SPI Infoamtion

Table of Contents

Preclinical models

Executive summary
Preclinical models in drug discovery and development
In vivo models in preclinical research
In vitro models in preclinical research
In silico models in preclinical research
Systems biology models in drug discovery

Chapter 1 Preclinical models in drug discovery and development

Summary
Introduction: importance of preclinical models for toxicity screening in
drug development

Preclinical ADMET testing systems
The challenge: reducing drug attrition rates in preclinical screening
Importance of ADMET screening

Applying of ADMET to the drug discovery and development
process

Importance of in vivo models
Established in vivo and in vitro ADMET tools to screen compounds

Toxicity and genotoxicity screening

Predicting toxicity with paracellular markers

In vitro ADMET screening in preclinical drug development

Advantages and disadvantages of conventional ADME screening tools in
preclinical drug development

Oral absorption prediction
Metabolism prediction

In vivo ADMET animal models

Established ADMET study methods in animal models

Radiolabels
Cassette dosing
Semi-simultaneous dosing
Conclusion

Limitations of traditional in vitro and in vivo ADMET screening methods

New approaches to predict ADMET in preclinical development

Metabolomics

Advantages of metabolomics in drug discovery and development
Lead prioritization using metabolomics
Metabolomics and ADMET studies
Strengths and limitations of metabolomics for preclinical research

Metabolomics and "systems biology" - a unified approach to preclinical ADMET screening

Company focus: Merrimack Pharmaceuticals

Other emergent technologies used in preclinical drug discovery and development

Nanotechnologies in preclinical studies
Novel imaging systems

Preclinical research and recent multinational pharmaceutical company activities

Bayer AG and Nimbus Biotechnology
Pfizer/Johnson and Johnson and WuXi Pharma Tech
Roche
Sanofi-Aventis
UCB Pharma

Chapter 2 In vivo models in preclinical research

Summary
Vertebrate animal models in preclinical discovery and development

Assessment of predictive value of animal models
Rodent models

The need for improved small animal models
Humanized rodent models

Advantages and disadvantages of zebrafish models in preclinical research

Recent progress with vertebrate models

ADMET screens and zebrafish models: company developments and technologies

Discovery Genomics
Evotec AG
Phylonix
Summit
ZF Biolabs
Zygogen

ADMET screens in rodent models: selected company developments and technologies

Lexicon Pharmaceuticals
Taconic
Xenogen's (now part of Caliper)
Sigma-Aldrich

Invertebrate animal models in preclinical discovery and development

Drosophila melanogaster (fruit fly)

Aktogen
En Vivo Pharmaceuticals
Exelixis
MedrVos Pharmaceuticals

Caenorhadbitis elegans (nematode)
Novel in vivo/ex-vivo focus: Locusta migratoria (locust)

Chapter 3 In vitro models in preclinical research

Summary
Importance of in vitro models in preclinical toxicity testing
In vitro technologies for drug discovery and development

Recent company developments

Affymetrix
Beckman Coulter
Covance
Gene Logic
HemoGenix

Recent developments in drug transport and metabolism

Qualyst
Xenobiotic Laboratories

Progress in cell-based in vitro assays

Use of cultured cells for ADMET studies in preclinical research

In vitro distribution
In vitro solubility

In vitro ADMET assays and cell-type selection

Recent developments in cell-based platforms for preclinical drug screening

Cell-based assays and liver toxicity
Stem cells in drug discovery and development
Stem cells and ADMET in drug discovery and development

Novel in vitro technologies in preclinical research

Nanotechnologies and ADMET in drug discovery and development

Chapter 4 In silico models in preclinical research

Summary
In silico models in drug discovery and development

Molecular modeling in silico
Computer models to predict ADMET

Methodological approaches to in silico models

Recent commercial developments and activities

Accelrys
Advanced Chemistry Development
Aureus Pharma
Chemical Computing Group
Entelos
Gene Network Sciences
Leadscope
Life Technologies Corporation
Molecular Discovery
Molecular Networks
Noray Bioinformatics
Schr?dinger
Simcyp
Simulations Plus
TerraBase
Tripos

Chapter 5 Systems biology models in drug discovery

Summary
Systems biology: integrative science for drug discovery
Predictive biosimulation platforms to aid preclinical research

Virtual organs and patients

Pathway biology systems: recent commercial developments and activities

Ariadne Genomics
GeneGo
Genomatix
Genstruct
Ingenuity Systems
Merrimack Pharmaceuticals
Physiomics

Considerations for preclinical models in drug discovery and development

Key points and recommendations

Appendix

Abbreviations and acronyms
Primary research methodology

References
Other sources

Index
List of Figures
Figure 1.1: Established preclinical ADMET systems and models for drug discovery and development
Figure 1.2: Common reasons for a drug candidate's failure
Figure 1.3: Key advantages & disadvantages of animal models in preclinical drug development
Figure 1.4: Animal models (%) used in preclinical ADMET studies
Figure 2.5: Advantages and disadvantages of zebrafish for preclinical ADMET screening in drug discovery and development
Figure 2.6: Preclinical ADMET screen types offered by Evotec AG
Figure 2.7: Rationale for use of Drosophila as preclinical model for neurobiological disease
Figure 4.8: Factors limiting the use of in silico ADMET models
Figure 5.9: Drivers of systems biology in pharmaceutical R&D

List of Tables
Table 1.1: Routine screens to assess ADME of drug candidates in discovery
Table 2.2: Key advantages of Drosophila in preclinical drug discovery and development
Table 3.3: Commonly used cultured cells for in-vitro permeability assays