Early Drug Development

Contents to Volume 1

Preface xv

A Personal Foreword xix

1 Early Drug Development: Progressing a Candidate Compound to the Clinics 1
Fabrizio Giordanetto

References 7

Part I Drug Substance 9

2 Early Phase API Process Development Overview 11
J. Christopher McWilliams and Mark Guinn

3 The Discovery/Development Transition 31
Christopher M. Cimarusti and David R. Kronenthal

4 Active Pharmaceutical Ingredient Cost of Goods: Discovery to Early Development 49
Neal G. Anderson and Todd D. Nelson

5 New Technologies in Process Development 73
Peter W. Sutton, Joseph P. Adams, Charles Wade, and Katherine Wheelhouse

6 Vortioxetine and Early Drug Development Considerations at the Interface of R&D 125
Morten Jorgensen, Kim Christensen, Martin Juhl, and Benny Bang-Andersen

7 Development of a Practical Synthesis of 4'-Azido-2'-Methyl-2'-Desoxycytosine and Its Prodrugs as HCV Chemotherapeutic Agents 145
Sebastien Lemaire, Tom Govaerts, and Vittorio Farina

Part II Drug Product 169

8 Solubility, Permeability, and Their Interplay 171
Avital Beig, Milica Markovic, and Arik Dahan

9 Solid-State Properties 203
Si-Wei Zhang, Robert F. Dunn, and Alfred Y. Lee

10 Salt and Cocrystal Screening 229
Ann Newman, Cen Chen, and Carlos Sanrame

11 Particle Size Reduction: From Microsizing to Nanosizing 271
Dedong Wu and Beth A. Sarsfield

12 Early Drug Development: From a Drug Candidate to the Clinic 305
Mark McAllister, Joanne Bennett, John Davis, Brian Henry, and MeiWong

13 A Practical Guide for the Preparation of Drug Nanosuspensions for Preclinical Studies: Including In Vivo Case Studies 333
Kalle Sigfridsson, Urban Skantze, Pia Skantze, and Lennart Lindfors

Contents to Volume 2

A Personal Foreword xxiii

Part III Pharmacokinetics and Pharmacodynamics 365

14 Integration of Pharmacokinetic and Pharmacodynamic Reasoning and Its Importance in Drug Discovery 367
Johan Gabrielsson and Stephan Hjorth

15 Prediction of Human Pharmacokinetics and Pharmacodynamics 399
Ulf Bredberg

16 Translational Modeling and Simulation for Molecularly Targeted Small Molecule Anticancer Agents: Case Studies of Multiple Tyrosine Kinase Inhibitors, Crizotinib and Lorlatinib 433
Shinji Yamazaki

17 Informing Decisions in Discovery and Early Development Research Through Quantitative and Translational Modeling 467
Tjerk Bueters, Christopher R. Gibson, Prajakti A. Kothare,Mallika Lala, Eric M. Parker,Matthew L. Rizk, Daniel Tatosian, Maria E. Trujillo, Pavan Vaddady, and Sandra A.G. Visser

Contents to Volume 2

Part IV Toxicology 497

18 Preclinical Toxicology Evaluation 499
Sara Moses, Ulf Andersson, and Martin Billger

19 Nonclinical Safety Pharmacology 527
Bruce H. Morimoto

20 Early Drug Development 549
Luis G. Valerio Jr.

21 Addressing Genotoxicity Risk in Lead Optimization: A PDE10A Inhibitor Case Study 581
Bie M. P. Verbist, Marjolein Crabbe, Freddy Van Goethem, and Hinrich W. H. Gohlmann

22 The Integrated Optimization of Safety and DMPK Properties Enabling Preclinical Development: A Case History with S1P1 Agonists 603
Simon Taylor

23 From TRAIL to ONC201: Case Study on the Safety Benefit of Developing Targeted Agents Against Cancer-selective Pathways 631
Christina Leah B. Kline, JessicaWagner, Amriti Lulla,Marie D. Ralff, Avital Lev, Lanlan Zhou, Varun V. Prabhu, Martin Stogniew, Lee Schalop,Wolfgang Oster, Joshua E. Allen, andWafik S. El-Deiry

Part V Intellectural Property 647

24 Patent Law Relevant to Early Drug Development 649
Joanna T. Brougher Esq.,MPH and Audrey Ogurchak

25 Patent Protection Strategy 667
Mark A. Borsos

26 Intellectual Property: The Patent Landscape Viewed from Generic and Originator Perspectives 691
Jonathan D.M. Atkinson D.Phil; EPA; C Chem. FRSC

27 Patent Considerations in Collaborative Drug Development 721
Mary Anne Armstrong

Index 749