Safety pharmacology in pharmaceutical development and approval

1380fm.pdf......Page 1
Safety Pharmacology in Pharmaceutical Development and Approval......Page 2
Dedication......Page 4
Contents......Page 5
Preface......Page 9
The Author......Page 12
Selected regulatory and toxicological acronyms......Page 0
chapter 1: Safety pharmacology: background, history, issues, and concerns......Page 13
General vs. safety pharmacology......Page 14
History......Page 15
Reasons for poor predictive performance......Page 18
Why tiers?......Page 19
Study designs and principles......Page 20
Selection of methodology and species......Page 23
Issues......Page 24
Integral vs. separate......Page 25
Summary......Page 26
References......Page 27
Regulatory requirements......Page 29
Web Sources......Page 33
Introduction......Page 34
Characteristics of screens......Page 36
Uses of screens......Page 39
Single stage......Page 40
Criterion: development and use......Page 41
Analysis of screening data......Page 43
Control charts......Page 44
Central tendency plots......Page 45
The analog plot......Page 47
Study design......Page 48
Group size......Page 50
References......Page 51
Special case (and concern) — QT prolongation......Page 54
Regulatory developments......Page 56
HERG protein expression system......Page 66
Relevance of HERG to QT prolongation......Page 67
Cardiovascular function testing......Page 68
Six-lead EKG measurement in the conscious dog......Page 70
Systems for recording cardiac action potentials......Page 71
References......Page 72
chapter 5: Central nervous system......Page 75
General behavioral observation......Page 77
Observational assessments......Page 78
Locomotor activity......Page 79
Pain sensitivity......Page 80
Higher cognitive function......Page 81
Morris maze......Page 82
Set up apparatus and begin acquisition testing......Page 83
Isolated tissue assays......Page 84
CNS function: electroencephalography......Page 86
Neurochemical and biochemical assays......Page 87
References......Page 88
chapter 6: Respiratory system......Page 90
Plethysmography......Page 95
General considerations......Page 97
Study design......Page 98
Dose selection......Page 99
References......Page 100
chapter 7: Renal function......Page 103
Major functions of the kidney......Page 104
Clearance......Page 105
Free water clearance and renal concentrating ability......Page 110
Glucosuria......Page 112
The rat......Page 113
Examples of species differences in drug sensitivity......Page 114
References......Page 115
chapter 8: The gastrointestinal system......Page 116
Drug-induced alterations of GI transit or motility......Page 117
GI function......Page 118
Assessment of intestinal transit......Page 119
Determination of intestinal absorption......Page 120
Methods of administering test substance......Page 121
Appearance in systemic fluids......Page 122
Gastric emptying rate and gastric pH changes: a new model......Page 124
Candidate drugs to evaluate for effects on gut immune system......Page 125
References......Page 126
Introduction......Page 129
PCA test for potential antigenicity of compound......Page 131
Test method......Page 133
CDER guidance for investigational new drugs......Page 134
Overview of the immune system......Page 135
Immunotoxic effects......Page 142
Immunosuppression......Page 143
Antimetabolites......Page 144
Glucocorticosteroids......Page 147
Nitrogen mustards......Page 148
Heavy metals......Page 149
Hypersensitivity......Page 150
Type I......Page 153
Type III......Page 154
Type IV......Page 155
Photosensitization......Page 156
Autoimmunity......Page 157
References......Page 161
chapter 10: Integration of evaluations of safety pharmacology endpoints into existing study designs......Page 166
Rodent acute toxicity......Page 167
Nonrodent acute toxicology......Page 168
Body weight......Page 171
Clinical signs......Page 172
Pharmacokinetics and metabolism......Page 173
Integration......Page 177
References......Page 179
Selected regulatory and toxicological acronyms......Page 181
Safety pharmacology labs......Page 184