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

Safety pharmacology is the evaluation and study of the pharmacological effects of a potential drug that are unrelated to the desired therapeutic effect. These effects often present a hazard—particularly in individuals with compromised or limited organ system functions. **Safety Pharmacology in Pharmaceutical Development: Approval and Post Marketing Surveillance, Second Edition** covers safety pharmacology from the regulatory requirements down to the studies that must be done to justify them. Using the author’s more than 30 years of direct experience, the book incorporates tricks and practical insights for making studies work and understanding why they fail. The second edition includes current regulations, including USFDA and those from Europe and Japan. Presenting a clear description of what is needed and why for supporting drug development, the book focuses on updated test methods, interpretation, and science. It covers the core and supplemental batteries of test procedures and how to do them and provides an overview of available facilities and contract organizations for performing studies. Front Cover 1 Contents 9 Preface 13 About the Author 17 Chapter 1: Safety pharmacology : Background, history, issues, and concerns 19 1.1 General versus safety pharmacology 20 1.2 History 22 1.3 Reasons for poor predictive performance 25 1.4 Why tiers? 26 1.5 Study designs and principles 27 1.5.1 Selection of methodology and species 27 1.6 Issues 30 1.7 Integral versus separate 31 1.8 Summary 33 References 33 Chapter 2: Regulatory requirements : ICH, FDA, EMA, and Japan 37 2.1 Regulatory requirements 37 References 41 Chapter 3: Principles of screening and study design 43 3.1 Introduction 43 3.2 Characteristics of screens 45 3.3 Uses of screens 48 3.4 Types of screens 50 3.5 Criterion: Development and use 50 3.6 Analysis of screening data 53 3.6.1 Univariate data 53 3.6.2 Multivariate data 56 3.7 Study design 59 3.7.1 Animal model 59 3.7.2 Group size 60 3.7.3 Statistical design 60 References 60 Chapter 4: Cardiovascular system 63 4.1 Introduction 63 4.2 History 63 4.2.1 Special case (and concern)— QT prolongation 63 4.2.2 Patch- clamp studies using recombinant cells expressing hERG channels 75 4.2.3 hERG protein expression system 75 4.2.4 Cardiovascular function testing 77 4.2.5 Conscious rodent, dog, and primate telemetry studies 82 4.2.6 Systems for recording cardiac action potentials 83 4.3 Summary 84 References 84 Chapter 5: Central nervous system 87 5.1 Core battery CNS procedures 90 5.1.1 General behavioral observation 90 5.1.2 Functional observational battery 91 5.2 Rat 92 5.2.1 Observational assessments 92 5.2.2 Locomotor activity 93 5.2.3 Motor coordination 93 5.2.4 Pain sensitivity 94 5.2.5 Convulsive threshold 94 5.3 Dog 95 5.3.1 Neurobehavioral screen 95 5.4 Sleep induction and interaction with hypnotics 99 5.5 Higher cognitive function 99 5.5.1 Passive avoidance 99 5.5.2 Morris maze 100 5.6 Isolated tissue assays 102 5.6.1 Electrophysiology methods 102 5.7 CNS function: Electroencephalography 104 5.8 Neurochemical and biochemical assays 105 References 106 Chapter 6: Respiratory system 109 6.1 Plethysmography 114 6.2 Design of respiratory function safety studies 117 6.2.1 General considerations 117 6.2.2 Study design 117 6.2.3 Capnography 118 6.3 Study design considerations 119 6.3.1 Dose selection 119 6.3.2 Species selection 119 6.4 Summary 119 References 120 Chapter 7: Renal function 123 7.1 Major functions of the kidney 124 7.2 Acute renal failure 126 7.3 Functional reserve of the kidney 127 7.4 Clearance 127 7.5 Free water clearance and renal concentrating ability 132 7.5.1 Renal blood flow 134 7.5.2 Fractional excretion of sodium 134 7.6 Clinical chemistry measures 134 7.7 Animal models 135 7.7.1 Rat 135 7.7.2 Dog 136 7.8 Examples of species differences in drug sensitivity 136 References 137 Chapter 8: The gastrointestinal system 139 8.1 Drug-induced alterations of GI transit or motility 140 8.2 Gastrointestinal function 140 8.3 Assessment of intestinal transit 142 8.4 Determination of intestinal absorption 144 8.4.1 Methods of administering test substance 144 8.4.2 Methods for quantitating degree of absorption 145 8.5 Gastric emptying rate and gastric pH changes: A new model 148 8.6 Effects of drugs on gut immune system (jejunum, ileum, colon) 149 8.7 Candidate drugs to evaluate for effects on gut immune system 149 8.8 Conclusions 150 References 150 Chapter 9: The immune system 153 9.1 Introduction to the immune system and adverse modulation activities of drugs 153 9.1.1 Passive cutaneous anaphylaxis: Test for potential antigenicity of compound 155 9.1.2 Center for Drug Evaluation and Research guidance for investigational new drugs 159 9.2 Overview of the immune system 160 9.3 Immunotoxic effects 166 9.3.1 Immunosuppression 167 9.3.2 Immunosuppressive drugs 169 9.3.3 Immunostimulation 175 References 187 Appendix A: Acronyms 193 Appendix B: Laboratories conducting safety pharmacology testing 197 Back Cover 199 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--provided By Publisher. Ch. 1. Safety Pharmacology : Background, History, Issues, And Concerns -- Ch. 2. Regulatory Requirements : Ich, Fda, Ema, And Japan -- Ch. 3. Principles Of Screening And Study Design -- Ch. 4. Cardiovascular System -- Ch. 5. Central Nervous System -- Ch. 6. Respiratory System -- Ch. 7. Renal Function -- Ch. 8. The Gastrointestinal System -- Ch. 9. The Immune System. Shayne C. Gad. Rev. Ed. Of: Safety Pharmacology In Pharmaceutical Development And Approval. C2004. Includes Bibliographical References And Index. "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"--Résumé de l'éditeur