in pharmacology and on new compounds. He is currently a member of the Task Force General/Safety Pharmacology German/ Swiss Pharmaceutical Companies. A member of several national and international scientific societies, Dr. Hock is a founding member of Safety Pharmacology Society, Neurowissenschaftliche Gesellschaft e.v. and European Behavioural Pharmacology Society. He served since several years as a member of the program Committee of the Safety Pharmacology Society. He is member of several domestic and international scientific societies.

15 About the Editors xv Dieter Mayer Dieter Mayer studied veterinary medicine at the University of Munich, Germany. Thereafter, he worked on a thesis on biochemical mechanisms of heavy metal intoxication at the Institute of Pharmacology and Toxicology at the Ludwigs-Maximilian-University of Munich. In 1975 he joined Hoechst AG Frankfurt, Germany. He worked there at the Institute of Industrial Toxicology and was in charge of the safety assessment of Acesulfam, an artificial sweetener. Further projects consisted of fluorocarbons as replacements for chlorofluoro-carbons. He contributed to the development of several pesticides. Dieter Mayer was a member of the German MAK (TLV) committee for about 12 years. He worked at the University of Davis, California and at the Centre International de Toxicologie (affiliation of Hoechst AG), Evreux, France, where he held the position of Scientific Director. In 1986 he became Head of the central toxicology department at Hoechst AG. This entailed responsibility for the entire Hoechst portfolio, and hence also for pharmaceuticals. He was involved in the successful development of antiinfectives, cardiovascular drugs, several insulins, CNS drugs and anti-rheumatics. In 1998 he was promoted to Vice President of Lead Optimization (Toxicology, DMPK and Clin. Pharmacology). Prof. Mayer has been teaching toxicology at the University of Frankfurt since 1991 and has authored more than 90 scientific articles, abstracts and oral presentations. Today Dieter Mayer is a Consultant for the global pharmaceutical industry and is a member of the Advisary Board of National German Research Associations.

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17 Contents Volume 1 Part 1 Safety Pharmacology Safety Pharmacology: Introduction... 3 Franz J. Hock 2 Status of Safety Pharmacology and Present Guidelines... 5 Franz J. Hock 3 Central Nervous System (CNS) Safety Pharmacology Studies Vincent Castagné, Christelle Froger-Colléaux, Elise Esneault, Hernier Anne Marie, Martine Lemaire, and Roger D. Porsolt 4 Methods in Cardiovascular Safety Pharmacology Pascal Champeroux, Brian D. Guth, Michael Markert, and Georg Rast 5 Renal System in Safety Pharmacology Susan G. Emeigh Hart 6 Respiratory Function Assays in Safety Pharmacology Dennis J. Murphy 7 Safety Pharmacology in Metabolism Pharmacology Andreas W. Herling 8 Peripheral Nervous System H. Gerhard Vogel 9 Safety of Intravenous and Inhalation Anesthetics Lars Arendt-Nielsen 10 Drug-Addiction and Drug-Dependency Charles P. France 11 Blood Constituents and Safety Pharmacology Shaker A. Mousa 12 Ocular Safety Tests Beat P. Mertz 13 Side Effects of Central Analgesic Drugs Lars Arendt-Nielsen xvii

18 xviii Contents 14 Endocrine Pharmacology J urgen Sandow 15 Skin Pharmacology Thais H. Sakuma, Hongbo Zhai, and Howard Maibach 16 Safety Pharmacology Assessment of Biopharmaceuticals Hamid R. Amouzadeh and Hugo M. Vargas 17 Magnetic Resonance Imaging in Pharmaceutical Safety Assessment Paul D. Hockings 18 Oncology Pharmacology Jason H. Gill 19 Transgenic Animals Will S. Redfern and Jean-Pierre Valentin 20 Zebrafish in Drug Discovery: Safety Assessment Adrian Hill 21 Chronobiology and the Implications for Safety Pharmacology Björn Lemmer and Maxim Soloviev 22 Biomaterials in Their Role in Creating New Approaches for the Delivery of Drugs, Proteins, Nucleic Acids, and Mammalian Cells Larry R. Brown 23 Nanotechnology and Safety Pharmacology A. Michael Bloh 24 Safe Chemicals/REACH Thomas R ucker 25 Study Design and Statistics S. W. Mittelstadt Volume 2 Part 2 Pharmacokinetics Safety Pharmacokinetics: Introduction Jochen Maas 27 Absorption: In Vitro Tests Cell Based Katharina Mertsch 28 Absorption: In Vitro Tests Non Cell Based Markus Kohlmann 29 Absorption: In Vivo Tests (Radiolabeled) Volker Krone

19 Contents xix 30 Bioanalytical Assays: Gas Chromatography (GC) Dietmar Schmidt 31 Bioanalytical Assays LC-MS/MS Joern Krause and Ronald Schmidt 32 Bioanalytical Assays: RIA/EIA Heinz J urgen Skrzipczyk and Patrick Verdier 33 Bioanalytical Assays Toxicokinetics Karl-Heinz Lehr 34 Distribution - In Vitro Tests - Protein Binding Jens Riedel 35 Distribution In Vivo Perfused Organs Andreas W. Herling 36 Distribution: Across Barriers Tanja Eisenblaetter, Yohannes Hagos, Saskia Flörl, and Annett K uhne 37 Distribution In Vivo Manfred Zimmer 38 Distribution In Vivo: Other Methods Yves Archimbaud 39 Drug Drug Interaction: Enzyme Induction Peter B unning 40 Drug Drug Interaction: Enzyme Inhibition Angela Dudda and Gert Ulrich Kuerzel 41 In-Silico ADME Modeling Hans Matter and Wolfgang Schmider 42 Metabolism Studies In Vitro and In Vivo Angela Dudda and Gert Ulrich Kuerzel 43 Pharmacogenomics in Drug Metabolizing Enzymes and Transporters Jochen Maas, Roland Wesch, and Dietmar Weitz 44 Physicochemical Properties Heiko Tietgen and Michael Walden 45 Clinical Pharmacokinetic Studies Axel Steinstraesser, Roland Wesch, and Annke Frick 46 Population Pharmacokinetics Willi Weber and Diether R uppel 47 Typical PK/PD Approaches in Preclinical and Clinical Development Willi Weber

20 xx Contents Part 3 Safety Toxicology Safety Toxicology: Introduction Dieter Mayer 49 International Guidelines Gerd Bode 50 Testing of Medical Devices Felix Chevalier 51 In Silico Methods Alexander Amberg 52 Genotoxicity Ingo Stammberger, Andreas Czich, and Knut Braun 53 Reproductive Toxicology Thomas Hofmann 54 In Vitro Toxicology Mostafa Kabiri 55 OMICS Technologies Christina S. Schmitt, Philip Hewitt, Mostafa Kabiri, and Alexander Amberg Index

21 List of Contributors Alexander Amberg R&D DSAR Preclinical Safety, Sanofi Deutschland GmbH, Frankfurt am Main, Germany Hamid R. Amouzadeh Toxicology Sciences, Safety and Exploratory Pharmacology, CBSS, Amgen, Inc, Thousand Oaks, CA, USA Yves Archimbaud DMPK/Preclinical CRVA-Local, Vitry-Sur-Seine, France Lars Arendt-Nielsen Center for Sensory-Motor Interaction, Department of Health Science and Technology, School of Medicine, Aalborg University, Aalborg E, Denmark A. Michael Bloh Consultant Drug Safety, Philadelphia, PA, USA Peter B unning Sanofi Deutschland GmbH, Frankfurt am Main, Germany Gerd Bode Altana AG, Hamburg, Germany Knut Braun Mainz-Kastel, Germany Larry R. Brown MIT, Cambridge, MA, USA Vincent Castagné Porsolt SAS, Boulogne-Billancourt, France Pascal Champeroux CERB, Chemin de Montifault, Baugy, France Felix Chevalier Sanofi Deutschland GmbH, Industrial Development & Innovation Frankfurt Injectables, Frankfurt am Main, Germany Andreas Czich Research & Development, Preclinical Safety, Sanofi Germany, Frankfurt am Main, Germany Angela Dudda Sanofi Deutschland GmbH, Frankfurt am Main, Germany Tanja Eisenblaetter R&D Drug Metabolims and Pharmacokinetics, Sanofi Deutschland GmbH, Frankfurt am Main, Germany Susan G. Emeigh Hart Nonclinical Drug safety, Boehringer Ingelheim Pharmaceutics, Inc, Ridgefield, CT, USA Elise Esneault Porsolt SAS, Boulogne-Billancourt, France Saskia Flörl PortaCellTec biosciences GmbH, Humboldtallee 23, Göttingen, Germany Charles P. France Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA xxi

22 xxii List of Contributors Annke Frick Sanofi Deutschland GmbH, Frankfurt am Main, Germany Christelle Froger-Colléaux Porsolt SAS, Boulogne-Billancourt, France Jason H. Gill Wolfson Research Institute, Durham University, Thornaby-on Tees, County Durham, United Kingdom Brian D. Guth Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany Yohannes Hagos Department of Vegetative Physiology and Pathology, Georg-August University, Göttingen, Germany Andreas W. Herling Sanofi Deutschland GmbH, Frankfurt am Main, Germany Hernier Anne Marie Porsolt SAS, Boulogne-Billancourt, France Philip Hewitt Merck Darmstadt KG, Institut f ur Toxikologie, Darmstadt, Germany Adrian Hill Business Engagement & Innovation Services, University of Nottingham, Nottingham, United Kingdom Franz J. Hock Business Development Consultant, CorDynamics, Dieburg, Germany Paul D. Hockings PHB Imaging AstraZeneca, Mölndal, Sweden Thomas Hofmann Experimental Toxicology and Ecology, GV/TE, BASF SE, Ludwigshafen, Germany Mostafa Kabiri Sanofi Pharma Deutschland GmbH, A company of the Sanofi-Aventis Group DSE, Hattersheim, Germany Annett K uhne PortaCellTec biosciences GmbH, Humboldtallee 23, Göttingen, Germany Markus Kohlmann Sanofi Deutschland GmbH, Frankfurt am Main, Germany Joern Krause Sanofi Deutschland GmbH, Frankfurt am Main, Germany Volker Krone DI & A DMPK, Sanofi Pharma Deutschland GmbH, Frankfurt, Germany Gert Ulrich Kuerzel Sanofi Deutschland GmbH, Frankfurt am Main, Germany Karl-Heinz Lehr Frankfurt, Germany Martine Lemaire Porsolt SAS, Boulogne-Billancourt, France Björn Lemmer Institute of Experimental and Clinical Pharmacology and Toxicology, University of Heidelberg, Mannheim, Germany Jochen Maas R&D Diabetes Division Leitung R&D FF Industriepark Höchst, Sanofi Deutschland GmbH, Frankfurt am Main, Germany Howard Maibach Department of Dermatology, UC San Francisco, San Francisco, CA, USA Michael Markert Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany

23 List of Contributors xxiii Hans Matter R&D, Lead Generation and Candidate Realization, Sanofi Deutschland GmbH, Frankfurt am Main, Germany Dieter Mayer Idstein, Germany Katharina Mertsch Sanofi Deutschland GmbH, Frankfurt am Main, Germany Beat P. Mertz SD Pharma Solutions Inc., Victoria, BC, Canada S. W. Mittelstadt Departments of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA Shaker A. Mousa The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA Dennis J. Murphy Department of Safety Pharmacology, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, USA Roger D. Porsolt Porsolt SAS, Boulogne-Billancourt, France Georg Rast Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany Thomas R ucker ENVIRON Germany GmbH, Germany Will S. Redfern Safety Pharmacology Department, Global Safety Assessment, AstraZeneca R&D, Cheshire, United Kingdom Jens Riedel Sanofi Deutschland GmbH, Frankfurt am Main, Germany Diether R uppel Sanofi Pharma Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany Thais H. Sakuma Department of Dermatology, UC San Francisco, San Francisco, CA, USA J urgen Sandow Frankfurt-Main University, Centre of Pharmacology, Germany Wolfgang Schmider R&D, Disposition, Safety and Animal Research, Sanofi Deutschland GmbH, Frankfurt am Main, Germany Ronald Schmidt Sanofi Deutschland GmbH, R&D DSAR / Drug Disposition FF, Industriepark Höchst, Frankfurt am Main, Germany Dietmar Schmidt DI & A DMPK, Sanofi Pharma Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany Christina S. Schmitt Heinz J urgen Skrzipczyk Global Metabolism and Pharmacokinetics, Sanofi Pharma Deutschland GmbH, Frankfurt, Germany Maxim Soloviev Incyte Corporation, Wilmington, DE, USA Ingo Stammberger Dr. Stammberger - Toxicological Consulting Services, Hattersheim am Main, Germany Axel Steinstraesser Sanofi Deutschland GmbH, Frankfurt am Main, Germany Heiko Tietgen Sanofi Deutschland GmbH, Frankfurt am Main, Germany

24 xxiv List of Contributors Jean-Pierre Valentin Safety Pharmacology Department, Global Safety Assessment, AstraZeneca R&D, Cheshire, United Kingdom Hugo M. Vargas Toxicology Sciences, Safety and Exploratory Pharmacology, CBSS, Amgen, Inc, Thousand Oaks, CA, USA Patrick Verdier DMPK Bioanalysis France, Sanofi-Aventis Group, Vitry-sur-Seine, France H. Gerhard Vogel * Michael Walden Sanofi Deutschland GmbH, Frankfurt am Main, Germany Willi Weber Sanofi Pharma Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany Dietmar Weitz Sanofi Deutschland GmbH, Frankfurt am Main, Germany Roland Wesch Sanofi Deutschland GmbH, Frankfurt am Main, Germany Hongbo Zhai Department of Dermatology, UC San Francisco, San Francisco, CA, USA Manfred Zimmer DI & A DMPK, Sanofi Pharma Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany * Deceased