Safety Pharmacology in Pharmaceutical Development: Approval and Post Marketing Surveillance, Second Edition

by Gad; Shayne Cox

• ISBN13: 9781439845677
• ISBN10: 1439845670
• Edition: 2nd
• Format: Hardcover
• Copyright: 2012-04-26
• Publisher: CRC Press

Summary

This book covers the regulatory required evaluation and study of the potentially adverse pharmacological effects of new drugs, from the general regulatory requirements to the specific studies that must be done and how they are performed and interpreted. Based on more than 30 years of direct experience, the author describes tricks and practical insights for making studies work and understanding why they don't. The second edition includes current regulations (US FDA and international-especially Europe and Japan) and updated test methods, interpretation, and science.

Table of Contents

Preface	p. xi
About the Author	p. xv
Safety pharmacology: Background, history, issues, and concerns	p. 1
General versus safety pharmacology	p. 2
History	p. 4
Reasons for poor predictive performance	p. 7
Why tiers?	p. 4
Study designs and principles	p. 9
Selection of methodology and species	p. 9
Issues	p. 12
Integral versus separate	p. 13
Summary	p. 15
References	p. 15
Regulatory requirements: ICH, FDA, EMA, and Japan	p. 19
Regulatory requirements	p. 19
References	p. 23
Principles of screening and study design	p. 25
Introduction	p. 25
Characteristics of screens	p. 27
Uses of screens	p. 30
Types of screens	p. 32
Criterion: Development and use	p. 32
Analysis of screening data	p. 35
Univariate data	p. 35
Control charts	p. 35
Central tendency plots	p. 37
Multivariate data	p. 38
Analog plot	p. 39
Study design	p. 41
Animal model	p. 41
Group size	p. 42
Statistical design	p. 42
Dose levels and test concentrations	p. 42
References	p. 42
Cardiovascular system	p. 45
Introduction	p. 45
History	p. 45
Special case (and concern)-QT prolongation	p. 45
Regulatory developments	p. 47
Patch-clamp studies using recombinant cells expressing hERG channels	p. 57
hERG protein expression system	p. 57
Relevance of hERG to QT prolongation	p. 58
Expression and recording systems	p. 58
Cardiovascular function testing	p. 59
Conscious rodent, dog, and primate telemetry studies	p. 64
Six-lead ECG measurement in the conscious dog	p. 64
Systems for recording cardiac action potentials	p. 65
Cloned human potassium channels	p. 65
Cardiac action potential in vitro-Purkirnje fibers	p. 65
Monophasic action potential in anesthetized guinea pigs	p. 65
ECG by telemetry in conscious guinea pigs	p. 65
Hemodynamics and ECG in anesthetized or conscious dogs or primates	p. 66
Summary	p. 66
References	p. 66
Central nervous system	p. 69
Core battery CNS procedures	p. 72
General behavioral observation	p. 72
Functional observational battery	p. 73
Rat	p. 74
Observational assessments	p. 74
Locomotor activity	p. 75
Motor coordination	p. 75
Pain sensitivity	p. 76
Convulsive threshold	p. 76
Dog	p. 77
Neurobehavioral screen	p. 77
Sleep induction and interaction with hypnotics	p. 81
Higher cognitive function	p. 81
Passive avoidance	p. 81
Morris maze	p. 82
Materials	p. 82
Set up apparatus and begin acquisition testing	p. 83
Continue trials	p. 83
Isolated tissue assays	p. 84
Electrophysiology methods	p. 84
CNS function: Electroencephalography	p. 86
Neurochemical and biochemical assays	p. 87
References	p. 88
Respiratory system	p. 91
Plethysmography	p. 96
Design of respiratory function safety studies	p. 99
General considerations	p. 99
Study design	p. 99
Capnography	p. 100
Study design considerations	p. 101
Dose selection	p. 101
Species selection	p. 101
Summary	p. 101
References	p. 102
Renal function	p. 105
Major functions of the kidney	p. 106
Acute renal failure	p. 108
Functional reserve of the kidney	p. 109
Clearance	p. 109
Free water clearance and renal concentrating ability	p. 114
Renal blood flow	p. 116
Fractional excretion of sodium	p. 116
Clinical chemistry measures	p. 116
Animal models	p. 117
Rat	p. 117
Dog	p. 118
Examples of species differences in drug sensitivity	p. 118
References	p. 119
The gastrointestinal system	p. 121
Drug-induced alterations of GI transit or motility	p. 122
Gastrointestinal function	p. 122
Assessment of intestinal transit	p. 124
Determination of intestinal absorption	p. 126
Methods of administering test substance	p. 126
Methods for quantitating degree of absorption	p. 127
Appearance in systemic fluids	p. 127
Gastric emptying rate and gastric pH changes: A new model	p. 130
Effects of drugs on gut immune system (jejunum, ileum, colon)	p. 131
Candidate drugs to evaluate for effects on gut immune system	p. 131
Conclusions	p. 132
References	p. 132
The immune system	p. 135
Introduction to the immune system and adverse modulation activities of drugs	p. 135
Passive cutaneous anaphylaxis: Test for potential antigenicity of compound	p. 137
Test method for pulmonary sensitization	p. 140
Center for Drug Evaluation and Research guidance for investigational new drugs	p. 141
Overview of the immune system	p. 142
Immunotoxic effects	p. 148
Immunosuppression	p. 149
Immunosuppressive drugs	p. 151
Antimetabolites	p. 151
Glucocorticosteroids	p. 154
Cyclosporine	p. 155
Nitrogen mustards	p. 155
Estrogens	p. 156
Heavy metals	p. 156
Antibiotics	p. 157
Immunostimulation	p. 157
Hypersensitivity	p. 159
Photosensitization	p. 164
Autoimmunity	p. 165
References	p. 169
Appendix A: Acronyms	p. 175
Appendix B: Laboratories conducting safety pharmacology testing	p. 179
Index	p. 181
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