Principles of CNS Drug Development (eBook)

Dr. John Kelly, Senior Lecturer, Department of Pharmacology and Therapeutics, NUI, Galway, Ireland.

Principles of CNS drug development 3
Contents 9
Acknowledgements 13
Preface 15
Abbreviations 19
1 Introduction 23
1.1 The global burden of CNS disease 24
1.2 Assessment of the global burden of disease 25
1.3 The prevalence of CNS disorders 27
1.4 Disability due to CNS disorders 27
1.5 Economic Costs 30
1.6 Concluding comments 33
References 33
2 An overview of the major CNS disorders 35
2.1 Introduction 35
2.2 Overview of psychiatric disorders 39
2.3 Overview of neurological/neurodegenerative disorders 53
2.4 Concluding comments 59
References 60
3 Neurobiological substrates of CNS disorders 65
3.1 Introduction 65
3.2 Brief introduction to the principles of chemical neurotransmission 66
3.3 Stages of chemical neurotransmission 69
3.4 Approaches to investigating CNS alterations in CNS disorders 72
3.5 Evidence for a neurobiological rationale for CNS disorders 75
3.6 Concluding comments 83
References 84
4 Current pharmacological targets 87
4.1 Introduction 87
4.2 Pharmacological treatments for depression 89
4.3 Pharmacological treatments for schizophrenia 93
4.4 Pharmacological treatments for anxiety disorders 97
4.5 Pharmacological treatments for epilepsy 99
4.6 Pharmacological treatments for Parkinson’s disease 102
4.7 Pharmacological treatments for Alzheimer’s disease 104
4.8 Concluding comments 105
References 106
5 Premarketing efficacy evaluation 109
5.1 Introduction 109
5.2 Target identification 112
5.3 Lead optimisation 113
5.4 Target validation in animal models 119
5.5 The use of genetically modified animals in CNS drug development 122
5.6 A selection of animal models of psychiatric disease 123
5.7 A selection of animal models of neurodegenerative disease 130
5.8 Which models to choose 133
5.9 Clinical trials that evaluate drug efficacy 134
5.10 Specific drug profiles 142
References 143
6 Pharmacokinetic considerations: Absorption, distribution, metabolism and elimination 149
6.1 Introduction 149
6.2 What are the ‘ideal’ pharmacokinetic properties for a CNS drug? 151
6.3 Absorption 153
6.4 Distribution 163
6.5 Metabolism 172
6.6 Elimination 180
6.7 Measurement of drug concentrations 182
6.8 Factors that affect pharmacokinetics 183
6.9 Allometric scaling 185
6.10 Microdosing (Phase 0) Studies 185
6.11 Dose prediction and therapeutic drug monitoring 186
6.12 Stereoselectivity of metabolism of drugs 186
6.13 Specific drug profiles 187
6.14 Concluding comments 188
References 188
7 Safety concerns 195
7.1 Introduction 195
7.2 Postmarketing surveillance 196
7.3 Acute poisoning 197
7.4 Quantification of the relative risk of fatalities from CNS drugs 198
7.5 Adverse drug reactions (ADRs) 204
7.6 Specific types of toxicity encountered with psychotropic drugs 205
7.7 Safety concerns following long-term administration of CNS Drugs 207
7.8 Polypharmacy 221
7.9 Specific drug profiles 223
7.10 Concluding comments 225
References 226
Websites 232
8 Preclinical and clinical safety evaluation 233
8.1 Introduction 233
8.2 Preclinical exploratory toxicology and safety pharmacology evaluations 237
8.3 Primary and secondary pharmacology 238
8.4 Safety pharmacology 242
8.5 Toxicology studies required for regulatory purposes 246
8.6 Clinical Studies 260
8.7 Specific drug profiles 261
8.8 Concluding comments 262
References 263
Websites 266
9 CNS drug targets in development and future perspectives 267
9.1 Introduction 267
9.2 How much does it cost to develop a drug? 269
9.3 Clinical drug development times 270
9.4 Harmonisation between regulatory agencies 270
9.5 Development of biomarkers for clinical efficacy 271
9.6 Quality of life issues 277
9.7 Cost-effectiveness of novel treatments 279
9.8 Patient advocacy groups 280
9.9 Novel targets for CNS disorders 281
9.10 Targets in selected CNS disorders 283
9.11 Targeting of signalling pathways 292
9.12 Cardiovascular drugs in Alzheimer’s disease 295
9.13 Modifying oxidative stress and inflammatory responses 296
9.14 Targeting of the amyloid-? protein in Alzheimer’s disease 298
9.15 Concluding comments 300
References 301
Appendices 309
Index 317

"The data that have been presented in this book are accurate and
informative." (Canadian Journal of Neurological Sciences,
November 2010)