Predictive ADME and Toxicology Strategies: Challenges and Opportunities for In Vivo, In Vitro and In Silico Predictive Technologies

Researchers in the pharmaceutical and biotech industry have been developing tools over the years to maximize the efficacy of drugs while minimizing toxicity, and advances have been made. A decade ago, the number of drugs failing preclinically due to poor pharmacokinetics was upwards of 40%, but improved in vitro and animal models have reduced that rate to about 10%. Failures due to ADME and toxicology, however, are still in the 50% to 60% range, making it the number one reason for preclinical attrition. That disparity is likely due to outdated tools, says "Innovation and Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products," a white paper published last year by FDA: "Despite some efforts to develop better methods, most of the tools used for toxicology and human safety testing are decades old. Although traditional animal toxicology has a good track record for ensuring the safety of clinical trial volunteers, it is laborious, time-consuming, requires large quantities of product, and may fail to predict the specific safety problem that ultimately halts development."

The white paper noted that one pharmaceutical company estimated that clinical failures based on liver toxicity cost them more than $2 billion over the last decade. Measuring the ADME/Tox properties early can be one method of minimizing failure. The process of drug discovery and development requires that a drug’s behavior in the human body is modelled in other systems before being actually tested in humans. When considering the drug discovery process backwards, certain toxicities must be determined before long-term use is allowed. Prior to this, the correct starting dose for human tests must be estimated. This over simplification illustrates some of the reasons for the processes being analysed with ADME and toxicology for most drugs.

This report provides an in-depth analysis of emerging and rapidly growing ADME/Tox screening technologies. The report focuses on emerging technologies, market drivers, restraints, challenges, and provides in-depth company profiles and key market engineering parameters for in vitro and in silico ADME/Tox screening markets. SHOW LESS READ MORE >

Executive Summary
Introduction to predictive ADME/Tox screening 10
Traditional methods of ADME/Tox testing 11
Novel in vitro and in vivo predictive models 12
In silico ADME/Tox 13

Chapter 1 Introduction to predictive ADME/Tox screening
Summary 16
Objectives and scope of report 17
Overview 17
A historical review of the drug discovery process 18
Drug attrition rates in preclinical and clinical testing phases 22
The importance of ADME/Tox testing 25
Early ADME studies 27
Current market landscape 27
Market challenges 29
Market drivers and restraints 30

Chapter 2 Traditional methods of ADME/Tox testing
Summary 34
Introduction 35
Absorption 35
Distribution 39
Metabolism 39
Excretion 42
Toxicity testing 43
Physiochemical characterization and stability 44
Conventional in vitro ADME/Tox screening methods 46
Caco-2 46
MDCK 48
CYP 450 and hepatic microsomes 48
Paracellular markers, MTT test, and LDH test 49
Conventional in vivo ADME/Tox models 50
Radiolabels 51
Cassette dosing 51
Semi-simultaneous dosing 52
Limitations of traditional in vitro and in vivo ADME/Tox screening methods 54

Chapter 3 Novel in vivo and in vitro predictive models
Summary 56
Introduction 57
In vitro screening 58
Cultured cells 59
Membrane vesicles (BBMV, BLMV) 59
Caco-2 Cells 59
Madin-Darby Canine Kidney (MDCK) Model 60
HT29 61
T84 and IEC-18 cell lines 61
Immobilized Artificial Membrane (IAM) Columns 62
Parallel Artificial Membrane Permeation Assay (PAMPA) 62
P-Glycoprotein (PGP)-drug transporter 63
Solubility 63
Log P 64
Plasma protein binding 64
Toxicity 64
Automated and high throughput in vitro ADME/Tox screening 66
Millipore 96-well filter-based assays and the Hamilton Microlab Star liquid handling workstation 66
MultiScreen Caco-2 Assay System 67
LeadStream 68
Hurel Microfluidic Circuit 69
NanoStream CL system 70
NanoMate and ESI chip system 71
RapidFire Lead Discovery System 72
The Biomek FX system 72
B-Clear, Accutate and AccuPro systems 73
Liquid handling systems 74
In vivo models 74
Drosophila 75
C. elegans 76
Rodent models 77
Zebrafish models 80
Competitive structure 83

Company profiles 85
Aclara Biosciences 85
Advion Biosciences 86
Agilent Technologies 87
Amphioxus Cell Technologies 87
Applied Biosciences 87
BD Biosciences 88
BioTrove Inc. 88
Caliper Life Sciences 89
Covance 89
DanioLabs 90
Eksigent Technologies 91
Gene Logic 91
Hurel Corporation 92
LGC Limited 92
Nanostream Inc. 93
NemaRx Pharmaceuticals Inc. 93
Nimbus Biotechnology 93
Novascreen 93
Perkin Elmer 94
Phylonix 94
Qualyst 95
Tecan 95
Thermo Electron Corp. 96
Xenogen 96
Zygogen 97
Zyomyx 97
Market analysis 97
In vitro ADME/Tox screening market 97
In vivo ADME/Tox market 99

Chapter 4 In silico predictive models
Summary 102
Introduction 103
Current technologies 104
Mathematical methods 105
Oral bioavailability 106
Solubility 106
Blood-brain barrier penetration 107
Absorption/membrane permeability 107
Toxicity 108
Metabolism 108
Physicochemical properties 109
“Global” and “Local” models 109
Commercially available products 110
GastroPlus™ 112
ADMET Modeler™ 113
DDDPlus™ 115
ADMET Predictor™ 115
DEREK for Windows 117
Meteor 119
Vitic 119
Accord for Excel 119
Cerius2 ADME/Tox Package 120
ACD/LogD Suite and ACD/LogD Sol Suite 121
Metabolite ID™ 121
AurScope® ADME/DDI 122
Bio-Loom™ 122
KnowItAll™ 122
Pallas Software Family 124
HazardExpert™ 125
MetabolExpert™ 125
ToxAlert™ 125
MDL Metabolite™ Database 126
MDL Toxicity™ Database 126
MetaDrug™ 126
VolSurf™ 126
MetaSite™ 127
Emerging technologies 127
Factors limiting the impact of in silico ADME/Tox models 130
Competitive structure 132

Company profiles 132
Accelrys 132
Applied Biosystems 133
Aureus Pharma 133
BG Medicine 133
BioByte Corporation 134
BioKin Limited 134
Bio-Rad Laboratories 135
ChemSilico 135
Chenomx 135
ComGenex Inc. 136
CompuDrug 136
Cyprotex 136
Elsevier MDL 137
GeneGo 137
Leadscope 138
LHASA Limited 138
Molecular Discovery Ltd. 139
Pharma Algorithms 139
Simulations Plus 140
Market analysis 140

Chapter 5 Appendix
Research methodology 144
Abbreviations and acronyms 145

Index

List of Figures
Figure 1.1: The major phases of drug discovery 19
Figure 1.2: The drug discovery phase of a typical project aimed at producing a drug 20
Figure 1.3: Typical success rates at each step of drug discovery and development 23
Figure 1.4: Factors that cause the failure of potential drug candidates 24
Figure 1.5: ADME/Tox market challenges 29
Figure 1.6: ADME/Tox market challenges 30
Figure 3.1: The Hamilton Microlab Star Liquid Handling System 67
Figure 3.2: MultiScreen Caco-2 Assay System Components 68
Figure 3.3: The LeadStream system 69
Figure 3.4: The NanoStream LC system 70
Figure 3.5: ESI Biochip 71
Figure 3.6: The Biomek FX Laboratory Automation Workstation 72
Figure 3.7: VivoVision system for retn-luc expression in male and female mice 79
Figure 3.8: Utility of the Zebrafish model in drug design 80
Figure 3.9: In vitro ADME/Tox revenue forecasts, 2004-2012 98
Figure 3.10: In vivo ADME/Tox revenue forecasts, 2004-2012 100
Figure 4.11: ADMET Modeler™ overview 114
Figure 4.12: ADMET Predictor™ screen shot 117
Figure 4.13: KnowItAll concept 123
Figure 4.14: In silico ADME/Tox revenue forecasts 141

List of Tables
Table 2.1: Typical experiments to assess the ADME properties of potential drug candidates 45
Table 2.2: Percentage of pharmacokinetic studies by in vivo model 50
Table 3.1: In vitro and in vivo ADME/Tox companies and products, A-M 84
Table 3.2: In vitro and in vivo ADME/Tox companies and products, N-Z 85
Table 3.3: In vitro ADME/Tox revenues, 2004-2012 98
Table 3.4: In vivo ADME/Tox revenues, 2004-2012 99
Table 4.5: Mathematical models for predictive ADME/Tox 105
Table 4.6: Advantages and disadvantages of “global” predictive models 109
Table 4.7: Advantages and disadvantages of “local” predictive models 110
Table 4.8: Commercially available in silico ADME/Tox products 111
Table 4.9: In silico ADME/Tox revenues, 2004-2010 140

- Aclara Biosciences
- Advion Biosciences
- Agilent Technologies
- Amphioxus Cell Technologies
- Applied Biosciences
- BD Biosciences
- BioTrove Inc.
- Caliper Life Sciences
- Covance
- DanioLabs
- Eksigent Technologies
- Gene Logic
- Hurel Corporation
- LGC Limited
- Nanostream Inc.
- NemaRx Pharmaceuticals Inc.
- Nimbus Biotechnology
- Novascreen
- Perkin Elmer
- Phylonix
- Qualyst
- Tecan
- Thermo Electron Corp.
- Xenogen
- Zygogen
- Zyomyx
- Accelrys
- Applied Biosystems
- Aureus Pharma
- BG Medicine
- BioByte Corporation
- BioKin Limited
- Bio-Rad Laboratories
- ChemSilico
- Chenomx
- ComGenex Inc.
- CompuDrug
- Cyprotex
- Elsevier MDL
- GeneGo
- Leadscope
- LHASA Limited
- Molecular Discovery Ltd.
- Pharma Algorithms
- Simulations Plus