Drug Discovery Toxicology: From Target Assessment to Translational Biomarkers

Description

Developing novel pharmaceuticals requires nonclinical safety studies on candidate drugs to assess general toxicology (through in vivo experiments), safety pharmacology (effects on major organ systems), and genetic toxicity tests. These data provide risk assessment data that supports progression of candidate drugs from discovery phase through clinical development, to regulatory submission and registration. Traditionally, however, less emphasis was placed on the evaluation of safety issues for projects while still in the drug design phase.

In response to this costly attrition, many pharmaceutical companies invested in drug discovery toxicology or drug discovery safety to identify hazards and take steps to design out or significantly reduce undesirable safety liabilities earlier; with the ultimate aim of enhancing the probability of success in non–clinical and clinical drug development. Because of this, there is a strong need for personnel involved with toxicology and pharmacology studies need to understand the varied tools and approaches to perform early drug discovery safety analysis.

Drug Discovery Toxicology: From Target Assessment to Translational Biomarkers serves as a valuable tool for those discovery scientists. The authors, writing from firsthand industry experience, give readers insight into the strategy and execution of predictive toxicology practices, including what experiments are possible and useful. In addition, they offer a view into the future, indicating key areas to watch for new predictive methods. Broken into different sections, the book deals with the key topics Safety Lead Optimization Strategies, In Vitro–In Vivo Pharmacokinetics Translation, Predicting Organ Toxicity In Vitro, False Negative Space, ––Omics in Predictive Toxicology, Translational Biomarkers, and Signal Investigation Rationale and Practices.

As a guide for pharmaceutical professionals to the issues and practices of drug discovery toxicology, this book integrates and reviews the strategy and application of tools and methods throughout the pre–clinical drug discovery development process.

Contents

PREFACE
Eric Blomme

PART I. INTRODUCTION

1. EMERGING TECHNOLOGIES AND THEIR ROLE IN REGULATORY REVIEW

Thomas Colatsky

PART II. SAFETY LEAD OPTIMIZATION STRATEGIES

2. Small Molecule Safety Lead Optimization

Donna Dambach

3. Safety Assessment Strategies and Predictive Safety of Biopharmacueticals and Antibody Drug Conjugates

Michelle Horner, Mary–Jane Hinrichs, Nicholas Buss

4. Discovery and Development Strategies for Small Interfering RNAs

Scott Barros, Gregory Hinkle

PART III. BASIS FOR IN VITRO – IN VIVO PK TRANSLATION

5. Physicochemistry and the off target effects of drug molecules

Dennis Smith

6. The need for exposure projection in the interpretation of preclinical in vitro and in vivo ADME tox data

Patrick Poulin

7. ADME properties leading to toxicity

Katya Tsaioun

PART IV. PREDICTING ORGAN TOXICITY

8. Liver

Gerry Kenna, Mikael Persson, Scott Siler, Ke Yu, Weida Tong, Joshua Xu, Minjun Chen, Chuchu Hu, Yvonne Will, Mike Aleo

9. Cardiac

David Gallacher, Robert Hamlin, Gary Gintant, Hugo Vargas, Kimberly Hoagland, Najah Abi–Gergis, HR Lu

10. Predictive In Vitro Models for Assessment of Nephrotoxicity and Drug–Drug Interactions in Vitro

Lawrence Lash

11. Predicting organ toxicity in vitro: Bone marrow

Ivan Rich, Andrew Olaharski 

12. Predicting Organ Toxicity In Vitro: Dermal Toxicity
Patrick Hayden, Michael Bachelor  

13. In Vitro Methods in Immunotoxicity Assessment
Xu Zhu, Ellen Evans

14. Strategies and assays for minimizing risk of ocular toxicity during early development of systemically administered drugs

Chris Somps, Jay Forner, Kerri Cannon, Wenhu Huang, Paul Butler
  
15. Predicting organ toxicity in vitro – Central Nervous System

Greet Teuns, Alison Easter 

16. Biomarkers, Cell Models and In Vitro Assays for Gastrointestinal Toxicology
Gina Yanochko, Allison Vitsky 

17. Preclinical Safety assessment of Drug Candidate–Induced pancreatic toxicity
Karrie Brenneman, Shashi Ramaiah, Lauren Gauthier    

PART V. ADDRESSING THE FALSE NEGATIVE SPACE– INCREASING PREDICTIVITY 

18. Animal models of disease for future toxicity predictions

Sherry Morgan and Chandikumar Elangbam 

19. The Use of Genetically–Modified Animals in Discovery Toxicology
Dolores Diaz and Jonathan Maher  

20. Addressing the False Negative Space– Increasing Predictivity
Allison Harrill, Ted Choi  

PART VI. STEM CELLS IN TOXICOLOGY  

21. Application of pluripotent stem cells in drug–induced liver injury safety assessment
Chris S. Pridgeon, Fang Zhang, James A. Heslop, Charlotte M.L. Nugues, Neil R. Kitteringham, B. Kevin Park, Chris E.P. Goldring  

22. Human pluripotent stem cell–derived cardiomyocytes

Praveen Shukla, Priyanka Garg, Joseph Wu  

23 Stem cell–derived renal cells and predictive renal in vitro models
Jacqueline Kai, Yue Ning, Peng Huang, Daniel Zink  

PART VII. CURRENT STATUS OF PRECLINICAL IN VIVO TOXICITY BIOMARKERS 

24 Predictive Cardiac Hypertrophy Biomarkers in Non clinical Studies
Steven Engle  

25. Vascular Injury Biomarkers
Tanya Zabka and Kaidre Bendjama 

26. Novel Translational Biomarkers of Skeletal Muscle Injury
Peter Burch and Warren Glaab  

27. Translational Mechanistic Biomarkers and Model for Predicting Drug–Induced Liver Injury
Daniel Antoine  

PART VIII. Kidney Injury Biomarkers 

28. Assessing and Predicting Drug–Induced Kidney Injury, Functional Change and Safety in Preclinical Studies in Rats
Yafei Chen  

29. Canine Kidney Safety Protein Biomarkers
Manisha Sonee 

30. Traditional Kidney Safety Protein Biomarkers and Next–Generation Drug–Induced Kidney Injury Biomarkers in Nonhuman Primates
Jean–Charles Gautier and Xiaobing Zhou 

 31. Rat Kidney MicroRNA Atlas

Aaron Smith  

32. MicroRNAs as Next–Generation Kidney Tubular Injury Biomarkers in Rats

Heidrun Ellinger–Ziegelbauer and Rounak Nassirpour 

33. MicroRNAs as Novel Glomerular Injury Biomarkers in Rats
Rachel Church 

34. Integrating Novel Imaging Technologies to Investigate Drug–Induced Kidney Toxicity
Bettina Wilm and Neal Burton 

35. In vitro–to–In Vivo Relationships with Respect to Kidney Safety Biomarkers
Paul Jennings 

36. Case Study: Fully Automated Image Analysis of Podocyte Injury Biomarker Expression in Rats
Jing Ying Ma 

37. Case Study: Novel Renal Biomarkers translation to humans
Deborah Burt  

38. Case Study: MicroRNAs as Novel Kidney Injury Biomarkers in Canines
Craig Fisher, Erik Koenig, and Patrick Kirby 

39. Novel Testicular Injury Biomarkers
Hungyun Lin 

PART IX. Best Practices in Biomarker Evaluations 

40. Best Practices in Preclinical Biomarker Sample Collections
Jacqueline Tarrant 

41. Best Practices in Novel Biomarker Assay Fit–for–Purpose Testing
Karen Lynch

42. Best Practices in Evaluating Novel Biomarker Fit–for–Purpose and Translatability
Amanda Baker  

43. Best Practices in Translational Biomarker Data Analysis
Robin Mogg and Daniel Holder 

44 Translatable Biomarkers in Drug Development
John–Michael Sauer, Elizabeth G Walker, and Amy C Porter 

PART X CONCLUSIONS 

45 Toxicogenomics in Drug Discovery Toxicology
Brandon Jeffy, Richard Brennan, Joseph Milano 

46 Issue Investigation and Practices in Discovery Toxicology
Dolores Diaz, Dylan Hartley Ray Kemper 

Concluding Remarks
Yvonne Will, Eric McDuffie, Andrew Olaharski and Brandon Jeffy 

Index