Front Cover 1
Drug Monitoring and Clinical Chemistry 4
Copyright Page 5
Contents 8
Preface 6
Chapter 1. Sample preparation for the analysis of drugs in biological fluids 20
1.1 Introduction 20
1.2 Conventional sample preparation for biological samples 21
1.3 Microextraction methods for biological analyses 26
1.4 Future prospects in biological sample preparation methods 29
1.5 Acknowledgements 30
1.6 References 30
Chapter 2. Chromatographic methods for the analysis of drugs in biological fluids 34
2.1 Introduction 34
Part I. Chromatographic methods of analysis of drugs in biological fluids 35
2.2 HPLC 35
2.3 LC/MS 58
2.4 GC 61
2.5 GC/MS 61
2.6 Other methods 66
Part II. Chromatographic methods for the analysis of chiral drugs in biological fluids 68
2.7 Introduction 68
2.8 Pirkle concept chiral columns 75
2.9 Cellulose-derivative chiral columns 75
2.10 Amylose-derivative chiral columns 82
2.11 Cyclodextrin-derivative chiral columns 83
2.12 Cyclodextrin-derivative chiral mobile phase additives 83
2.13 Protein chiral columns 84
2.14 Macrocylic antibiotic chiral columns 85
2.15 GC 86
2.16 Indirect chiral chromatographic methods 86
2.17 Other methods 87
2.18 List of abbreviations 87
2.19 References 88
Chapter 3. Capillary electrophoresis for the determination of drugs in biological fiuids 96
3.1 Introduction 97
3.2 CE, HPLC and immunoassays in drug analysis 97
3.3 Instrumentation and detection 98
3.4 Modes of CE in drug analysis and detection 99
3.5 Buffers 100
3.6 Sample size and injection 100
3.7 Sample preparation in CE 100
3.8 Precision 104
3.9 CE and basic information for drugs 104
3.10 Selected applications of drugs analyzed by CE 107
3.11 References 111
Chapter 4. Immunoassays for therapeutic drug monitoring and clinical toxicology 114
4.1 Introduction 114
4.2 Immunoassays 117
4.3 References 129
Chapter 5. Validation of bioanalytical methods 132
5.1 Introduction 132
5.2 Requirements for bioanalytical methods 132
5.3 Pre-study validation 133
5.4 Within study validation 139
5.5 Definitions 144
5.6 Abbreviations 146
5.7 References 147
Chapter 6. Pharmacokinetic methods for analysis, interpretation, and management of TDM data, and for individualizing drug dosage regimens optimally 148
6.1 Introduction and overview 148
6.2 The need for models 151
6.3 Maximum aposteriori probability (MAP) Bayesian individualization of drug dosage regimens 152
6.4 Analyzing assay and environmental sources of error 155
6.5 Examples of MAP Bayesian target-oriented, model-based, approaches to patient care 158
6.6 Other studies of outcome and cost of TDM 160
6.7 Why we really monitor serum concentrations: for clinician-managed, model-based, target-oriented individualized drug therapy 165
6.8 Optimal TDM monitoring strategies 166
6.9 Special cases: entering initial conditions – changing population models during the fitting procedure 169
6.10 Linked pharmacodynamic models: bacterial growth and kill 171
6.11 Other linked pharmacodynamic models: aminoglycoside nephrotoxicity and ototoxicity 174
6.12 Limitations of current map bayesian adaptive control 176
6.13 Overcoming the separation principle: “multiple model” design of maximally precise drug dosage regimens 177
6.14 The future of individualized drug therapy 184
6.15 Acknowledgments 185
6.16 References 185
Chapter 7. Dose and therapy individualisation in cancer chemotherapy 188
7.1 Introduction 188
7.2 Concepts of dose finding in oncology 189
7.3 5-Fluorouracil (5-FU) 205
7.4 In-vitro-cytotoxicity as a tool for therapy individualisation 205
7.5 Dosing based surrogate markers 206
7.6 Conclusions 206
7.7 References 207
Chapter 8. Rationale and utility of therapeutic drug monitoring for the optimization of antibiotic therapy 214
8.1 Introduction 214
8.2 Vancomycin 215
8.3 Aminoglycosides 218
8.4 Antitubercular agents 224
8.5 Antiretroviral therapeutic drug monitoring (ATDM) 229
8.6 Conclusion 231
8.7 References 231
Chapter 9. Therapeutic drug monitoring of antiepileptic drugs 240
Abstract 240
9.1 Introduction 240
9.2 Established antiepileptic drugs 245
9.3 Newer antiepileptic drugs 256
9.4 References 267
Chapter 10. Therapeutic drug monitoring of antidepressant and antipsychotic drugs 274
10.1 Introduction 274
10.2 Rationales for use of therapeutic drug monitoring of antidepressant and antipsychotic drugs 274
10.3 Antidepressants 277
10.4 Antipsychotics 284
10.5 Lithium 287
10.6 Conclusion 287
10.7 References 288
Chapter 11. Monitoring immunosuppressive drugs 292
11.1 Introduction 292
11.2 Cyclosporin 293
11.3 Tacrolimus 296
11.4 Mycophenolic acid 299
11.5 Sirolimus 302
11.6 Everolimus 305
11.7 External proficiency testing 305
11.8 Conclusions 306
11.9 References 307
Chapter 12. Pharmacogenomics: Methodologies for genotyping and phenotyping 316
12.1 Introduction 316
12.2 Methods for phenotyping 316
12.3 Discovery of unknown polymorphisms 317
12.4 Identification of known polymorphisms 319
12.5 Conclusion 334
12.6 References 335
Chapter 13. Applications of genotyping and phenotyping for clinically-relevant polymorphisms of drug metabolizing enzymes and drug transporters 340
13.1 Introduction 340
13.2 Thiopurine-S-Methyltransferase (TPMT) 342
13.3 Dihydropyrimidine dehydrogenase (DPD) 343
13.4 Thymidylate synthase (TS) 345
13.5 N-Acetyltransferase type 2 (NAT2) 346
13.6 Cytochrome P450 2D6 (CYP2D6) 349
13.7 Cytochrome P450 2C9 (CYP2C9) 352
13.8 Cytochrome P450 2C19 (CYP2C19) 354
13.9 Cytochrome P450 3A4 (CYP3A4) 356
13.10 P-Glycoprotein (PGP) 359
13.11 Perspective 362
13.12 References 362
Subject index 374