Preface v

1. Strategic Use of Preclinical Pharmacokinetic Studies and In Vitro

Models in Optimizing ADME Properties of Lead Compounds

Dhiren R. Thakker 1

2. Role of Mechanistic Transport Studies in Lead Optimization

Jerome Hochman, Qin Mei, Masayo Yamazaki, Cuyue Tang, Thomayant Prueksaritanont, Mark Bock, Sookhee Ha and Jiunn Lin 25

3. Metabolic Activation-Role in Toxicity and Idiosyncratic


John S. Walsh 49

4. Case History - Use of ADME Studies for Optimization of Drug Candidates

Liang-Shang Gan, Frank W. Lee, Nelamangala Nagaraja, Ping Li, Jason Labutti, Wei Yin, Cindy Xia, Hua Yang, Vinita Uttamsingh, Chuang Lu, Sandeepraj Pusalkar, J. Scott Daniels, Ron Huang, Mark Qian, Jing-Tao Wu, Kym Cardoza, Suresh K. Balani, and Gerald T. Miwa 81

5. Solubility, Solubilization and Dissolution in Drug Delivery

During Lead Optimization

Michael J. Hageman 99

6. Lipid-based Systems, Drug Exposure and Lead Optimization

William N. Charman, Susan A. Charman and Christopher J. H. Porter 131

7. Biopharmaceutics Modeling and the Role of Dose and Formulation on Oral Exposure

Brian R. Rohrs, Ph.D 151

8. Application of Physicochemical Data to Support Lead

Optimization by Discovery Teams

Li Di and Edward H. Kerns 167

9. Computational Models Supporting Lead Optimization in Drug Discovery

Philip S. Burton, Italo Poggesi, Massimiliano Germani and Jay T. Goodwin 195

10. Prodrug Strategies for Improving Drug-Like Properties

Valentino J. Stella 221

11. The Application of Multivariate Data Analysis to Compound Property Optimization

John W. Ellingboe 243

12. Case History: Toxicology Biomarker Development Using Toxicogenomics

David E. Watson, Timothy P. Ryan and James L. Stevens 255

13. Predicting Idiosyncratic Drug Reactions

Alastair Cribb, DVM PhD 271

14. Elementary Predictive Toxicology for Advanced Applications

Constantine Kreatsoulas, Stephen K. Durham, Laura L. Custer and Greg M. Pearl 301

15. The Application of PK/PD Modeling and Simulations During Lead Optimization

Stuart Friedrich, Ph.D., Evelyn Lobo, Ph.D., Karen Zimmerman, Anthony Borel, Ph.D. and Carlos O. Garner, Ph.D 323

16. Early Preclinical Evaluation of Brain Exposure in Support of Hit Identification and Lead Optimization

Thomas J. Raub, Barry S. Lutzke, Paula K. Andrus

Geri A. Sawada and Brian A. Staton 355

17. Optimizing Biomarker Development for Clinical Studies at the Lead Optimization Stage of Drug Development

Geoffrey S Ginsburg, Julie Lekstrom-Himes and William Trepicchio 411

18. The Relevance of Transporters in Determining Drug Disposition

Hartmut Glaeser, Ph.D. and Richard B. Kim, M.D 423

Index 461

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