Preclinical Models: Innovative solutions to accelerate drug discovery and development

Preclinical models are developed to test lead compounds for toxicity and efficacy. They are valuable tools to minimize development costs and reduce failures prior to commencement of human trials. Problems with traditional animal models such as cost, ethics, and suitability has prompted researchers to develop new models and systems to overcome such disadvantages. Alternative approaches include new vertebrate, nonvertebrate, computer-based and imaging models that offer new perspectives and utility to aid the drug discovery and development process.

This report explores novel preclinical models that show promise to expedite and improve the target validation and lead optimization timeline and discusses the various advantages and disadvantages of ADMET screening technologies to provide insight on which models or systems may enhance the R&D function of pharmaceutical and biotechnology organisations.
Additionally, the report provides an outlook for preclinical testing over the next decade and how pharmaceutical companies may need to adjust to new systems and models to improve their efficiencies. It uniquely focuses on more than 60 companies that are involved in using or developing ADMET technologies to advance preclinical research and provides an update on recent company activities and developments where new models and systems are employed to accelerate the discovery and development process.

Key features of this report

• Analysis of current developments in preclinical ADMET research for drug discovery and development
• Evaluation of the drivers behind innovation in preclinical research.
• Identifies the current trends in ADMET research and how technology companies are developing new models to improve and accelerate discovery and development.
• Analysis of current in-vivo, in-vitro, in-silico, and systems biology models that are advancing toxicity prediction in early drug discovery.

Scope of this report

• Understand the basis to ADMET testing and why it is a necessary and important component of preclinical research
• Up-to-date information on the preclinical models and systems currently used in drug discovery and development.
• Evaluation of the key recent developments and activities of companies who are developing and licensing new ADMET technologies.
• Identifies existing models and how new ones are being developed to improve productivity and knowledge. 

Key Market Issues

• Established preclinical models correlate poorly with human in-vivo biological responses therefore innovation is needed to approximate more accurately the human response.
• Technology and software providers are developing novel models to expand the ADMET market in order to accelerate drug discovery and development.
• In-vivo, in-vitro, and in-silico models are increasingly becoming more sophisticated and a push for integration is creating demand for highly efficient centralized platforms to expedite predictive ADMET insight.

Key findings from this report

•  Innovation in preclinical research is rapidly changing the landscape for ADMET testing and new models are accelerating decision-making in discovery and development.
•  Novel in-vivo, in-vitro, in-silico and systems biology models are accelerating the discovery and development timeline for pharmaceutical companies.
•  Demand to reduce in-vivo whole-organism ADMET testing has stimulated in-silico research but novel animal models and in-vitro screens will be needed to complement and correlate in-silico prediction.
•  New vertebrate and invertebrate whole organism preclinical models include humanized rodents and zebrafish that provide disease-state environments, which better predict biological responses to investigational compounds.    

Key questions answered

1.  What are preclinical models and how are they important to the pharmaceutical industry?
2.  What are the advantages and disadvantages of preclinical models in ADMET screening?
3.  What are the innovations in preclinical models?
4.  What are the trends in preclinical research?
5.  How are in-vivo, in-vitro, in-silico and systems biology models being developed for ADMET?
6.  How are companies building ADMET capabilities?

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

Medros 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

Schrödinger

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