Predictive ADMET: Integrated Approaches in Drug Discovery and Development

This book helps readers integrate  in silico, in vitro , and  in vivo  ADMET (absorption, distribution, metabolism, elimination and toxicity) and PK (pharmacokinetics) data with routine testing applications so that pharmaceutical scientists can diagnose ADMET problems and present appropriate recommendations to move drug discovery programs forward. The book introduces the current clinical practice for drug discovery and development along with the impact on early risk assessment; consolidates the tools and models to intelligently integrate existing  in silico, in vitro  and  in vivo  ADMET data; and demonstrates successful cases and lessons learned from real drug discovery and development. In short, it is a book aimed to provide a practical road map for drug discovery and development scientists to generate efficacious and safe drugs for unmet medical needs.

PREFACE ix CONTRIBUTORS xi I INTRODUCTION TO THE CURRENT SCIENTIFIC, CLINICAL, AND SOCIAL ENVIRONMENT OF DRUG DISCOVERY AND DEVELOPMENT 1 Current Social, Clinical, and Scientific Environment of Pharmaceutical R&D 3 Laszlo Urban, Jean–Pierre Valentin, Kenneth I Kaitin, and Jianling Wang 2 Polypharmacology and Adverse Bioactivity Profiles Predict Potential Toxicity and Drug–related ADRs 23 Teresa Kaserer, Veronika Temml, and Daniela Schuster II INTELLIGENT INTEGRATION AND EXTRAPOLATION OF ADMET DATA 3 ADMET Diagnosis Models 49 Bernard Faller, Suzanne Skolnik, and Jianling Wang 4 PATH (Probe ADME and Test Hypotheses): A Useful Approach Enabling Hypothesis–driven ADME Optimization 63 Leslie Bell, Suzanne Skolnik, and Dallas Bednarczyk 5 PK–MATRIX—A Permeability: Intrinsic Clearance System for Prediction, Classification, and Profiling of Pharmacokinetics and Drug–drug Interactions 89 Urban Fagerholm 6 Maximizing the Power of a Local Model for ADMET–property Prediction 103 Sebastien Ronseaux, Jeremy Beck, and Clayton Springer 7 Chemoinformatic and Chemogenomic Approach to ADMET 125 Virginie Y. Martiny, Ilza Pajeva, Michael Wiese, Andrew M. Davis, and Maria A. Miteva 8 Multiparameter Optimization of ADMET for Drug Design 145 Matthew D. Segall and Edmund J. Champness 9 PBPK: Integrating In Vitro and In Silico Data in Physiologically Based Models 167 Hannah M. Jones and Neil Parrott 10 Emerging Full Mechanistic Physiologically Based Modeling 189 Kiyohiko Sugano 11 Pharmacokinetic/Pharmacodynamic Modeling in Drug Discovery: A Translational Tool to Optimize Discovery Compounds Toward the Ideal Target–specific Profile 211 Patricia Schroeder III ASSESSMENT AND MITIGATION OF CRITICAL CLINICALLY RELEVANT ADMET RISKS IN DRUG DISCOVERY AND DEVELOPMENT 12 In Vitro–In Silico Tools to Predict Pharmacokinetics of Poorly Soluble Drug Compounds 235 Christian Wagner and Jennifer B. Dressman 13 Evaluation of the Collective Impact of Passive Permeability and Active Transport on In Vivo Blood–brain Barrier and Gastrointestinal Drug Absorption 263 Donna A. Volpe, Hong Shen, and Praveen V. Balimane 14 Integrated Assessment of Drug Clearance and Cross–Species Scalability 291 Kevin Beaumont, James R. Gosset, and Chris E. Keefer 15 Practical Anticipation of Human Efficacious Doses and Pharmacokinetics using Preclinical In Vitro and In Vivo Data 319 Tycho Heimbach, Rakesh Gollen, and Handan He 16 Management and Mitigation of Human Drug–drug Interaction Risks in the Drug Discovery and Development Phases 353 Heidi J. Einolf and Imad Hanna 17 Integrated Assessment and Clinical Translation of In Vitro Off–target Safety Pharmacology Risks 397 Patrick Y. Muller and Christian F. Trendelenburg 18 Integrated Risk Assessment of Cardiovascular Safety in Drug Discovery 407 G¨ul Erdemli and Ruth L. Martin 19 Drug–induced Hepatotoxicity: Advances in Preclinical Predictive Strategies and Tools 433 Donna M. Dambach 20 Carcinogenicity and Teratogenicity Assessment 467 Hans–J¨org Martus, David Beckman, and Lutz Mueller 21 Nephrotoxicity: Development of Biomarkers for Preclinical and Clinical Application 491 Frank Dieterle and Estelle Marrer IV SUCCESS STORIES AND LESSONS LEARNED 22 Early Intervention with Formulation Strategies for Multidimensional Problems to Optimize for Success 507 Stephanie Dodd, Christina Capacci–Daniel, Christopher Towler, Riccardo Panicucci, and Keith Hoffmaster 23 Cytochrome P450–mediated Drug Interaction and Cardiovascular Safety: The Seldane to Allegra Transformation 523 F. Peter Guengerich 24 Clinical Toxicity Profile of VEGF Inhibitors 535 Mark P. S. Sie and Ferry A. L. M. Eskens 25 Cardiomyopathy: Drug Induced and Predisposed 555 Shirley A. Aguirre and Eileen R. Blasi 26 Safety Management by Pharmacokinetic Considerations: Ranibizumab (Lucentis) and Bevacizumab (Avastin) 569 Nicole H. Siegel and Manju L. Subramanian INDEX 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).