Jianling Wang is the Cambridge Head of Discovery ADME at Novartis Institutes for BioMedical Research. He has published over 40 journal papers, reviews, and book chapters and lectured at over 30 scientific conferences and courses.Laszlo Urban is the Executive Director for Preclinical Safety Profiling at Novartis Institutes for BioMedical Research. He has over 10 years of experience in academia and 20 years in the pharmaceutical industry. Among Dr. Urban’s publications are over 120 peer-reviewed scientific papers, 3 books including Hit and Lead Profiling: Identification and Optimization of Drug-like Molecules (Wiley, 2009).

“In conclusion, this volume fulfills its promise of being a very useful tool for guidance and diagnosis on ADMET matters, and I would recommend it to any scientist in the field.”  (ChemMedChem, 1 June 2015)

• Preface ixContributors xiI Introduction to the Current Scientific, Clinical, and Social Environment of Drug Discovery and Development1 Current Social, Clinical, and Scientific Environment of Pharmaceutical R&D 3Laszlo Urban, Jean-Pierre Valentin, Kenneth I Kaitin, and Jianling Wang2 Polypharmacology and Adverse Bioactivity Profiles Predict Potential Toxicity and Drug-related ADRs 23Teresa Kaserer, Veronika Temml, and Daniela SchusterII Intelligent Integration and Extrapolation of Admet Data3 ADMET Diagnosis Models 49Bernard Faller, Suzanne Skolnik, and Jianling Wang4 PATH (Probe ADME and Test Hypotheses): A Useful Approach Enabling Hypothesis-driven ADME Optimization 63Leslie Bell, Suzanne Skolnik, and Dallas Bednarczyk5 PK-MATRIX—A Permeability: Intrinsic Clearance System for Prediction, Classification, and Profiling of Pharmacokinetics and Drug–drug Interactions 89Urban Fagerholm6 Maximizing the Power of a Local Model for ADMET-property Prediction 103Sebastien Ronseaux, Jeremy Beck, and Clayton Springer7 Chemoinformatic and Chemogenomic Approach to ADMET 125Virginie Y. Martiny, Ilza Pajeva, Michael Wiese, Andrew M. Davis, and Maria A. Miteva8 Multiparameter Optimization of ADMET for Drug Design 145Matthew D. Segall and Edmund J. Champness9 PBPK: Integrating In Vitro and In Silico Data in Physiologically Based Models 167Hannah M. Jones and Neil Parrott10 Emerging Full Mechanistic Physiologically Based Modeling 189Kiyohiko Sugano11 Pharmacokinetic/Pharmacodynamic Modeling in Drug Discovery: A Translational Tool to Optimize Discovery Compounds Toward the Ideal Target-specific Profile 211Patricia SchroederIII Assessment and Mitigation of Critical Clinically Relevant Admet Risks in Drug Discovery and Development12 In Vitro–In Silico Tools to Predict Pharmacokinetics of Poorly Soluble Drug Compounds 235Christian Wagner and Jennifer B. Dressman13 Evaluation of the Collective Impact of Passive Permeability and Active Transport on In Vivo Blood-brain Barrier and Gastrointestinal Drug Absorption 263Donna A. Volpe, Hong Shen, and Praveen V. Balimane14 Integrated Assessment of Drug Clearance and Cross-Species Scalability 291Kevin Beaumont, James R. Gosset, and Chris E. Keefer15 Practical Anticipation of Human Efficacious Doses and Pharmacokinetics using Preclinical In Vitro and In Vivo Data 319Tycho Heimbach, Rakesh Gollen, and Handan He16 Management and Mitigation of Human Drug–drug Interaction Risks in the Drug Discovery and Development Phases 353Heidi J. Einolf and Imad Hanna17 Integrated Assessment and Clinical Translation of In Vitro Off-target Safety Pharmacology Risks 397Patrick Y. Muller and Christian F. Trendelenburg18 Integrated Risk Assessment of Cardiovascular Safety in Drug Discovery 407Gül Erdemli and Ruth L. Martin19 Drug-induced Hepatotoxicity: Advances in Preclinical Predictive Strategies and Tools 433Donna M. Dambach20 Carcinogenicity and Teratogenicity Assessment 467Hans-Jörg Martus, David Beckman, and Lutz Mueller21 Nephrotoxicity: Development of Biomarkers for Preclinical and Clinical Application 491Frank Dieterle and Estelle MarrerIV Success Stories and Lessons Learned22 Early Intervention with Formulation Strategies for Multidimensional Problems to Optimize for Success 507Stephanie Dodd, Christina Capacci-Daniel, Christopher Towler, Riccardo Panicucci, and Keith Hoffmaster23 Cytochrome P450-mediated Drug Interaction and Cardiovascular Safety: The Seldane to Allegra Transformation 523F. Peter Guengerich24 Clinical Toxicity Profile of VEGF Inhibitors 535Mark P. S. Sie and Ferry A. L. M. Eskens25 Cardiomyopathy: Drug Induced and Predisposed 555Shirley A. Aguirre and Eileen R. Blasi26 Safety Management by Pharmacokinetic Considerations: Ranibizumab (Lucentis) and Bevacizumab (Avastin) 569Nicole H. Siegel and Manju L. SubramanianIndex 583

Jianling Wang is the Cambridge Head of Discovery ADME at Novartis Institutes for BioMedical Research. He has published over 40 journal papers, reviews, and book chapters and lectured at over 30 scientific conferences and courses.Laszlo Urban is the Executive Director for Preclinical Safety Profiling at Novartis Institutes for BioMedical Research. He has over 10 years of experience in academia and 20 years in the pharmaceutical industry. Among Dr. Urban’s publications are over 120 peer-reviewed scientific papers, 3 books including Hit and Lead Profiling: Identification and Optimization of Drug-like Molecules (Wiley, 2009).

“In conclusion, this volume fulfills its promise of being a very useful tool for guidance and diagnosis on ADMET matters, and I would recommend it to any scientist in the field.”  (ChemMedChem, 1 June 2015)

• Preface ixContributors xiI Introduction to the Current Scientific, Clinical, and Social Environment of Drug Discovery and Development1 Current Social, Clinical, and Scientific Environment of Pharmaceutical R&D 3Laszlo Urban, Jean-Pierre Valentin, Kenneth I Kaitin, and Jianling Wang2 Polypharmacology and Adverse Bioactivity Profiles Predict Potential Toxicity and Drug-related ADRs 23Teresa Kaserer, Veronika Temml, and Daniela SchusterII Intelligent Integration and Extrapolation of Admet Data3 ADMET Diagnosis Models 49Bernard Faller, Suzanne Skolnik, and Jianling Wang4 PATH (Probe ADME and Test Hypotheses): A Useful Approach Enabling Hypothesis-driven ADME Optimization 63Leslie Bell, Suzanne Skolnik, and Dallas Bednarczyk5 PK-MATRIX—A Permeability: Intrinsic Clearance System for Prediction, Classification, and Profiling of Pharmacokinetics and Drug–drug Interactions 89Urban Fagerholm6 Maximizing the Power of a Local Model for ADMET-property Prediction 103Sebastien Ronseaux, Jeremy Beck, and Clayton Springer7 Chemoinformatic and Chemogenomic Approach to ADMET 125Virginie Y. Martiny, Ilza Pajeva, Michael Wiese, Andrew M. Davis, and Maria A. Miteva8 Multiparameter Optimization of ADMET for Drug Design 145Matthew D. Segall and Edmund J. Champness9 PBPK: Integrating In Vitro and In Silico Data in Physiologically Based Models 167Hannah M. Jones and Neil Parrott10 Emerging Full Mechanistic Physiologically Based Modeling 189Kiyohiko Sugano11 Pharmacokinetic/Pharmacodynamic Modeling in Drug Discovery: A Translational Tool to Optimize Discovery Compounds Toward the Ideal Target-specific Profile 211Patricia SchroederIII Assessment and Mitigation of Critical Clinically Relevant Admet Risks in Drug Discovery and Development12 In Vitro–In Silico Tools to Predict Pharmacokinetics of Poorly Soluble Drug Compounds 235Christian Wagner and Jennifer B. Dressman13 Evaluation of the Collective Impact of Passive Permeability and Active Transport on In Vivo Blood-brain Barrier and Gastrointestinal Drug Absorption 263Donna A. Volpe, Hong Shen, and Praveen V. Balimane14 Integrated Assessment of Drug Clearance and Cross-Species Scalability 291Kevin Beaumont, James R. Gosset, and Chris E. Keefer15 Practical Anticipation of Human Efficacious Doses and Pharmacokinetics using Preclinical In Vitro and In Vivo Data 319Tycho Heimbach, Rakesh Gollen, and Handan He16 Management and Mitigation of Human Drug–drug Interaction Risks in the Drug Discovery and Development Phases 353Heidi J. Einolf and Imad Hanna17 Integrated Assessment and Clinical Translation of In Vitro Off-target Safety Pharmacology Risks 397Patrick Y. Muller and Christian F. Trendelenburg18 Integrated Risk Assessment of Cardiovascular Safety in Drug Discovery 407Gül Erdemli and Ruth L. Martin19 Drug-induced Hepatotoxicity: Advances in Preclinical Predictive Strategies and Tools 433Donna M. Dambach20 Carcinogenicity and Teratogenicity Assessment 467Hans-Jörg Martus, David Beckman, and Lutz Mueller21 Nephrotoxicity: Development of Biomarkers for Preclinical and Clinical Application 491Frank Dieterle and Estelle MarrerIV Success Stories and Lessons Learned22 Early Intervention with Formulation Strategies for Multidimensional Problems to Optimize for Success 507Stephanie Dodd, Christina Capacci-Daniel, Christopher Towler, Riccardo Panicucci, and Keith Hoffmaster23 Cytochrome P450-mediated Drug Interaction and Cardiovascular Safety: The Seldane to Allegra Transformation 523F. Peter Guengerich24 Clinical Toxicity Profile of VEGF Inhibitors 535Mark P. S. Sie and Ferry A. L. M. Eskens25 Cardiomyopathy: Drug Induced and Predisposed 555Shirley A. Aguirre and Eileen R. Blasi26 Safety Management by Pharmacokinetic Considerations: Ranibizumab (Lucentis) and Bevacizumab (Avastin) 569Nicole H. Siegel and Manju L. SubramanianIndex 583

Jianling Wang is the Cambridge Head of Discovery ADME at Novartis Institutes for BioMedical Research. He has published over 40 journal papers, reviews, and book chapters and lectured at over 30 scientific conferences and courses.Laszlo Urban is the Executive Director for Preclinical Safety Profiling at Novartis Institutes for BioMedical Research. He has over 10 years of experience in academia and 20 years in the pharmaceutical industry. Among Dr. Urban’s publications are over 120 peer-reviewed scientific papers, 3 books including Hit and Lead Profiling: Identification and Optimization of Drug-like Molecules (Wiley, 2009).

“In conclusion, this volume fulfills its promise of being a very useful tool for guidance and diagnosis on ADMET matters, and I would recommend it to any scientist in the field.”  (ChemMedChem, 1 June 2015)

• Preface ixContributors xiI Introduction to the Current Scientific, Clinical, and Social Environment of Drug Discovery and Development1 Current Social, Clinical, and Scientific Environment of Pharmaceutical R&D 3Laszlo Urban, Jean-Pierre Valentin, Kenneth I Kaitin, and Jianling Wang2 Polypharmacology and Adverse Bioactivity Profiles Predict Potential Toxicity and Drug-related ADRs 23Teresa Kaserer, Veronika Temml, and Daniela SchusterII Intelligent Integration and Extrapolation of Admet Data3 ADMET Diagnosis Models 49Bernard Faller, Suzanne Skolnik, and Jianling Wang4 PATH (Probe ADME and Test Hypotheses): A Useful Approach Enabling Hypothesis-driven ADME Optimization 63Leslie Bell, Suzanne Skolnik, and Dallas Bednarczyk5 PK-MATRIX—A Permeability: Intrinsic Clearance System for Prediction, Classification, and Profiling of Pharmacokinetics and Drug–drug Interactions 89Urban Fagerholm6 Maximizing the Power of a Local Model for ADMET-property Prediction 103Sebastien Ronseaux, Jeremy Beck, and Clayton Springer7 Chemoinformatic and Chemogenomic Approach to ADMET 125Virginie Y. Martiny, Ilza Pajeva, Michael Wiese, Andrew M. Davis, and Maria A. Miteva8 Multiparameter Optimization of ADMET for Drug Design 145Matthew D. Segall and Edmund J. Champness9 PBPK: Integrating In Vitro and In Silico Data in Physiologically Based Models 167Hannah M. Jones and Neil Parrott10 Emerging Full Mechanistic Physiologically Based Modeling 189Kiyohiko Sugano11 Pharmacokinetic/Pharmacodynamic Modeling in Drug Discovery: A Translational Tool to Optimize Discovery Compounds Toward the Ideal Target-specific Profile 211Patricia SchroederIII Assessment and Mitigation of Critical Clinically Relevant Admet Risks in Drug Discovery and Development12 In Vitro–In Silico Tools to Predict Pharmacokinetics of Poorly Soluble Drug Compounds 235Christian Wagner and Jennifer B. Dressman13 Evaluation of the Collective Impact of Passive Permeability and Active Transport on In Vivo Blood-brain Barrier and Gastrointestinal Drug Absorption 263Donna A. Volpe, Hong Shen, and Praveen V. Balimane14 Integrated Assessment of Drug Clearance and Cross-Species Scalability 291Kevin Beaumont, James R. Gosset, and Chris E. Keefer15 Practical Anticipation of Human Efficacious Doses and Pharmacokinetics using Preclinical In Vitro and In Vivo Data 319Tycho Heimbach, Rakesh Gollen, and Handan He16 Management and Mitigation of Human Drug–drug Interaction Risks in the Drug Discovery and Development Phases 353Heidi J. Einolf and Imad Hanna17 Integrated Assessment and Clinical Translation of In Vitro Off-target Safety Pharmacology Risks 397Patrick Y. Muller and Christian F. Trendelenburg18 Integrated Risk Assessment of Cardiovascular Safety in Drug Discovery 407Gül Erdemli and Ruth L. Martin19 Drug-induced Hepatotoxicity: Advances in Preclinical Predictive Strategies and Tools 433Donna M. Dambach20 Carcinogenicity and Teratogenicity Assessment 467Hans-Jörg Martus, David Beckman, and Lutz Mueller21 Nephrotoxicity: Development of Biomarkers for Preclinical and Clinical Application 491Frank Dieterle and Estelle MarrerIV Success Stories and Lessons Learned22 Early Intervention with Formulation Strategies for Multidimensional Problems to Optimize for Success 507Stephanie Dodd, Christina Capacci-Daniel, Christopher Towler, Riccardo Panicucci, and Keith Hoffmaster23 Cytochrome P450-mediated Drug Interaction and Cardiovascular Safety: The Seldane to Allegra Transformation 523F. Peter Guengerich24 Clinical Toxicity Profile of VEGF Inhibitors 535Mark P. S. Sie and Ferry A. L. M. Eskens25 Cardiomyopathy: Drug Induced and Predisposed 555Shirley A. Aguirre and Eileen R. Blasi26 Safety Management by Pharmacokinetic Considerations: Ranibizumab (Lucentis) and Bevacizumab (Avastin) 569Nicole H. Siegel and Manju L. SubramanianIndex 583