Preclinical Models: Innovative solutions to accelerate drug discovery and development

Date: February 22, 2010
Pages: 131
US$ 3,835.00
Publisher: Business Insights
Report type: Strategic Report
Delivery: E-mail Delivery (PDF), Hard Copy Mail Delivery, CD-ROM Mail Delivery
ID: P426F4C123BEN

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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 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


    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


    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


    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


    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


    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


    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


    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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