Appropriate Dose Selection - How to Optimize Clinical Drug Development (eBook)

Preface 5
Contents 10
List of Editors and Contributors 12
Editors 12
Contributors 12
1 Extrapolation of Preclinical Data into Clinical Reality – Translational Science 16
2 Smarter Candidate Selection – Utilizing Microdosing in Exploratory Clinical Studies 21
2.1 The Need for Exploratory Clinical Studies in the Successful Development of New Drugs 22
2.2 Concept of Microdosing 24
2.3 Applicability and Advantages of Microdosing 25
2.4 Prerequisites and Preparation for a Human Microdosing Study 27
2.5 Future of Microdosing 31
2.6 Conclusion 40
References 40
3 The Applications of Biomarkers in Early Clinical Drug Development to Improve Decision- Making Processes 42
3.1 Introduction 43
3.2 Definition and Classification 44
3.3 Why DoWe Need Biomarkers? 45
3.4 Validation 47
3.5 Regulatory Aspects 48
3.6 Examples for Using Biomarkers in Early Clinical Development 50
3.7 Conclusions 55
References 55
4 Using Exposure – Response and Biomarkers to Streamline Early Drug Development 59
Abbreviations 60
4.1 Guiding Principles 61
4.2 Role of Biomarkers in Drug Development 65
4.3 Case Example 70
4.4 Conclusions 73
References 74
5 Experiences with Dose Finding in Patients in Early Drug Development: The Use of Biomarkers in Early Decision Making 76
5.1 Introduction 77
5.2 Use of Biomarkers in Early Decision Making 78
5.3 Characterising the Dose Response 79
5.4 Applied Clinical Biomarkers: Two Examples from the Genitourinary Therapeutic Area 80
5.5 Summary 89
References 90
6 Genotype and Phenotype Relationship in Drug Metabolism 91
6.1 Introduction 92
6.2 Genotype–Phenotype Relations Leading to Dosage Recommendations 94
6.3 Genotype-Based Therapeutic Failure with 5- Hydroxytryptamine Type- 3 Receptor Antagonists 97
6.4 Individual Variations in CYP2C19-Metabolism of Proton Pump Inhibitors Determine Their Efficacy 98
6.5 Cyclophosphamide Kinetics Related to CYP2C19 Polymorphism 100
6.6 CYP2C9 Polymorphism 101
6.7 Estrogen Metabolism by CYP1A1 Variants 102
6.8 Genotype–Phenotype Relations in Drug Transporters 103
6.9 Some Concluding Statements Regarding Pharmacogenetics 106
References 107
7 Clinical Trials in Elderly Patients 111
7.1 Pharmacokinetics 112
7.2 Pharmacodynamics 115
7.3 Adverse Drug Reactions 116
7.4 Drug Interactions 117
7.5 Clinical Trial Design 117
7.6 Conclusions 118
References 119
8 Dose Finding in Pediatric Patients 120
8.1 Peculiarities of Childhood and Adolescence 121
8.2 Reasons for the Lack of Clinical Trials in Children 121
8.3 How to Select the Appropriate Dose? 122
8.4 Do We Need New Drugs? 124
8.5 The Role of Therapy Optimizing Studies in Pediatric Oncology 126
8.6 The Future 127
References 128
9 Integration of Pediatric Aspects into the General Drug Development Process 131
9.1 Clinical Drug Development is a Young Discipline 132
9.2 Off-Patent Use of Medicines in Children 132
9.3 US Pediatric Legislation and the Emerging EU Pediatric Regulation 133
9.4 Timing of Pediatric Development, Deferrals, andWaivers 135
9.5 Integrating Pediatric Aspects into the General Drug Development Process 136
9.6 Building up Pediatric Competency in Pharmaceutical Companies 138
9.7 Will the EU Draft Regulation Leading to More Pediatric Research in the Near Future? 138
9.8 Globalization of Clinical Research and Europe’s Competitiveness 139
9.9 Conclusions 140
References 140
10 Current Stumbling Blocks in Oncology Drug Development 143
10.1 Introduction 144
10.2 Multitude of Targets: How to Select a Target? 144
10.3 Validation of a Target 145
10.4 Dose and Dose Regimen Findings with Molecularly Targeted Drugs 151
10.5 Appropriate Selection of Clinical Endpoints for Benefit Prediction 152
10.6 Integration of New Drugs into Standard Treatment 153
10.7 Conclusions 155
References 155
11 Exploratory IND: A New Regulatory Strategy for Early Clinical Drug Development in the United States 158
11.1 Introduction: Challenges in Drug Development Today 159
11.2 New Regulatory Pathways for Exploratory Development 161
11.3 Conclusion 169
References 170
12 Ethnic Aspects of Cancer Trials in Asia 171
12.1 Ethnic Differences in Cancer Epidemiology 172
12.2 Differences in Pathology and Etiology of Cancer 173
12.3 Interethnic Differences in Drug Response 174
12.4 Cultural Differences 174
12.5 Conclusion 175
References 175
13 Evaluation of the Effect on Cardiac Repolarization ( QTc Interval) of Oncologic Drugs 176
13.1 Background 177
13.2 Basic ECG Issues Relevant to Clinical Research 178
13.3 Recent Regulatory Guidances on the Use of ECGs in Clinical Research 180
13.4 Clinical Problems with Assessing ECG Effects of Cytotoxic Oncology Drugs 183
13.5 A New Technology to Record Standard 12-Lead ECGs 186
13.6 What Is the Regulatory Implication of Finding a Drug Prolongs Cardiac Repolarization? 187
References 188
14 The Role of PET Scanning in Determining Pharmacoselective Doses in Oncology Drug Development 190
14.1 Background to Molecular Imaging 191
14.2 Preclinical Work 191
14.3 In Vivo Pharmacokinetics 191
14.4 Pharmacodynamics 194
14.5 Conclusion 196
References 197
15 Biometrical Aspects of Drug Development 199
15.1 Introduction 199
15.2 Phase I Trials 200
15.3 Continual Reassessment Method 204
15.4 Practicalities 207
References 210
16 Preventing Postmarketing Changes in Recommended Doses and Marketing Withdrawals 212
16.1 Introduction 213
16.2 How Often Are Marketed Doses Changed? 213
16.3 Why Are Marketed Doses Changed? 214
16.4 What Are the Implications or Consequences of Getting the Marketed Dose Wrong? 215
16.5 How to Avoid Postmarketing Dosage Changes 216
16.6 Conclusions 218
References 218