Pharmacogenics - Challenges and Opportunities in Therapeutic Implementation

PHARMACOGENOMICS......Page 1
Copyright......Page 2
Dedication......Page 3
List of Contributors......Page 4
Preface......Page 6
1 - Principles of Pharmacogenomics: Pharmacokinetic, Pharmacodynamic, and Clinical Implications......Page 8
Introduction......Page 9
Polymorphisms in Cytochrome P450 Enzymes......Page 10
CYP2D6......Page 11
CYP2C19......Page 16
CYP2C9......Page 18
CYP3A4/5/7......Page 20
CYP2B6......Page 22
CYP1A2......Page 24
UDP-Glucuronosyl Transferase......Page 25
Dihydropyrimidine Dehydrogenase (DYPD)......Page 26
Glutathione-S-transferase......Page 27
ABCB1......Page 28
ABCG2......Page 30
OAT1B1......Page 31
Organic Cation Transporters......Page 33
Polymorphisms in Drug-Target Genes......Page 34
Drug Target Receptor Genes in Oncology......Page 35
Drug Target Receptor Genes in Cardiology......Page 37
Drug Target Genes in Pain Management......Page 39
Signal Transduction Proteins......Page 40
Enzyme Genes......Page 41
Ion Channel Genotype......Page 43
References......Page 44
2 - Governmental and Academic Efforts to Advance the Field of Pharmacogenomics......Page 61
Introduction......Page 62
Historical Efforts......Page 63
International HapMap Project......Page 64
1000 Genomes Project......Page 65
The ENCyclopedia of DNA Elements (ENCODE) Project......Page 66
Therapeutics for Rare and Neglected Diseases (TRND) Program......Page 67
Pharmacogenomics Research Network (PGRN)......Page 68
Pharmacogenomics Knowledge Base (PharmGKB)......Page 69
Clinical Pharmacogenetics Implementation Consortium (CPIC)......Page 70
Pharmacogene Variation (PharmVar) Consortium......Page 72
ClinGen......Page 73
Electronic Medical Records and Genomics (eMERGE) Network......Page 74
Implementing Genomics in Practice (IGNITE)......Page 75
The Role of the Food and Drug Administration and Other International Government Agencies......Page 76
Biomarker Qualification Program (BQP)......Page 77
Guidance Development......Page 78
Pharmacogenomics Biomarkers in Drug Labeling......Page 79
Diagnostic Approval/Clearance......Page 80
European Medicines Agency (EMA), European Union......Page 82
Questions for Discussion......Page 83
References......Page 84
3 - Incorporating Pharmacogenomics in Drug Development: A Perspective From Industry......Page 87
Introduction......Page 88
Genetic Research and New Drug Target Identification......Page 89
Genetics and Preclinical Animal Toxicology Studies......Page 91
Pharmacogenomic/Pharmacokinetic Research......Page 92
Pharmacogenomic/Pharmacodynamic Research......Page 93
Gefitinib......Page 94
Imatinib......Page 95
Irinotecan......Page 96
Challenges in Applying Pharmacogenomics to Drug Development......Page 98
Future Perspectives......Page 101
References......Page 102
Objectives......Page 108
Complexity of Genetic Variabilities and Nongenetic Influences......Page 109
Analytical Validity, Clinical Validity, and Clinical Utility......Page 111
Evaluation of Cost-Effectiveness......Page 114
Regulatory Approval of Pharmacogenomic Diagnostic Tests......Page 115
Integration of Testing Within the Healthcare Environment......Page 116
Reimbursement Issues......Page 119
Ethical, Legal, and Social Issues......Page 120
Incorporating Pharmacogenomics Into Drug Development......Page 122
Questions for Discussion......Page 123
References......Page 124
Introduction......Page 128
Therapy for Non-small-Cell Lung Cancer......Page 129
Therapy for Breast Cancer......Page 130
Therapy for Metastatic Colorectal Cancer......Page 131
Additional Biomarkers for Drug Toxicity......Page 132
The Path Forward for Implementation of Precision Oncology......Page 133
References......Page 134
6 - Pharmacogenetics in Cardiovascular Diseases......Page 138
Introduction......Page 139
CYP2C19 Genotype and Clopidogrel Responsiveness......Page 142
Paraoxonase-1 (PON1) Genotype and Clopidogrel Responsiveness......Page 145
Alternative Treatment Approaches in Patients With a CYP2C19 Nonfunctional Allele......Page 146
Guidelines for the Clinical Use of CYP2C19 Genotyping With Clopidogrel......Page 147
Randomized Controlled Trials Examining Outcomes With CYP2C19-Guided Antiplatelet Therapy......Page 148
Clinical Implementation of CYP2C19-Guided Antiplatelet Therapy......Page 149
Challenges With Warfarin......Page 150
Genes Affecting Warfarin Pharmacokinetics and Pharmacodynamics......Page 151
CYP2C9......Page 152
VKORC1......Page 153
CALU......Page 154
Warfarin Pharmacogenetics Dosing Algorithms......Page 155
Early Studies of Genotype-Guided Warfarin Dosing......Page 156
Large Randomized Clinical Trials of Genotype-Guided Warfarin Therapy......Page 157
Pharmacogenetic Guidelines......Page 159
Opportunities and Challenges for Warfarin Pharmacogenetics......Page 160
Pharmacogenetics of Statin Safety......Page 161
Pharmacogenetics of Statin Efficacy......Page 163
Ezetimibe Pharmacogenetics and NPC1L1 Genotype......Page 164
Tacrolimus Pharmacogenetics......Page 165
Genetic Determinants of β-Blocker Response......Page 166
Genetic Determinants of Response to Thiazide Diuretics......Page 167
Current Approach to Heart-Failure Management......Page 168
Pharmacogenetics of ACE Inhibitors in Heart Failure......Page 169
ADRB1 Genotype: A Case for Targeted β-Blocker Therapy......Page 170
Opportunity in Pharmacogenetics: Potential to Streamline Heart-Failure Therapy......Page 171
Pharmacogenetics of Drug-Induced Long QT Syndrome......Page 172
Questions for Discussion......Page 174
References......Page 175
7 - Pharmacogenomics in Psychiatric Disorders......Page 185
Antidepressants......Page 186
Antipsychotics......Page 189
Genes Encoding Drug Transporters......Page 190
Serotonin Transporter......Page 191
5-Hydroxytryptamine 2A (5-HT2A) Receptor......Page 195
Glutamate Receptor......Page 197
Genome-Wide Association Studies......Page 198
Potential Role of Other Molecular Pathways......Page 199
Dopamine Receptors......Page 200
Serotonergic System......Page 202
Additional Regulatory and Development Genes......Page 203
Adverse Drug Reaction with Antipsychotics......Page 204
Adverse Drug Reaction to Carbamazepine......Page 206
Application of Pharmacogenomics in Psychiatry......Page 208
Clinical Validity and Utility of Psychopharmacogenomics......Page 209
Cost-Effectiveness of Psychopharmacogenomics......Page 210
Challenge Posed by Ethnic Variation in Allele Frequency......Page 211
Clinical Application in Selective Patients......Page 213
Conclusions......Page 215
References......Page 216
Introduction......Page 230
Abacavir......Page 231
Tenofovir......Page 234
Zidovudine......Page 235
Efavirenz......Page 236
Nevirapine......Page 238
Atazanavir......Page 239
Raltegravir......Page 241
Dolutegravir......Page 242
Conclusion......Page 243
References......Page 244
Objectives......Page 249
Lessons From Diabetes-Susceptibility Genes......Page 250
Sulfonylureas......Page 252
Drug Targets......Page 254
Diabetes-Risk Alleles......Page 256
Drug Transporters......Page 257
Drug Targets......Page 258
Thiazolidinediones......Page 259
Drug Targets......Page 260
Other Antidiabetic Drugs......Page 261
Challenges and Opportunities of Pharmacogenomics in Diabetes......Page 262
Questions for Discussion......Page 263
References......Page 264
10 - A Look to the Future: Pharmacogenomics and Data Technologies of Today and Tomorrow......Page 272
Measuring Genes......Page 273
Measuring Drugs......Page 275
Structuring Data for Sharing......Page 276
Drug Data Standards......Page 277
Phenotype Data Standards......Page 279
Data Exchange Standards......Page 280
Federated Data Models......Page 281
Primary Evidence......Page 282
Tertiary Analysis......Page 283
Quantitative Summary Methods......Page 284
Conclusion......Page 285
References......Page 286
11 - The Importance of Ethnicity Definitions and Pharmacogenomics in Ethnobridging and Pharmacovigilance......Page 290
Introduction......Page 291
Ethnicity......Page 292
Japan......Page 293
China......Page 294
Malaysia......Page 295
Indonesia......Page 296
Ethnicity and Race as Defined by the US FDA......Page 297
Intrinsic Factor: (Pharmaco)genetics......Page 298
CYP2D6......Page 299
CYP2C9 and VKORC1......Page 300
CYP2C19: Clopidogrel......Page 301
Food......Page 302
Alternative, Complementary, and Traditional Medicines Use......Page 303
Conclusion......Page 306
Acceptability of Foreign Clinical Data......Page 308
Acceptability of Foreign Clinical Data and Drug Regulatory Procedures in East and Southeast Asia......Page 310
East Asia......Page 311
Southeast Asia......Page 314
Global Drug Development and Pharmacogenomics......Page 315
Pharmacogenomics and Ethnicity in Global Drug Development......Page 316
Conclusion......Page 318
References......Page 319
12 - Pharmacogenomics in Latin American Populations......Page 329
Latin American Admixture and Population Structure......Page 330
Latin America and Self-Reported Ethnicity......Page 333
Pharmacogenomic Variants Among Latin Americans......Page 336
Pharmacogenomic Variants in the Brazilian Population......Page 344
Pharmacogenomic Research in the Latin Americas......Page 350
Pharmacogenomic Research Studies in Brazil......Page 351
Pharmacogenomic Implementation in the Latin Americas......Page 355
Conclusion and Future Directions......Page 357
References......Page 358
Further Reading......Page 366
13 - Reactive, Point-of-Care, Preemptive, and Direct-to-Consumer Pharmacogenomics Testing......Page 369
Validity and Utility......Page 370
Point-of–Care Pharmacogenomic Testing......Page 371
Challenges of Preemptive Pharmacogenomics Testing......Page 373
Examples of Preemptive PGx Implementation......Page 374
Direct-to-Consumer Pharmacogenomic Testing......Page 376
Direct-To-Consumer Pharmacogenomics Testing Regulatory Landscape......Page 378
Advantages of Direct-To-Consumer Pharmacogenomics Testing......Page 379
Challenges of Direct-To-Consumer Pharmacogenomics Testing......Page 380
Conclusion and Future Perspective......Page 381
References......Page 382
Introduction......Page 385
Clinical Utility......Page 386
Cost-Effectiveness of Psychopharmacogenomic Testing......Page 389
Lessons Learned and Moving Forward......Page 391
References......Page 393
15 - Pharmacogenomics Education and Clinical Practice Guidelines......Page 395
Background......Page 396
Guideline Writing Process......Page 398
Applications in Clinical Practice......Page 399
Guideline Writing Process......Page 401
Applications in Clinical Practice......Page 402
Potential Needs......Page 403
Barriers and Challenges......Page 404
Clinician Education in Professional Schools......Page 406
Patient Education......Page 407
References......Page 411
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