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Drug Discovery and Evaluation: Methods in Clinical Pharmacology-[1st Edition.]-[2011]-[pdf]-[H.Gerhard Vogel, Jochen Maas, Alexander Gebauer]

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    书籍信息:
    标题: Drug Discovery and Evaluation: Methods in Clinical Pharmacology
    语言: English
    格式: pdf
    大小: 9.4M
    页数: 549
    年份: 2011
    作者: H.Gerhard Vogel, Jochen Maas, Alexander Gebauer
    版次: 1st Edition.
    出版社: Springer
    DOI: 10.1007/978-3-540-89891-7_A.1

    简介

    Drug Discovery and Evaluation has become a more and more difficult, expensive and time-consuming process. The effect of a new compound has to be detected by in vitro and in vivo methods of pharmacology. The activity spectrum and the potency compared to existing drugs have to be determined. As these processes can be divided up stepwise we have designed a book series "Drug Discovery and Evaluation" in the form of a recommendation document. The methods to detect drug targets are described in the first volume of this series "Pharmacological Assays" comprising classical methods as well as new technologies. Before going to man, the most suitable compound has to be selected by pharmacokinetic studies and experiments in toxicology. These preclinical methods are described in the second volume „Safety and Pharmacokinetic Assays". Only then are first studies in human beings allowed. Special rules are established for Phase I studies. Clinical pharmacokinetics are performed in parallel with human studies on tolerability and therapeutic effects. Special studies according to various populations and different therapeutic indications are necessary. These items are covered in the third volume: „Methods in Clinical Pharmacology".


    目录
    General Introduction......Page 2
    Introduction......Page 4
    B.2.1 Human Clearance Prediction by Allometric Scaling......Page 6
    B.2.4 Human CL Scaling by ``Liver blood Flow´´ - Scaling with Monkey Data......Page 9
    REFERENCES AND FURTHER READING......Page 10
    B.3.1.3 Study Design......Page 12
    B.3.2 Use of Previous Data to Design Study......Page 13
    B.3.7 Additional Pharmacokinetic Parameters After Oral Dosing......Page 14
    B.3.9 Need to Measure Drug in Urine......Page 15
    REFERENCES AND FURTHER READING......Page 18
    B.4.3 Mechanisms Leading to Lack of Dose Proportionality......Page 20
    B.4.5.2 Discrete Model......Page 21
    B.4.6 Exploratory Assessment of Dose Linearity/Proportionality: Single Dose Study Design......Page 22
    B.4.6.3 Study Design......Page 23
    B.4.6.9.1 Plasma Concentrations......Page 24
    B.4.6.9.2 Pharmacokinetic Parameters......Page 25
    B.4.7.6 Criteria for PK Evaluation......Page 27
    B.4.7.8.4 Assessment of the Dose-Exposure Relationship Based on a Discrete Model for Doses per Kilogram Body Weight......Page 28
    B.4.7.9 Results......Page 29
    B.4.8.5 Treatments......Page 32
    B.4.8.8.2 Dose Effect......Page 33
    B.4.8.9.1 Plasma Concentrations......Page 34
    B.4.8.9.2 Pharmacokinetic Parameters......Page 35
    REFERENCES AND FURTHER READING......Page 37
    B.5.1.1.4 Treatments......Page 38
    B.5.2 Example......Page 39
    B.5.3.1 Protocol Outline......Page 40
    B.5.3.1.6 Pharmacokinetic Data......Page 41
    B.5.4.3 Statistical/Analytical Issues......Page 42
    REFERENCES AND FURTHER READING......Page 45
    Special Populations: Profiling the Effect of Obesity on Drug Disposition and Pharmacodynamics......Page 46
    B.6.5 Pharmacodynamics......Page 47
    B.6.6.1.1 Healthy Lean Subject Population......Page 48
    B.6.6.2.2 Obese Subject Population......Page 49
    REFERENCES AND FURTHER READING......Page 50
    Special Populations: Renal Impairment......Page 52
    B.7.2 Evaluation......Page 53
    B.7.5 PK Study......Page 54
    B.7.7 Dose Adjustment......Page 56
    REFERENCES AND FURTHER READING......Page 58
    Special Populations: Hepatic Impairment......Page 60
    B.8.1 Protocol......Page 61
    B.8.2 PK Study......Page 62
    REFERENCES AND FURTHER READING......Page 63
    Special Populations: Protein Binding Aspects......Page 64
    REFERENCES AND FURTHER READING......Page 68
    B.10.1 Introduction and Guidelines......Page 70
    B.10.2 Dosimetry......Page 71
    B.10.2.2 Dosimetry Calculation......Page 72
    B.10.4.2 Primary Objectives......Page 76
    B.10.4.7 Exclusion Criteria......Page 77
    B.10.5 Analytic Instrumentation and Methods Used During Preparation, Conduct, and Evaluation of hADME Studies......Page 78
    B.10.5.1 Metabolic Profiling......Page 79
    B.10.5.2 Structure Elucidation......Page 83
    B.10.6.2 Example 2: Study Design and Kinetic and Mass Balance Results......Page 91
    B.10.6.3 Example 3: Metabolic Profiling......Page 96
    REFERENCES AND FURTHER READING......Page 98
    B.11.2.1 Technical Considerations for 14C-Labeling......Page 102
    B.11.2.3 Planning of a 14C-Synthesis......Page 103
    B.11.2.4 Methods for 14C-Syntheses......Page 104
    B.11.2.8 Analysis......Page 108
    B.11.3.2 Chemical Methods for 3H-Labeling......Page 109
    B.11.4.1 General Study Requirements Dain et al. 1994......Page 110
    B.11.4.4 General Quality-Related Measures that Should be Applied for the Synthesis of Radioactive APIs......Page 111
    B.11.5 Conclusion and Outlook......Page 112
    REFERENCES AND FURTHER READING......Page 113
    B.12.1.0.0 References and Further Reading......Page 116
    B.12.2.1.2 Study Design......Page 117
    B.12.2.1.6 Pharmacokinetic Data......Page 118
    B.12.2.2.1 Results: Pharmacokinetics......Page 119
    B.12.3.1.2 Study Design......Page 120
    B.12.3.1.6 Pharmacokinetic Data......Page 121
    B.12.3.2.1 Results: Pharmacokinetics......Page 122
    B.12.4 Profiling the Effect of an Enzyme Inducer on Pharmacokinetics and Pharmacodynamics of Oral Contraceptives......Page 123
    B.12.4.1.5 Treatments......Page 124
    B.12.4.2.1 Results......Page 125
    REFERENCES AND FURTHER READING......Page 127
    B.13.1 Introduction......Page 130
    Intravenous Administration......Page 131
    B.13.1.2 Basic Equations and Authorities Requirements......Page 147
    B.13.1.3 Mechanistic Static Model MSM......Page 148
    B.13.1.4 Mechanistic Dynamic Model MDM......Page 151
    B.13.1.5 MSM Versus MDM......Page 152
    REFERENCES AND FURTHER READING......Page 154
    Specific Studies for Formulation Development......Page 158
    B.14.1.1.5 Pharmacokinetic Data......Page 159
    B.14.2.1.3 Study Design......Page 160
    Treatment Group II......Page 161
    B.14.2.1.6 Pharmacokinetic Data......Page 162
    B.14.2.1.8 Results - Hypothetical In Vivo Dissolution......Page 163
    REFERENCES AND FURTHER READING......Page 168
    Absolute and Relative Bioavailability......Page 170
    B.15.1.1.5 Pharmacokinetic Data......Page 171
    B.15.1.2.1 Results - Pharmacokinetics......Page 172
    B.15.2.1.5 Pharmacokinetic Data......Page 173
    B.15.2.2.2 Results - Pharmacokinetics......Page 174
    B.15.2.3.2 Treatment A vs. Treatment C......Page 175
    B.15.2.3.3 Treatment B vs. Treatment C......Page 176
    REFERENCES AND FURTHER READING......Page 177
    B.16.2.2 Other Crossover Designs......Page 178
    B.16.3.1 Statistical Analysis for the 2x2 Crossover......Page 179
    B.16.4 Sample Size Determination......Page 180
    B.16.5 Onset of Action......Page 181
    B.16.6.2 Two-Stage Two-Group Sequential Design......Page 182
    B.16.6.3 Scaled Average BE......Page 183
    B.16.6 AppendixB.16.3. Example of SABE Analysis......Page 184
    REFERENCES AND FURTHER READING......Page 185
    B.17.1.1.1 Sources of Pharmacokinetic Variability......Page 186
    B.17.1.1.3 Prior Knowledge for Individual PK Estimates......Page 187
    B.17.1.2.2 Relationship Between Concentration and Clinical Success......Page 188
    B.17.1.2.3 Success Rate Depending on CL/F and Dose Rate......Page 189
    B.17.2.1 Introduction......Page 190
    B.17.2.2.2 Population Level of the Pharmacokinetic Model......Page 191
    B.17.2.3.1 Relationship Between Css and Clinical Outcome......Page 192
    B.17.2.3.2 Dose Recommendation......Page 193
    B.17.2.3.4 Relevance of Covariates?......Page 194
    B.17.3 Conclusion......Page 195
    B.17.4.2.1 Materials and Methods......Page 196
    B.17.4.2.2 Results......Page 197
    B.17.4.3.1 Materials and Methods......Page 198
    B.17.4.3.2 Results......Page 199
    B.17.4.4 Conclusions......Page 201
    REFERENCES AND FURTHER READING......Page 202
    B.18.2 Mass Analyzers......Page 204
    B.18.3 Internal Standards......Page 205
    B.18.6 Protein Precipitation......Page 206
    B.18.9 Eleven Steps on Method Development......Page 207
    B.18.10 Sample Preparation for ``Large Molecules´´......Page 208
    B.18.12 Validation......Page 209
    B.18.13.5 Acceptance Criteria for Stability, Dilution, Hemolysis, and Concomitant Medications......Page 210
    B.18.13.10 Matrix Effects......Page 211
    B.18.13.11 Sample Analysis Routine Application of the Assay......Page 212
    B.18.15 Incurred Sample Reproducibility ISR......Page 213
    B.18.16 Incurred Sample Accuracy ISA......Page 214
    B.18.17 Incurred Sample Stability ISS......Page 215
    REFERENCES AND FURTHER READING......Page 216
    B.19.2 Biomarker Definitions......Page 220
    B.19.3 Current Status and Trends in Biomarker Science......Page 221
    B.19.3.1 Biomarkers Are Currently Used in:......Page 222
    B.19.4 Biomarker Assay Development and Validation......Page 223
    B.19.4.1 Development of Assay......Page 224
    B.19.4.3 Validation Samples and Quality Controls Samples......Page 226
    B.19.4.11 Processed Sample Stability......Page 227
    B.19.5.1 Characterization of Animal Models Using Clinically Validated Biomarkers......Page 228
    B.19.5.2 Use of Biomarkers for Preclinical Profiling of New Drugs......Page 231
    B.19.5.3 Use of Biomarkers for Demonstrating Proof of Concept, Regimen and Dose Selection......Page 232
    B.19.6 Pharmacogenomic Biomarkers and Personalized Medicine......Page 235
    B.19.7 Initiatives and Consortia in Biomarker Discovery and Development......Page 238
    REFERENCES AND FURTHER READING......Page 239
    Development of Regulations for Submitting Pharmacogenomic Data to Authorities......Page 242
    REFERENCES AND FURTHER READING......Page 245
    B.21.1 General Introduction......Page 246
    B.21.2.1 NMEs as an Inhibitor of Transporters......Page 248
    B.21.2.2 NMEs as a Substrate of Transporters......Page 249
    B.21.3.1 P-gp......Page 250
    B.21.3.1.1 Experimental Design to Identify P-gp Substrates......Page 251
    B.21.3.2 Uptake Transporters of the SLC Family......Page 253
    B.21.3.3.1 Drug Transport Mediated by ABC Transporters Using Eukaryotic Membrane Vesicles......Page 256
    REFERENCES AND FURTHER READING......Page 258
    Relevance of Transporters in Clinical Studies......Page 260
    B.22.0.0.0 References and Further Reading......Page 261
    B.22.1.1.5 Treatments......Page 266
    B.22.1.1.9 Results......Page 267
    B.22.1.1.9 References and Further Reading......Page 269
    B.22.1.2.7 PK Sampling and Bioanalytical Methods......Page 270
    B.22.1.2.9 Results......Page 271
    B.22.1.2.9 References and Further Reading......Page 272
    B.22.2.1.1 Title......Page 273
    B.22.2.1.8 Statistical Methods......Page 274
    B.22.2.1.9 Results......Page 275
    B.22.2.2 Metformin as Probe Substrate of OCTs......Page 277
    B.22.2.2.7 PK Sampling and Bioanalytical Methods......Page 278
    B.22.2.2.9 Results......Page 279
    B.22.2.3.2 Objectives......Page 281
    B.22.2.3.8 Statistical Methods......Page 282
    B.22.2.3.9 Results......Page 283
    B.22.2.3.9 References and Further Reading......Page 284
    B.23.1 Primary Objectives......Page 286
    B.23.6 PK Data......Page 287
    B.23.12 Blood Sampling......Page 289
    B.23.13 Repeated Dose Studies......Page 290
    REFERENCES AND FURTHER READING......Page 291
    B.24.1.1 CYP1A2......Page 292
    B.24.1.1.0 References and Further Reading......Page 293
    B.24.1.2 CYP2C9......Page 294
    B.24.1.2.0 References and Further Reading......Page 295
    B.24.1.3 CYP2C19......Page 296
    B.24.1.4 CYP2D6......Page 297
    B.24.1.4.0 References and Further Reading......Page 298
    B.24.2 Phenotyping......Page 299
    B.24.2.1 OTHER CYPS......Page 300
    B.24.2.4 CYP2C8......Page 301
    B.24.3 PHASE II ENZYMES......Page 302
    B.24.3.1 N-ACETYLTRANSFERASES......Page 303
    B.24.3.1.0 References and Further Reading......Page 304
    B.24.3.3 Methyltransferases......Page 305
    B.24.3.4.0 References and Further Reading......Page 306
    B.25.1 Mathematical Models in Biology......Page 308
    B.25.5 Baselines......Page 309
    B.25.7 Basic Concentration Effect Relationships......Page 310
    B.25.8.3 Hard and Soft Link......Page 311
    B.25.12 One- or Two-Step Approach......Page 312
    B.25.16 Physiology of the Glucose Regulatory System......Page 313
    B.25.19 Modeling the Effects of Drugs......Page 314
    B.25.20 Modeling at the Short-Term Timescale......Page 315
    B.25.21.1 Under Steady State Conditions HOMA......Page 316
    B.25.21.2 Effect of Gliclazide, Pioglitzone, and Metformin......Page 319
    B.25.24 Discussion......Page 321
    REFERENCES AND FURTHER READING......Page 322
    Methodologies of PD Assessment: Scales......Page 324
    REFERENCES AND FURTHER READING......Page 338
    C.2.2 Design of Pharmacodynamic Studies......Page 340
    C.2.4 Analysis of Pharmacodynamic Studies......Page 342
    C.2.6.1.3 Study Design......Page 343
    C.2.6.2.5 Statistical Analysis......Page 344
    C.2.6.3 Summary......Page 345
    C.2.7 Part B......Page 346
    C.2.7.1.1 Inclusion Criteria......Page 348
    C.2.9.1 Demographics and Baseline Characteristics......Page 349
    C.2.9.4 Results - Pharmacodynamics......Page 350
    Conclusions......Page 353
    REFERENCES AND FURTHER READING......Page 359
    C.3.2 Dose/Concentration Effect Curve Analysis......Page 360
    C.3.3 Isobolograms......Page 362
    C.3.4 Schild Plots......Page 364
    C.3.5 Factorial Design Trials......Page 365
    REFERENCES AND FURTHER READING......Page 367
    C.4.1.1.1 How to Manage the Safety Assessment of a Drug......Page 370
    C.4.2 Categorization of Adverse Events for Decision Making......Page 371
    C.4.5 Clinical Adverse Events Monitoring Physical Examination by the Clinical Investigator......Page 372
    C.4.8.1 Blood Pressure......Page 373
    C.4.11.1 Glucose......Page 374
    C.4.15.1 Phosphatase......Page 375
    C.4.19.1 Creatinphosphokinase CPK......Page 376
    C.4.23.1 Activated Partial Thromboplastin Time aPTT......Page 377
    C.4.25 Visual Analogue Scale for Semiquantitatively Assessing Pain and Other Subjective Factors......Page 378
    REFERENCES AND FURTHER READING......Page 379
    C.5.1 Relevance and Constraints of Cardiovascular Investigations in the Early Development of Novel Drug Substances and Medicati......Page 380
    C.5.2.1 Empirical Quality Criteria......Page 381
    C.5.2.2 Issues with the Validity of Cardiovascular Methods......Page 382
    C.5.3.1 Standard 12-Lead ECG......Page 383
    C.5.3.2 Ambulatory ECG HOLTER......Page 385
    C.5.4.1 Timed Blood Pressure......Page 386
    C.5.4.2 Ambulatory Blood Pressure Monitoring ABPM......Page 388
    C.5.5.1 Finger Pulse Plethysmography......Page 389
    C.5.5.2 Venous Occlusion Plethysmography......Page 390
    C.5.5.3 Pulse Wave Analysis......Page 392
    C.5.6.1 Systolic Time Intervals......Page 393
    C.5.6.3 Noninvasive Estimates of Stroke Volume and Cardiac Output......Page 395
    C.5.7 Diastolic Performance......Page 397
    C.5.8.1 Background......Page 398
    C.5.8.2 Flow-Mediated Vasodilatation FMD, Endothelium-Dependent Vasodilatation EDV, Reactive Hyperemia......Page 399
    C.5.8.3 Forearm Perfusion Technique......Page 400
    C.5.8.4 Pulse Wave Analysis/Augmentation Index Aix......Page 401
    REFERENCES AND FURTHER READING......Page 402
    C.6.2.1 Introduction......Page 416
    C.6.3.1 Computerized Cognitive Assessment Systems......Page 418
    C.6.4.1 Simple and Choice Reaction Time......Page 419
    C.6.4.2 Vigilance Tasks......Page 420
    C.6.4.4 Rapid Visual Information Processing......Page 421
    C.6.4.5 Continuous Performance Tasks......Page 422
    C.6.4.6 Pencil-and-Paper Tests of Attention......Page 423
    C.6.4.7 The Stroop Test......Page 425
    C.6.6.1 Word Recall and Recognition......Page 426
    C.6.6.2 Picture or Object Recognition......Page 427
    C.6.7.2 Word Fluency - Letter and Category Fluency......Page 428
    C.6.8.1 Driving Simulators......Page 429
    C.6.8.2 On-Road Car Driving......Page 430
    C.6.9.1 Critical Flicker Fusion CFF Threshold......Page 431
    C.6.11 Saccadic Eye Movements......Page 432
    C.6.12.2 Pegboard Tests......Page 433
    C.6.13 Visual Tracking Tasks......Page 434
    C.6.14.2 Profile of Mood States POMS......Page 435
    C.6.14.3 Spielberger State-Trait Anxiety Inventory STAI......Page 436
    C.6.15.2 Karolinska Sleepiness Scale......Page 437
    C.6.16.1 Leeds Sleep Evaluation Questionnaire......Page 438
    C.6.16.2 St Mary´s Hospital Sleep Questionnaire SMHSQ......Page 439
    C.6.17.1 Electroencephalography......Page 440
    C.6.18 Imaging Techniques MRI, fMRI, PET, and SPECT......Page 441
    C.6.19.1 The Scopolamine Model of Dementia......Page 442
    C.6.19.2 Sleep Deprivation Models......Page 443
    REFERENCES AND FURTHER READING......Page 444
    C.7.1.2 Insulin Products......Page 450
    C.7.1.3 Guidelines on Pharmacodynamic and Pharmacokinetic Evaluation......Page 451
    C.7.2.1 Characterization of Prandial Versus Basal Insulin Products......Page 452
    C.7.2.2 Automated Versus Manual Techniques......Page 453
    C.7.3 Study Set-Up......Page 454
    C.7.3.1 Study Population and Baseline Characteristics......Page 457
    C.7.3.2 Study Procedures......Page 459
    C.7.3.3 Pharmacokinetic and Pharmacodynamic Assessments......Page 462
    C.7.3.4 Statistical Analyses......Page 463
    C.7.5 Epilog......Page 465
    C.7.6.2 Inhaled Insulin......Page 466
    C.7.6.3 Oral, Buccal, Sublingual, Nasal, and Dermal Insulin Delivery......Page 468
    REFERENCES AND FURTHER READING......Page 470
    C.8.2.1 In Vitro Cytokine Stimulation Assay......Page 476
    C.8.2.2 Ex Vivo Cytokine Stimulation Assay......Page 477
    C.8.3.2 Whole Blood Proliferation Assay Ex Vivo......Page 478
    REFERENCES AND FURTHER READING......Page 479
    C.9.2.1 Somatropin......Page 482
    C.9.2.2 Follitropin......Page 483
    C.9.2.6 LHRH Analogues......Page 484
    C.9.3.2 Parathormone......Page 485
    C.9.3.3 Teriparatide......Page 486
    C.9.3.5 Cinacalcet......Page 487
    C.9.4.1 Exploratory Studies, Mechanisms and Biomarkers......Page 488
    C.9.4.2 Compounds in Clinical Use......Page 489
    C.9.4.4 Pharmacotherapy and Study Design......Page 490
    C.9.4.6 Mineralocorticoid Antagonists......Page 491
    C.9.4.7 Clinical Summary......Page 492
    C.9.5 Thyroid Hormones......Page 493
    C.9.5.1 Recombinant Human Thyrotropin......Page 494
    C.9.5.3 Pathophysiology......Page 495
    C.9.5.4 Thyroid Cancer......Page 496
    C.9.5.6 Thyromimetics......Page 498
    C.9.6 Gonadal Steroid Hormones......Page 499
    C.9.6.1 Estrogenic Compounds......Page 500
    C.9.6.3 Contraceptives......Page 501
    C.9.6.4 Testosterone......Page 502
    C.9.6.5 Antiestrogens......Page 503
    C.9.6.10 Antiandrogens......Page 504
    REFERENCES AND FURTHER READING......Page 505
    Pharmacodynamic Evaluation: Dermatology......Page 516
    REFERENCES AND FURTHER READING......Page 523
    C.11.1 General Introduction......Page 526
    C.11.2 Conventional Chemotherapy with Cytotoxic Agents......Page 528
    C.11.2.1 What is Possible and Should Be Possible to Measure?......Page 529
    C.11.3 Targeted Therapies......Page 531
    C.11.4 ``In Vivo´´ Pharmacodynamic Evaluation Using Positron-Emission Tomography PET......Page 533
    REFERENCES AND FURTHER READING......Page 534
    Development of Regulations for Submitting Pharmacogenomic Data to Authorities......Page 538
    REFERENCES AND FURTHER READING......Page 541
    D.2.1 Drug Toxicities/Toxicogenomics......Page 542
    D.2.2 Phase 1......Page 543
    D.2.3 Phase 2 Activities: First Results in Different Indications......Page 544
    D.2.4 Phase 1/2/3 and Adaptive Trial Designs......Page 545
    D.2.6 Phase 4......Page 546
    REFERENCES AND FURTHER READING......Page 547

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