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?



Report Highlights
Companies mentioned in the report: Ariadne Genomics , GeneGo , Genomatix , Genstruct , Ingenuity Systems , Merrimack Pharmaceuticals , Physiomics , 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 , , , , , , , , , ,
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Table of Contents
Preclinical models
Executive summary 10
Preclinical models in drug discovery and development 10
In vivo models in preclinical research 11
In vitro models in preclinical research 12
In silico models in preclinical research 13
Systems biology models in drug discovery 14
Chapter 1 Preclinical models in drug discovery and development 16
Summary 16
Introduction: importance of preclinical models for toxicity screening in drug development 17
Preclinical ADMET testing systems 17
The challenge: reducing drug attrition rates in preclinical screening 19
Importance of ADMET screening 22
Applying of ADMET to the drug discovery and development process 22
Importance of in vivo models 23
Established in vivo and in vitro ADMET tools to screen compounds 25
Toxicity and genotoxicity screening 26
Predicting toxicity with paracellular markers 27
In vitro ADMET screening in preclinical drug development 27
Advantages and disadvantages of conventional ADME screening tools in preclinical drug development 28
Oral absorption prediction 28
Metabolism prediction 29
In vivo ADMET animal models 30
Established ADMET study methods in animal models 32
Radiolabels 32
Cassette dosing 32
Semi-simultaneous dosing 33
Conclusion 34
Limitations of traditional in vitro and in vivo ADMET screening methods 34
New approaches to predict ADMET in preclinical development 36
Metabolomics 36
Advantages of metabolomics in drug discovery and development 37
Lead prioritization using metabolomics 37
Metabolomics and ADMET studies 37
Strengths and limitations of metabolomics for preclinical research 38
Metabolomics and “systems biology” – a unified approach to preclinical
ADMET screening 40
Company focus: Merrimack Pharmaceuticals 41
Other emergent technologies used in preclinical drug discovery and development 42
Nanotechnologies in preclinical studies 42
Novel imaging systems 43
Preclinical research and recent multinational pharmaceutical company activities 44
Bayer AG and Nimbus Biotechnology 44
Pfizer/Johnson and Johnson and WuXi Pharma Tech 44
Roche 44
Sanofi-Aventis 45
UCB Pharma 45
Chapter 2 In vivo models in preclinical research 48
Summary 48
Vertebrate animal models in preclinical discovery and development 49
Assessment of predictive value of animal models 49
Rodent models 50
The need for improved small animal models 50
Humanized rodent models 51
Advantages and disadvantages of zebrafish models in preclinical research 52
Recent progress with vertebrate models 54
ADMET screens and zebrafish models: company developments and technologies 54
Discovery Genomics 54
Evotec AG 55
Phylonix 56
Summit 56
ZF Biolabs 57
Zygogen 58
ADMET screens in rodent models: selected company developments and technologies 59
Lexicon Pharmaceuticals 59
Taconic 59
Xenogen’s (now part of Caliper) 61
Sigma-Aldrich 62
Invertebrate animal models in preclinical discovery and development 63
Drosophila melanogaster (fruit fly) 63
Aktogen 64
En Vivo Pharmaceuticals 66
Exelixis 67
Medros Pharmaceuticals 67
Caenorhadbitis elegans (nematode) 68
Novel in vivo/ex-vivo focus: Locusta migratoria (locust) 68
Chapter 3 In vitro models in preclinical research 72
Summary 72
Importance of in vitro models in preclinical toxicity testing 73
In vitro technologies for drug discovery and development 74
Recent company developments 74
Affymetrix 74
Beckman Coulter 75
Covance 75
Gene Logic 75
HemoGenix 76
Recent developments in drug transport and metabolism 76
Qualyst 76
Xenobiotic Laboratories 77
Progress in cell-based in vitro assays 77
Use of cultured cells for ADMET studies in preclinical research 77
In vitro distribution 80
In vitro solubility 80
In vitro ADMET assays and cell-type selection 81
Recent developments in cell-based platforms for preclinical drug screening 83
Cell-based assays and liver toxicity 83
Stem cells in drug discovery and development 84
Stem cells and ADMET in drug discovery and development 85
Novel in vitro technologies in preclinical research 87
Nanotechnologies and ADMET in drug discovery and development 87
Chapter 4 In silico models in preclinical research 92
Summary 92
In silico models in drug discovery and development 93
Molecular modeling in silico 94
Computer models to predict ADMET 95
Methodological approaches to in silico models 95
Recent commercial developments and activities 97
Accelrys 97
Advanced Chemistry Development 97
Aureus Pharma 98
Chemical Computing Group 99
Entelos 99
Gene Network Sciences 101
Leadscope 102
Life Technologies Corporation 102
Molecular Discovery 103
Molecular Networks 104
Noray Bioinformatics 105
Schrödinger 105
Simcyp 105
Simulations Plus 106
TerraBase 107
Tripos 108
Chapter 5 Systems biology models in drug discovery 110
Summary 110
Systems biology: integrative science for drug discovery 111
Predictive biosimulation platforms to aid preclinical research 113
Virtual organs and patients 114
Pathway biology systems: recent commercial developments and activities 116
Ariadne Genomics 116
GeneGo 117
Genomatix 119
Genstruct 120
Ingenuity Systems 122
Merrimack Pharmaceuticals 123
Physiomics 124
Considerations for preclinical models in drug discovery and development 125
Key points and recommendations 125
Appendix 127
Abbreviations and acronyms 127
Primary research methodology 129
References 130
Other sources 130
Index 131

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List of Figures
Figure 1.1: Established preclinical ADMET systems and models for drug discovery and development 20
Figure 1.2: Common reasons for a drug candidate’s failure 21
Figure 1.3: Key advantages & disadvantages of animal models in preclinical drug development 24
Figure 1.4: Animal models (%) used in preclinical ADMET studies 31
Figure 2.5: Advantages and disadvantages of zebrafish for preclinical ADMET screening in drug discovery and development 53
Figure 2.6: Preclinical ADMET screen types offered by Evotec AG 55
Figure 2.7: Rationale for use of Drosophila as preclinical model for neurobiological disease 66
Figure 4.8: Factors limiting the use of in silico ADMET models 96
Figure 5.9: Drivers of systems biology in pharmaceutical R&D 112
List of Tables
Table 1.1: Routine screens to assess ADME of drug candidates in discovery 26
Table 2.2: Key advantages of Drosophila in preclinical drug discovery and development 64
Table 3.3: Commonly used cultured cells for in-vitro permeability assays 78

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