Pharmacogenomic Testing in Current Clinical Practice: Implementation in the Clinical Laboratory

Pharmacogenomic Testing in Current Clinical Practice: Implementation in the Clinical Laboratory (Molecular and Translational Medicine)......Page 1
Front-matter......Page 2
Pharmacogenomic Testing in Current Clinical Practice......Page 4
Copyright......Page 5
Preface......Page 6
Acknowledgements......Page 8
Contents......Page 10
Contributors......Page 12
Part I: Basic Concepts......Page 17
1.1 Clinical Laboratory Tests......Page 19
1.3 Current Barriers......Page 21
1.4.2 Clinical Trials......Page 22
1.4.5 Laboratory Aspects and Guidelines......Page 24
1.4.6 Reimbursements......Page 26
1.4.7 Education, Training, and Pharmacogenomics Resources......Page 27
1.5 Conclusion......Page 28
References......Page 29
2.1 Introduction......Page 31
2.3 Microarray-Based Genotyping Platforms......Page 33
2.3.2 eSensor® Technology......Page 34
2.3.3 INFINITI™ and Luminex xTAG® Allele-Specific Primer Extension\r......Page 35
2.3.4 Verigene Technology......Page 38
2.3.5.1 Hydrolysis Probes......Page 39
2.3.5.2 Hybridization Probes......Page 41
2.4 Invader® Assay......Page 42
2.5 Sequencing......Page 43
2.6 Pyrosequencing......Page 44
2.7 Mass Spectrometry......Page 46
2.8 Practical Considerations......Page 48
References......Page 49
3.1 Introduction......Page 51
3.2 Economic Outcome Measures......Page 52
3.3.1 Pharmacogenomic Testing for Thiopurine Methyltransferase......Page 55
3.3.2 Pharmacogenomic Testing for Warfarin Dosing......Page 57
3.3.4 Pharmacogenomic Testing for Antipsychotic Drugs......Page 58
3.3.5 Miscellaneous Other Pharmacoeconomic Studies......Page 59
References......Page 60
4.1 Introduction......Page 63
4.1.1 Drug Toxicity......Page 64
4.2 Legal Framework......Page 65
4.3 Forensic Pathology Perspectives......Page 66
4.4.1 Drug Hypersensitivity In Vitro Diagnostics......Page 67
4.5.3 Warfarin......Page 68
4.6 Conclusions......Page 69
Reference......Page 70
Part II: Chemotherapeutics......Page 73
5.1 Pharmacology......Page 75
5.2 Pharmacokinetics......Page 76
5.3 Pharmacodynamics......Page 77
5.4 Toxicity......Page 78
5.5 Pharmacogenetics......Page 79
5.6 Pharmacoethnicity......Page 81
5.7 Clinical Utility of UGT1A1 Genotyping......Page 82
5.8 Conclusion......Page 83
References......Page 84
6.2 Tamoxifen Pharmacology......Page 93
6.3.1 CYP2D6 Polymorphisms......Page 96
6.3.2 CYP2D6 Inhibitors......Page 97
6.3.3 Role of Other Polymorphisms in Tamoxifen Treatment Outcome......Page 98
6.4 CYP2D6 Genotyping and Tamoxifen: Clinical Practice and Case Studies......Page 99
6.4.2.1 Presentation......Page 100
6.4.3.1 Presentation......Page 101
References......Page 102
7.2.1 Clinical Indications and Target Patient Populations......Page 107
7.2.2 Pharmacodynamics/Pharmacokinetics......Page 108
7.2.3 Dosing, Toxicity, and Monitoring Considerations......Page 111
7.2.4 Markers of Treatment Efficacy and Toxicity......Page 112
7.3.1 Relevant TPMT SNPs and Haplotypes......Page 114
7.3.2 Future Gene Associations and GWAS Studies......Page 117
7.4 Clinical Utility of Pharmacogenetic Testing for Personalized Medicine......Page 118
7.4.1 Dosage Adjustments......Page 122
7.5 Case Report......Page 123
7.5.1 How Do We Interpret JB’s Findings?......Page 124
References......Page 125
Part III: Specific Pharmacogenomic Targets: Cardiovascular Drugs......Page 131
8.1 Introduction......Page 133
8.2 Pharmacology of Warfarin......Page 134
8.3.1 CYP2C9......Page 136
8.3.2 Vitamin K Epoxide Reductase Complex 1......Page 137
8.4.2 IWPC and Advanced Algorithms......Page 138
8.4.3 Limitations of Dosing Algorithms......Page 140
8.5 Genome-Wide Association Studies......Page 141
8.6 Warfarin Genotype Testing Technologies......Page 143
8.7.1 Published Trials......Page 144
8.7.3 Ongoing Clinical Trials......Page 146
8.8 Pharmacologic Alternatives to Warfarin......Page 148
References......Page 149
9.1.1.1 Mechanism of Action......Page 155
9.1.1.3 Dosing and Duration of Therapy......Page 156
9.1.2 Variable Response, Drug–Drug Interactions, and Pharmacogenetics of Clopidogrel......Page 157
9.1.3 Therapeutic Implications of Pharmacogenomics of Clopidogrel and Novel Antiplatelet Agents......Page 158
9.1.4 Pharmacogenetic Testing......Page 159
9.2.1.1 Mechanism of Action......Page 160
9.2.1.3 Clinical Efficacy and Dosing......Page 161
9.3 Case Study......Page 162
References......Page 163
10.1 Introduction......Page 171
10.2 Genotype-Guided Drug Therapy......Page 172
10.4.1 Low-Density Lipoprotein Cholesterol Lowering......Page 173
10.5 Mortality and Prevention of MACE......Page 177
10.6 Statin Safety......Page 178
10.7 Physiogenomic Research: Simultaneous Prediction of Efficacy and Side Effects......Page 181
10.8 Conclusion......Page 182
References......Page 183
11.1 Statin Therapy, Clinical Events and the Need for a New Approach......Page 191
11.1.1 Blood Cholesterol Lowering History......Page 192
11.1.2 Clinical Relevance of RRR, ARR, and NNT......Page 193
11.1.3 Atherosclerosis Pathophysiology......Page 194
11.2 Kinesin Proteins......Page 195
11.3 Discovery of KIF6 and Relationship to CHD risk......Page 196
11.4.2 The KIF6 Polymorphism is Associated with Coronary Heart Disease in the Women’s Health Study......Page 197
11.4.4 The KIF6 Polymorphism is Associated with Coronary Heart Disease in the Placebo Arms of the CARE and WOSCOPS Studies......Page 198
11.4.6 KIF6 Polymorphism Predicts Risk for Coronary Heart Disease as Shown in Six Prospective Studies......Page 199
11.5 Lack of KIF6 polymorphism Associated with CHD Risk in Some Studies......Page 200
11.6 Pharmacogenomics......Page 202
11.6.1 KIF6 719Arg Polymorphism Predicts Response to Statin Therapy for Coronary Events in the CARE and WOSCOPS Trials......Page 203
11.6.2 KIF6 Predicts Response to Statin Therapy in Elderly Patients with Prior Vascular Disease in the PROSPER Trial......Page 204
11.6.3 KIF6 Predicts Response to Statin Therapy After Acute Coronary Syndromes in the PROVE IT-TIMI 22 Trial......Page 206
11.6.4 KIF6 Predicts Clinical Event Response to Statin Therapy as Shown in Four Randomized Clinical Trials......Page 207
11.7.1.4 Basis for Decision......Page 208
11.7.2.3 Clinical Decision Problem......Page 209
11.8 Conclusions......Page 210
References......Page 211
Part IV: Drugs that Cause Delayed Hypersensitivity......Page 215
12.1 Pharmacology and Clinical Use of Abacavir......Page 217
12.2 Abacavir Side Effects......Page 218
12.3 Pharmacogenetics of Abacavir Hypersensitivity......Page 219
12.5 Predictive Value of Genotype Testing for Patients on Abacavir......Page 222
12.6 Application of HLA-B*5701 Screening to the Clinic......Page 223
12.7 Case Report......Page 225
References......Page 226
13.1 Pharmacology of Allopurinol......Page 229
13.1.2 Target Patient Populations......Page 230
13.1.4 Dosing, Pharmacokinetics, and Pharmacodynamics......Page 231
13.3 Pharmacogenetics and Pharmacogenomics of Allopurinol......Page 232
13.4 Clinical Utility of PGx Testing in Personalized Medicine......Page 235
References......Page 237
14.1.1 Clinical Indications and Patient Populations for Carbamazepine......Page 241
14.1.2 Alternative AED Medications for Carbamazepine......Page 242
14.1.3 Dosing, Pharmacokinetics and Pharmacodynamics of Carbamazepine......Page 243
14.1.4 Side Effects and Toxicities of Carbamazepine......Page 244
14.2.1 HLA-B*1502 and CBZ-SJS/TEN in Han Chinese......Page 245
14.2.2 HLA-B*1502 and CBZ-SJS/TEN in Asians and Caucasians......Page 246
14.2.4 HLA-B*1502 and Other AEDs-SJS/TEN......Page 247
14.3.1 Pharmacogenetic Test and FDA Recommendation......Page 248
14.4 Case Report......Page 249
References......Page 250
Part V: Miscellaneous Drugs......Page 253
15.1 Introduction......Page 255
15.2.2 Hepatotoxicity......Page 256
15.2.3 Pharmacogenetics......Page 257
15.3.1 General Pharmacology......Page 259
15.3.3 Pharmacogenetics......Page 260
References......Page 261
16.1 Clinical Indication and Mechanism of Action......Page 265
16.2 Dosing Variability and Toxicities......Page 267
16.3 Therapeutic Drug Monitoring and Pharmacodynamic Monitoring......Page 268
16.4 Pharmacogenetics and Pharmacogenomics......Page 270
16.5 Clinical Utility of Pharmacogenetic Testing......Page 273
16.7.1 Case 1. A 6-Month Long “Trial-and-Error” Tacrolimus Dose Titration......Page 274
References......Page 276
Index......Page 283