Venitz / Sittner Appropriate Dose Selection - How to Optimize Clinical Drug Development

1. Auflage 2007
ISBN: 978-3-540-49529-1
Verlag: Springer Berlin Heidelberg
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 59, 216 Seiten

Reihe: Ernst Schering Foundation Symposium Proceedings

Optimal dose individualization has become more important in improving clinical efficacy and safety, given the variability in drug response, e.g., due to concurrent illnesses or co-medications. Therefore, the role of optimal dose finding in early clinical drug development so as to maximize successful clinical use is emphasized. The continued use of biomarkers – based on the (known) pharmacology of the drug and/or biology of the underlying disease – along with exposure–response evaluation throughout all phases of drug development can quantitatively integrate clinical pharmacology knowledge, provide early proof of concept, and help in rational dose selection and rational drug product labeling for clinical use.

Autoren/Hrsg.

Venitz, J.

Sittner, W.

Inhaltsverzeichnis

1;Preface;5
2;Contents;10
3;List of Editors and Contributors;12
3.1;Editors;12
3.2;Contributors;12
4;1 Extrapolation of Preclinical Data into Clinical Reality – Translational Science;16
5;2 Smarter Candidate Selection – Utilizing Microdosing in Exploratory Clinical Studies;21
5.1;2.1 The Need for Exploratory Clinical Studies in the Successful Development of New Drugs;22
5.2;2.2 Concept of Microdosing;24
5.3;2.3 Applicability and Advantages of Microdosing;25
5.4;2.4 Prerequisites and Preparation for a Human Microdosing Study;27
5.5;2.5 Future of Microdosing;31
5.6;2.6 Conclusion;40
5.7;References;40
6;3 The Applications of Biomarkers in Early Clinical Drug Development to Improve Decision- Making Processes;42
6.1;3.1 Introduction;43
6.2;3.2 Definition and Classification;44
6.3;3.3 Why DoWe Need Biomarkers?;45
6.4;3.4 Validation;47
6.5;3.5 Regulatory Aspects;48
6.6;3.6 Examples for Using Biomarkers in Early Clinical Development;50
6.7;3.7 Conclusions;55
6.8;References;55
7;4 Using Exposure – Response and Biomarkers to Streamline Early Drug Development;59
7.1;Abbreviations;60
7.2;4.1 Guiding Principles;61
7.3;4.2 Role of Biomarkers in Drug Development;65
7.4;4.3 Case Example;70
7.5;4.4 Conclusions;73
7.6;References;74
8;5 Experiences with Dose Finding in Patients in Early Drug Development: The Use of Biomarkers in Early Decision Making;76
8.1;5.1 Introduction;77
8.2;5.2 Use of Biomarkers in Early Decision Making;78
8.3;5.3 Characterising the Dose Response;79
8.4;5.4 Applied Clinical Biomarkers: Two Examples from the Genitourinary Therapeutic Area;80
8.5;5.5 Summary;89
8.6;References;90
9;6 Genotype and Phenotype Relationship in Drug Metabolism;91
9.1;6.1 Introduction;92
9.2;6.2 Genotype–Phenotype Relations Leading to Dosage Recommendations;94
9.3;6.3 Genotype-Based Therapeutic Failure with 5- Hydroxytryptamine Type- 3 Receptor Antagonists;97
9.4;6.4 Individual Variations in CYP2C19-Metabolism of Proton Pump Inhibitors Determine Their Efficacy;98
9.5;6.5 Cyclophosphamide Kinetics Related to CYP2C19 Polymorphism;100
9.6;6.6 CYP2C9 Polymorphism;101
9.7;6.7 Estrogen Metabolism by CYP1A1 Variants;102
9.8;6.8 Genotype–Phenotype Relations in Drug Transporters;103
9.9;6.9 Some Concluding Statements Regarding Pharmacogenetics;106
9.10;References;107
10;7 Clinical Trials in Elderly Patients;111
10.1;7.1 Pharmacokinetics;112
10.2;7.2 Pharmacodynamics;115
10.3;7.3 Adverse Drug Reactions;116
10.4;7.4 Drug Interactions;117
10.5;7.5 Clinical Trial Design;117
10.6;7.6 Conclusions;118
10.7;References;119
11;8 Dose Finding in Pediatric Patients;120
11.1;8.1 Peculiarities of Childhood and Adolescence;121
11.2;8.2 Reasons for the Lack of Clinical Trials in Children;121
11.3;8.3 How to Select the Appropriate Dose?;122
11.4;8.4 Do We Need New Drugs?;124
11.5;8.5 The Role of Therapy Optimizing Studies in Pediatric Oncology;126
11.6;8.6 The Future;127
11.7;References;128
12;9 Integration of Pediatric Aspects into the General Drug Development Process;131
12.1;9.1 Clinical Drug Development is a Young Discipline;132
12.2;9.2 Off-Patent Use of Medicines in Children;132
12.3;9.3 US Pediatric Legislation and the Emerging EU Pediatric Regulation;133
12.4;9.4 Timing of Pediatric Development, Deferrals, andWaivers;135
12.5;9.5 Integrating Pediatric Aspects into the General Drug Development Process;136
12.6;9.6 Building up Pediatric Competency in Pharmaceutical Companies;138
12.7;9.7 Will the EU Draft Regulation Leading to More Pediatric Research in the Near Future?;138
12.8;9.8 Globalization of Clinical Research and Europe’s Competitiveness;139
12.9;9.9 Conclusions;140
12.10;References;140
13;10 Current Stumbling Blocks in Oncology Drug Development;143
13.1;10.1 Introduction;144
13.2;10.2 Multitude of Targets: How to Select a Target?;144
13.3;10.3 Validation of a Target;145
13.4;10.4 Dose and Dose Regimen Findings with Molecularly Targeted Drugs;151
13.5;10.5 Appropriate Selection of Clinical Endpoints for Benefit Prediction;152
13.6;10.6 Integration of New Drugs into Standard Treatment;153
13.7;10.7 Conclusions;155
13.8;References;155
14;11 Exploratory IND: A New Regulatory Strategy for Early Clinical Drug Development in the United States;158
14.1;11.1 Introduction: Challenges in Drug Development Today;159
14.2;11.2 New Regulatory Pathways for Exploratory Development;161
14.3;11.3 Conclusion;169
14.4;References;170
15;12 Ethnic Aspects of Cancer Trials in Asia;171
15.1;12.1 Ethnic Differences in Cancer Epidemiology;172
15.2;12.2 Differences in Pathology and Etiology of Cancer;173
15.3;12.3 Interethnic Differences in Drug Response;174
15.4;12.4 Cultural Differences;174
15.5;12.5 Conclusion;175
15.6;References;175
16;13 Evaluation of the Effect on Cardiac Repolarization ( QTc Interval) of Oncologic Drugs;176
16.1;13.1 Background;177
16.2;13.2 Basic ECG Issues Relevant to Clinical Research;178
16.3;13.3 Recent Regulatory Guidances on the Use of ECGs in Clinical Research;180
16.4;13.4 Clinical Problems with Assessing ECG Effects of Cytotoxic Oncology Drugs;183
16.5;13.5 A New Technology to Record Standard 12-Lead ECGs;186
16.6;13.6 What Is the Regulatory Implication of Finding a Drug Prolongs Cardiac Repolarization?;187
16.7;References;188
17;14 The Role of PET Scanning in Determining Pharmacoselective Doses in Oncology Drug Development;190
17.1;14.1 Background to Molecular Imaging;191
17.2;14.2 Preclinical Work;191
17.3;14.3 In Vivo Pharmacokinetics;191
17.4;14.4 Pharmacodynamics;194
17.5;14.5 Conclusion;196
17.6;References;197
18;15 Biometrical Aspects of Drug Development;199
18.1;15.1 Introduction;199
18.2;15.2 Phase I Trials;200
18.3;15.3 Continual Reassessment Method;204
18.4;15.4 Practicalities;207
18.5;References;210
19;16 Preventing Postmarketing Changes in Recommended Doses and Marketing Withdrawals;212
19.1;16.1 Introduction;213
19.2;16.2 How Often Are Marketed Doses Changed?;213
19.3;16.3 Why Are Marketed Doses Changed?;214
19.4;16.4 What Are the Implications or Consequences of Getting the Marketed Dose Wrong?;215
19.5;16.5 How to Avoid Postmarketing Dosage Changes;216
19.6;16.6 Conclusions;218
19.7;References;218