Early characterization of toxicity and efficacy would significantly impact the overall productivity of pharmaceutical R&D and reduce drug candidate attrition and failure. By describing the available platforms and weighing their relative advantages and disadvantages, including microarray data analysis, Genomics in Drug Discovery and Development introduces readers to the biomarker, pharmacogenomic, and toxicogenomics toolbox. The authors provide a valuable resource for pharmaceutical discovery scientists, preclinical drug safety department personnel, regulatory personnel, discovery toxicologists, and safety scientists, drug development professionals, and pharmaceutical scientists.
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Preface.
Chapter 1: Introduction: Genomics and Personalized Medicine (Dimitri Semizarov).
1.1. Fundamentals of genomics.
1.2. The concept of personalized medicine.
1.3. Genomics technologies in drug discovery.
1.4. Scope of this book.
References.
Chapter 2: Genomics Technologies as Tools in Drug Discovery (Dimitri Semizarov).
2.1. Introduction to genomics technologies.
2.2. Gene expression microarrays: technology.
2.3. Gene expression microarrays: data analysis.
2.4. Comparative genomic hybridization: technology.
2.5. Comparative genomic hybridization: data analysis.
2.6. Microarray-based DNA methylation profiling.
2.7. Microarray-based microRNA profiling.
2.8. Technical issues in genomics experiments and regulatory submissions of microarray data.
2.9. Conclusion.
References.
Chapter 3: Genomic Biomarkers (Dimitri Semizarov).
3.1. Introduction into genomic biomarkers.
3.2. DNA biomarkers.
3.3. RNA biomarkers.
3.4. Clinical validation of genomic biomarkers.
References.
Chapter 4: Fundamental Principles of Toxicogenomics (Eric Blomme).
4.1. Introduction.
4.2. Fundamentals of toxicogenomics.
4.3. Analysis of toxicogenomics data.
4.4. Practical and logistic aspects of toxicogenomics.
4.5. Toxicogenomics reference databases.
4.6. Conclusion.
References.
Chapter 5: Toxicogenomics: Applications to In Vivo Toxicology (Eric Blomme).
5.1. The value of toxicogenomics in drug discovery and development.
5.2. Basic principles of toxicology in drug discovery and development.
5.3. Toxicogenomics in predictive toxicology.
5.4. Toxicogenomics in mechanistic toxicology.
5.5. Toxicogenomics and target-related toxicity.
5.6. Predicting species-specific toxicity.
5.7. Evaluation of idiosyncratic toxicity with toxicogenomics.
5.8. Conclusion.
References.
Chapter 6: Toxicogenomics: Applications in In Vitro Systems (Eric Blomme).
6.1. Introductory remarks on in vitro toxicology.
6.2. Overview of the current approaches to in vitro toxicology.
6.3. Toxicogenomics in in vitro systems: technical considerations.
6.4. Proof-of-concept studies using primary rat hepatocytes.
6.5. Use of gene expression profiling to assess genotoxicity.
6.6. Application of gene expression profiling for the in vitro detection of phopholipidosis.
6.7. Toxicogenomics in the assessment of idiosyncratic hepatotoxicity.
6.8. Do peripheral blood mononuclear cells represent a useful alternative in vitro model?
6.9. Current and future use of in vitro toxicogenomics.
6.10. Conclusion.
References.
Chapter 7: Germ Line Polymorphisms and Drug Response (Dimitri Semizarov).
7.1. Introduction into germline polymorphisms.
7.2. Polymorphisms and drug response in oncology.
7.3. Polymorphisms and response to anticoagulants.
7.4. Polymorphisms in neuroscience.
7.5. Polymorphisms and drug response in immunology.
7.6. Polymorphisms and response to antiviral agents.
7.7. Gene copy number polymorphisms.
7.8. Conclusions: approaches to identification of polymorphisms as predictors of drug response.
References.
Chapter 8: Pharmacogenetics of Drug Disposition (Anahita Bhathena).
8.1. Introduction.
8.2. Genes and polymorphisms affecting drug disposition.
8.3. Genomic biomarkers for PK studies.
8.4. Utility of PG--PK studies in early clinical trials.
8.5. Limitations of PG--PK studies.
8.6. Genotyping technologies.
8.7. Conclusion.
References.
Chapter 9: Overview of Regulatory Developments and Initiatives Related to the Use of Genomic Technologies in Drug Discovery and Development (Eric Blomme).
9.1. Introduction into recent regulatory developments in the genomic area.
9.2. FDA guidance on pharmacogenomic data submission.
9.3. Pharmacogenomic data submission: draft companion guidance.
9.4. Drug-diagnostic co-development concept paper.
9.5. Regulations for in vitro diagnostic assays.
9.6. Biomarker qualification.
9.7. Current initiatives relevant to pharmacogenomics.
9.8. Future impact of genomic data on drug development.
References.
Index.