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 Falle, 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 Translationai 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-ln 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
Gül 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-Jörg Martus, David Bechnan, 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
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