Safety pharmacology in pharmaceutical development and approval / Shayne C. Gad.

Format:

Book

Author/Creator:

Gad, Shayne C., 1948-

Language:

English

Subjects (All):

Drugs--Toxicology.

Drugs.

Drugs--Safety measures.

Drug Evaluation, Preclinical.

Drug Approval.

Toxicity Tests.

Medical Subjects:

Drug Evaluation, Preclinical.

Drug Approval.

Toxicity Tests.

Physical Description:

189 pages : illustrations ; 25 cm

Place of Publication:

Boca Raton, Fla. : CRC Press, [2004]

Contents:

Chapter 1 Safety pharmacology: background, history, issues, and concerns 1

General vs. safety pharmacology 2

History 3

Reasons for poor predictive performance 6

Why tiers? 7

Study designs and principles 8

Selection of methodology and species 11

Issues 12

Integral vs. separate 13

Chapter 2 Regulatory requirements of ICH, U.S. FDA, EMEA, and Japan MHW 17

Regulatory requirements 17

Chapter 3 Principles of screening and study design 23

Characteristics of screens 25

Uses of screens 28

Types of screens 29

Single stage 29

Sequential 30

Tier or multistage 30

Criterion: development and use 30

Analysis of screening data 32

Univariate data 33

Control charts 33

Central tendency plots 34

Multivariate data 36

The analog plot 36

Study design 37

Animal models 39

Group size 39

Statistical design 40

Dose levels/test concentrations 40

Chapter 4 Cardiovascular system 43

History 43

Special case (and concern)

QT prolongation 43

Regulatory developments 45

Patch-clamp studies using recombinant cells expressing HERG channels 55

HERG protein expression system 55

Relevance of HERG to QT prolongation 56

Cardiovascular function testing 57

Hemodynamics, EKG, and respiration in anesthetized dogs or primates 59

Cardiac conduction studies 59

Conscious rodent, dog, and primate telemetry studies 59

Six-lead EKG measurement in the conscious dog 60

Systems for recording cardiac action potentials 60

Chapter 5 Central nervous system 65

Core battery CNS procedures 67

General behavioral observation 67

Functional observational battery 68

Observational assessments 68

Locomotor activity 69

Motor coordination 70

Pain sensitivity 70

Convulsive threshold 71

Sleep induction and interaction with hypnotics 71

Higher cognitive function 71

Passive avoidance 72

Morris maze 72

Isolated tissue assays 74

Electrophysiology methods 76

CNS function: electroencephalography 76

Neurochemical and biochemical assays 77

Chapter 6 Respiratory system 81

Plethysmography 86

Design of respiratory function safety studies 88

General considerations 88

Study design 89

Capnography 90

Study design considerations 90

Dose selection 90

Species selection 91

Chapter 7 Renal function 95

Major functions of the kidney 96

Acute renal failure (ARF) 97

Functional reserve of the kidney 97

Clearance 97

Free water clearance and renal concentrating ability 102

Renal blood flow 104

Fractional excretion of sodium 104

Clinical chemistry measures 104

Enzymuria 104

Proteinuria 104

Glucosuria 104

Urine concentration test 105

Animal models 105

The rat 105

The dog 106

Cautions 106

Examples of species differences in drug sensitivity 106

Chapter 8 The gastrointestinal system 109

Drug-induced alterations of GI transit or motility 110

GI function 111

Assessment of intestinal transit 112

Determination of intestinal absorption 113

Methods of administering test substance 114

Methods for quantitating degree of absorption 115

Appearance in systemic fluids 115

Gastric emptying rate and gastric pH changes: a new model 117

Effects of drugs on gut immune system (jejunum, ileum, colon) 118

Candidate drugs to evaluate for effects on gut immune system 118

Chapter 9 Safety pharmacology of the immune system 123

PCA test for potential antigenicity of compound 125

Test method 127

CDER guidance for investigational new drugs 128

Overview of the immune system 129

Immunotoxic effects 136

Immunosuppression 137

Immunosuppressive drugs 138

Antimetabolites 138

Glucocorticosteroids 141

Cyclosporine 142

Nitrogen mustards 142

Estrogens 143

Heavy metals 143

Antibiotics 144

Immunostimulation 144

Hypersensitivity 144

Photosensitization 150

Autoimmunity 151

Chapter 10 Integration of evaluations of safety pharmacology endpoints into existing study designs 161

Rodent acute toxicity 162

Nonrodent acute toxicology 163

Repeated dose (IND pivotal toxicity) studies 166

Body weight 166

Clinical signs 167

Clinical pathology 168

Pharmacokinetics and metabolism 168

Integration 172

Safety pharmacology labs 181.

Notes:

Includes bibliographical references and index.

ISBN:

0849313805

OCLC:

51667823