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".
Author(s): H.Gerhard Vogel, Jochen Maas, Alexander Gebauer
Series: Springer Reference Volume 3
Edition: 1st Edition.
Publisher: Springer
Year: 2011
Language: English
Pages: 577
Drug Discovery and Evaluation: Methods in Clinical Pharmacology......Page 1
Front-matter......Page 2
Drug Discovery and Evaluation: Methods in Clinical Pharmacology
......Page 4
CopyRight Page......Page 5
Table of Contents
......Page 6
List of Contributors
......Page 10
Section A: Introduction......Page 14
General Introduction......Page 16
Section B: Clinical Pharmacokinetics......Page 18
Dose Linearity and Proportionality......Page 20
B.10.1 Introduction and Guidelines......Page 86
B.2.1 Human Clearance Prediction by Allometric Scaling......Page 22
B.2.4 Human CL Scaling by ``Liver blood Flow´´ - Scaling with Monkey Data......Page 25
REFERENCES AND FURTHER READING......Page 26
B.21.1 General Introduction......Page 264
C.6.2.1 Introduction......Page 436
B.3.1.3 Study Design......Page 28
B.3.2 Use of Previous Data to Design Study......Page 29
C.6.4 Attention Tests......Page 70
B.19.4 Biomarker Assay Development and Validation......Page 30
REFERENCES AND FURTHER READING......Page 218
B.3.9 Need to Measure Drug in Urine......Page 31
REFERENCES AND FURTHER READING......Page 34
C.11.1 General Introduction......Page 187
C.5.2 Validation of Cardiovascular Test Criteria......Page 63
C.3.3 Isobolograms......Page 36
B.4.5 Statistical Assessment of Dose Linearity/Proportionality......Page 37
C.6.2.1.3 Reliability of Tests over Repeated Administration......Page 133
C.7.3 Study Set-Up......Page 438
B.4.6 Exploratory Assessment of Dose Linearity/Proportionality: Single Dose Study Design......Page 38
B.13.1.4 Mechanistic Dynamic Model (MDM)......Page 167
C.2.9.2 Multiplicity Issues......Page 39
B.4.6.9.1 Plasma Concentrations......Page 40
B.4.6.9.2 Pharmacokinetic Parameters......Page 41
D.2.7 Perspective......Page 43
B.4.7.8.4 Assessment of the Dose-Exposure Relationship Based on a Discrete Model for Doses per Kilogram Body Weight......Page 44
B.4.7.9 Results......Page 45
B.4.8.5 Treatments......Page 48
B.4.8.8.2 Dose Effect......Page 49
B.4.8.9.1 Plasma Concentrations......Page 50
Dose Proportionality......Page 51
REFERENCES AND FURTHER READING......Page 53
B.25.1 Mathematical Models in Biology......Page 326
C.4.1 Introduction/General Considerations......Page 54
B.22.1.1.5 Treatments......Page 284
B.21.3.2.2 Validation......Page 175
B.5.1.1.5 Pharmacokinetic Data......Page 55
B.17.1.2.3 Success Rate Depending on CL/F and Dose Rate......Page 205
B.22.2.1.1 Title......Page 291
B.5.3.1 Protocol Outline......Page 56
B.19.5.3.2 Dipeptidyl-Peptidase-4 (DPP-4) Activity as BM for Dose Selection and Go/Nogo Decisions......Page 57
B.24.1.4 CYP2D6......Page 92
B.5.4.3 Statistical/Analytical Issues......Page 58
C.7.3.4.4 Bioequivalence......Page 483
REFERENCES AND FURTHER READING......Page 61
Methodologies of Pharmacodynamic Assessment......Page 62
C.9.4.1 Exploratory Studies, Mechanisms and Biomarkers......Page 508
B.6.6.1 Pharmacokinetics......Page 64
C.11.2.1.1 Biomarkers......Page 549
B.24.1.4.0 References and Further Reading......Page 65
REFERENCES AND FURTHER READING......Page 66
Special Populations: Hepatic Impairment......Page 76
B.23.1 Primary Objectives......Page 69
C.4.5 Clinical Adverse Events Monitoring (Physical Examination by the Clinical Investigator)......Page 392
B.7.7 Dose Adjustment......Page 72
REFERENCES AND FURTHER READING......Page 74
B.8.1 Protocol......Page 77
B.8.2 PK Study......Page 78
B.24.3 PHASE II ENZYMES......Page 79
Special Populations: Protein Binding Aspects......Page 80
REFERENCES AND FURTHER READING......Page 84
B.10.2.2 Dosimetry Calculation......Page 88
Intravenous Administration......Page 147
B.10.2.2.3 Calculation of Ã......Page 89
B.10.2.2.5 Coefficients of Safety......Page 90
B.10.2.2.7 Effective Dose......Page 91
C.9.2.6 LHRH Analogues......Page 504
C.4.10.1 QT Interval......Page 93
C.7.3.3.2 Glucose Infusion Rates......Page 482
B.10.4.9 Duration of Study......Page 94
C.6.6.1 Word Recall and Recognition......Page 446
B.10.5.1 Metabolic Profiling......Page 95
B.10.5.2 Structure Elucidation......Page 99
REFERENCES AND FURTHER READING......Page 129
B.10.6.2 Example 2: Study Design and Kinetic and Mass Balance Results......Page 107
B.10.6.3 Example 3: Metabolic Profiling......Page 112
REFERENCES AND FURTHER READING......Page 114
Pharmacodynamic Evaluation: Dermatology......Page 118
B.15.1.2 Example 1......Page 119
C.4.8.1 Blood Pressure......Page 393
B.17.1.1.1 Sources of Pharmacokinetic Variability......Page 120
B.11.2.4.2 Biochemical Methods......Page 122
B.11.2.8 Analysis......Page 124
C.9.3.3 Teriparatide......Page 506
B.11.3.2 Chemical Methods for 3H-Labeling......Page 125
B.11.4.1 General Study Requirements (Dain et al. 1994)......Page 126
B.11.4.4 General Quality-Related Measures that Should be Applied for the Synthesis of Radioactive APIs......Page 127
REFERENCES AND FURTHER READING......Page 143
B.12.1.0.0 References and Further Reading......Page 132
Outline placeholder......Page 0
B.22.1.1.4 Inclusion Criteria......Page 134
C.7.3.2.3 Safety Assessments......Page 481
B.21.2.2 NMEs as a Substrate of Transporters......Page 135
C.7.3.3.3 Long-Acting Products......Page 136
C.8.3.1 Mixed Lymphocyte Reaction (MLR) In Vitro......Page 498
C.2.7.1.1 Inclusion Criteria......Page 137
C.8.3.2 Whole Blood Proliferation Assay Ex Vivo......Page 138
B.12.4 Profiling the Effect of an Enzyme Inducer on Pharmacokinetics and Pharmacodynamics of Oral Contraceptives......Page 139
B.12.4.1.5 Treatments......Page 140
B.12.4.2.1 Results......Page 141
Pharmacodynamic Evaluation: Inflammation/Immunology......Page 146
C.3.1 General Considerations......Page 380
Per os Administration......Page 148
General considerations:......Page 149
Competitive Inhibition......Page 154
Time-Dependent Inhibition......Page 157
Induction......Page 161
Microsomal Nonspecific Binding......Page 162
B.13.1.2 Basic Equations and Authorities Requirements......Page 163
B.13.1.3.1 Perpetrator Concentration at the Enzyme Site......Page 164
C.5.4.1 Timed Blood Pressure......Page 406
B.16.3 Statistical Data Analysis and Interpretation......Page 170
Specific Studies for Formulation Development......Page 174
B.18.13.2 Assay Variability......Page 176
Treatment Group II......Page 177
B.14.2.1.6 Pharmacokinetic Data......Page 178
B.14.2.1.8 Results - Hypothetical In Vivo Dissolution......Page 179
C.4.3 Decision Making on Dose Increase and to Stop the Study......Page 184
Absolute and Relative Bioavailability......Page 186
B.17.1.1.3 Prior Knowledge for Individual PK Estimates......Page 203
B.15.1.2.1 Results - Pharmacokinetics......Page 188
B.15.2.1.5 Pharmacokinetic Data......Page 189
B.15.2.2.2 Results - Pharmacokinetics......Page 190
B.25.20.1 Effect of GLP-1 Analogs......Page 191
B.15.2.3.3 Treatment B vs. Treatment C......Page 192
B.21.3 Functional Analysis of a NME as a Substrate and Inhibitor of Transporters......Page 268
Methodologies of PD Assessment: Scales......Page 194
C.6.4.1 Simple and Choice Reaction Time......Page 206
C.9.2.2 Follitropin......Page 503
B.16.3.1 Statistical Analysis for the 2x2 Crossover......Page 195
B.16.4 Sample Size Determination......Page 196
B.17.2.3 Comparing Clinical Outcome Between 10 and 20 mg......Page 198
C.4.11.1 Glucose......Page 199
B.16.6 AppendixB.16.3. Example of SABE Analysis......Page 200
REFERENCES AND FURTHER READING......Page 201
B.17.1.1 Optimizing the Dose Regimen......Page 202
B.17.1.2.1 Confirming Efficacy of a Drug......Page 204
C.9.2.3 Lutropin Alfa......Page 329
B.17.2.2.2 Population Level of the Pharmacokinetic Model......Page 207
C.6.4.6.7 The Digit Symbol Substitution Test (DSST)......Page 208
B.17.2.3.2 Dose Recommendation......Page 209
B.17.2.3.4 Relevance of Covariates?......Page 210
C.4.12.1 Potassium......Page 370
B.17.4.2.1 Materials and Methods......Page 212
B.17.4.2.2 Results......Page 213
B.17.4.3.1 Materials and Methods......Page 214
B.17.4.3.2 Results......Page 215
C.9.3.5 Cinacalcet......Page 507
D.2.2 Phase 1......Page 266
B.18.3 Internal Standards......Page 221
B.18.6 Protein Precipitation......Page 222
B.18.9 Eleven Steps on Method Development......Page 223
B.18.10 Sample Preparation for ``Large Molecules´´......Page 224
B.18.12 Validation......Page 225
B.18.13.4 Matrix Variability......Page 226
B.18.13.10 Matrix Effects......Page 227
B.18.13.11.2 Setting Up Analytical Runs......Page 228
B.18.15 Incurred Sample Reproducibility (ISR)......Page 229
B.18.16 Incurred Sample Accuracy (ISA)......Page 230
B.18.17 Incurred Sample Stability (ISS)......Page 231
REFERENCES AND FURTHER READING......Page 232
C.2.2 Design of Pharmacodynamic Studies......Page 236
B.19.3 Current Status and Trends in Biomarker Science......Page 237
C.7.3.1.1 Subjects with Diabetes Mellitus Type 1......Page 238
B.19.3.1.7 Toxicity/Safety......Page 239
B.24.1.2 CYP2C9......Page 240
B.19.4.11 Processed Sample Stability......Page 243
C.6.7.6 Tower of London......Page 244
C.4.25 Visual Analogue Scale for Semiquantitatively Assessing Pain and Other Subjective Factors......Page 398
B.19.5.3.1 Adiponectin: A Translational Biomarker......Page 248
B.19.5.3.3 Measurement of Target Receptor Occupancy in Order to Define Dosing Regimens (Example of CD33)......Page 250
B.23.6 PK Data......Page 251
B.19.7 Initiatives and Consortia in Biomarker Discovery and Development......Page 254
REFERENCES AND FURTHER READING......Page 569
B.20.3 Analytical Methods......Page 258
B.20.4.2 Dose Dependency of AUCand Cmax......Page 259
B.20.5 Most Sensitive Species......Page 260
B.20.10 Biotechnology-derivedPharmaceuticals......Page 261
REFERENCES AND FURTHER READING......Page 262
C.2.6.1.3 Study Design......Page 363
B.21.3.1.1 Experimental Design to Identify P-gp Substrates......Page 269
B.21.3.1.3.0 In Vitro/In Vivo Correlation......Page 270
B.21.3.2.3 Uptake Studies with Radiolabeled Substrates......Page 271
B.21.3.2.5 Inhibition Studies with Radiolabeled Probe Substrates......Page 272
B.21.3.2.6 In Vitro/In Vivo Correlation......Page 273
C.7.3.4.1 AUC and Cmax......Page 274
C.7.3.4.6 Fluctuation......Page 275
B.21.4 Outlook and Further Reading......Page 276
B.22.1.1.9 Results......Page 285
C.2.6.2.5 Statistical Analysis......Page 364
B.22.1.1.9 References and Further Reading......Page 287
B.22.1.2.7 PK Sampling and Bioanalytical Methods......Page 288
B.22.1.2.9 Results......Page 289
B.22.1.2.9 References and Further Reading......Page 290
C.7.1.3 Guidelines on Pharmacodynamic and Pharmacokinetic Evaluation......Page 471
B.22.2.1.8 Statistical Methods......Page 292
B.22.2.1.9 Results......Page 293
B.22.2.2 Metformin as Probe Substrate of OCTs......Page 295
B.22.2.2.7 PK Sampling and Bioanalytical Methods......Page 296
B.22.2.2.9 Results......Page 297
B.22.2.3.2 Objectives......Page 299
B.22.2.3.8 Statistical Methods......Page 300
B.22.2.3.9 Results......Page 301
B.22.2.3.9 References and Further Reading......Page 302
C.2.5 Descriptive Analyses......Page 305
B.23.12 Blood Sampling......Page 307
REFERENCES AND FURTHER READING......Page 379
B.23.13 Repeated Dose Studies......Page 308
REFERENCES AND FURTHER READING......Page 309
B.25.8.1 Direct and Indirect Link......Page 310
B.24.1.2.0 References and Further Reading......Page 313
B.24.1.3 CYP2C19......Page 314
B.24.1.3.0 References and Further Reading......Page 315
B.24.1.5 CYP3A......Page 317
C.8.2.1 In Vitro Cytokine Stimulation Assay......Page 496
B.24.2.1 OTHER CYPS......Page 318
B.24.2.4 CYP2C8......Page 319
C.6.4.6.2 Symbol Digit Modalities Test (SDMT)......Page 443
B.24.2.5.0 References and Further Reading......Page 320
B.24.3.1 N-ACETYLTRANSFERASES......Page 321
B.24.3.1.0 References and Further Reading......Page 322
B.24.3.3 Methyltransferases......Page 323
B.24.3.4.0 References and Further Reading......Page 324
B.25.4 Effects, Surrogates, and Biomarkers......Page 327
C.2.4 Analysis of Pharmacodynamic Studies......Page 362
C.4.7 Vital Signs......Page 328
B.25.12 One- or Two-Step Approach......Page 330
C.6.11 Saccadic Eye Movements......Page 452
B.25.16 Physiology of the Glucose Regulatory System......Page 331
B.25.19 Modeling the Effects of Drugs......Page 332
B.25.20 Modeling at the Short-Term Timescale......Page 333
B.25.21 Modeling at the Intermediate Timescale......Page 334
B.25.24 Discussion......Page 339
REFERENCES AND FURTHER READING......Page 340
Section C: Human Studies in Clinical Pharmacology......Page 342
D.2.1 Drug Toxicities/Toxicogenomics......Page 358
C.2.1 General Introduction......Page 360
C.2.6.3 Summary......Page 365
C.2.7 Part B......Page 366
C.2.7.1 Sample Size Justification......Page 368
C.2.9 Statistical Methods......Page 369
Conclusions......Page 373
C.7.2.1 Characterization of Prandial Versus Basal Insulin Products......Page 472
C.3.5 Factorial Design Trials......Page 385
REFERENCES AND FURTHER READING......Page 387
C.4.1.1.1 How to Manage the Safety Assessment of a Drug......Page 390
C.7.1.2 Insulin Products......Page 470
C.4.2 Categorization of Adverse Events for Decision Making......Page 391
C.7.3.4 Statistical Analyses......Page 413
C.6.4.2 Vigilance Tasks......Page 394
C.6.13 Visual Tracking Tasks......Page 395
C.4.19.1 Creatinphosphokinase (CPK)......Page 396
C.5.8.1 Background......Page 418
C.4.23.1 Activated Partial Thromboplastin Time (aPTT)......Page 397
REFERENCES AND FURTHER READING......Page 399
Development of Regulations for Submitting Pharmacogenomic Data to Authorities......Page 560
C.5.1 Relevance and Constraints of Cardiovascular Investigations in the Early Development of Novel Drug Substances and Medicati......Page 400
C.5.2.2 Issues with the Validity of Cardiovascular Methods......Page 402
C.5.3.1 Standard 12-Lead ECG......Page 403
C.5.3.2 Ambulatory ECG (HOLTER)......Page 405
C.6.4.3 Psychomotor Vigilance Tasks (PVTs)......Page 408
C.5.5.1 Finger Pulse Plethysmography......Page 409
C.5.5.2 Venous Occlusion Plethysmography......Page 410
Augmentation Index (AIx)......Page 412
C.7.6.2.1 Inhalation......Page 486
C.5.6.3 Noninvasive Estimates of Stroke Volume and Cardiac Output......Page 415
C.5.7 Diastolic Performance......Page 417
C.5.8.2 Flow-Mediated Vasodilatation (FMD), Endothelium-Dependent Vasodilatation (EDV), Reactive Hyperemia......Page 419
C.5.8.3 Forearm Perfusion Technique......Page 420
C.6.8.1 Driving Simulators......Page 449
REFERENCES AND FURTHER READING......Page 422
C.6.2.1.2 Sensitivity......Page 437
C.6.3.2 Noncomputerized Test Batteries......Page 439
C.6.4.4 Rapid Visual Information Processing......Page 441
C.6.4.5 Continuous Performance Tasks......Page 442
C.6.4.6.8 d2 Test of Attention......Page 444
C.6.4.7 The Stroop Test......Page 445
C.6.6.2 Picture or Object Recognition......Page 447
C.6.7.2 Word Fluency - Letter and Category Fluency......Page 448
C.6.8.2 On-Road Car Driving......Page 450
C.6.9.1 Critical Flicker Fusion (CFF) Threshold......Page 451
C.6.12.2 Pegboard Tests......Page 453
C.6.14.2 Profile of Mood States (POMS)......Page 455
C.6.14.3 Spielberger State-Trait Anxiety Inventory (STAI)......Page 456
C.6.15.2 Karolinska Sleepiness Scale......Page 457
C.6.16.1 Leeds Sleep Evaluation Questionnaire......Page 458
C.6.16.2 St Mary´s Hospital Sleep Questionnaire (SMHSQ)......Page 459
C.6.17.1 Electroencephalography......Page 460
C.6.18 Imaging Techniques MRI, fMRI, PET, and SPECT......Page 461
C.6.19.1 The Scopolamine Model of Dementia......Page 462
C.6.19.2 Sleep Deprivation Models......Page 463
REFERENCES AND FURTHER READING......Page 464
C.7.2.2 Automated Versus Manual Techniques......Page 473
C.7.2.3 Examples of Glucose Clamp Profiles......Page 474
C.7.3.1 Study Population and Baseline Characteristics......Page 477
C.7.3.1.3 Healthy Subjects......Page 478
Manual Adjustments......Page 479
C.7.3.4.5 Within-Subject Variability......Page 484
C.7.5 Epilog......Page 485
Methods......Page 487
C.7.6.3 Oral, Buccal, Sublingual, Nasal, and Dermal Insulin Delivery......Page 488
C.7.6.3.2 Buccal Insulin......Page 489
REFERENCES AND FURTHER READING......Page 490
C.8.2.2 Ex Vivo Cytokine Stimulation Assay......Page 497
REFERENCES AND FURTHER READING......Page 499
C.9.2.1 Somatropin......Page 502
C.9.3.2 Parathormone......Page 505
C.9.4.2 Compounds in Clinical Use......Page 509
C.9.4.4 Pharmacotherapy and Study Design......Page 510
C.9.4.6 Mineralocorticoid Antagonists......Page 511
C.9.4.7 Clinical Summary......Page 512
C.9.5 Thyroid Hormones......Page 513
C.9.5.1 Recombinant Human Thyrotropin......Page 514
C.9.5.3 Pathophysiology......Page 515
C.9.5.4 Thyroid Cancer......Page 516
C.9.5.6 Thyromimetics......Page 518
C.9.6 Gonadal Steroid Hormones......Page 519
C.9.6.1 Estrogenic Compounds......Page 520
C.9.6.3 Contraceptives......Page 521
C.9.6.4 Testosterone......Page 522
C.9.6.5 Antiestrogens......Page 523
C.9.6.10 Antiandrogens......Page 524
REFERENCES AND FURTHER READING......Page 525
Pharmacodynamic Evaluation: Oncology......Page 546
C.11.2 Conventional Chemotherapy with Cytotoxic Agents......Page 548
C.11.3 Targeted Therapies......Page 551
C.11.4 ``In Vivo´´ Pharmacodynamic Evaluation Using Positron-Emission Tomography (PET)......Page 553
REFERENCES AND FURTHER READING......Page 554
Section D: Regulations......Page 558
REFERENCES AND FURTHER READING......Page 563
Pharmacogenomic-Guided Drug Development......Page 564
D.2.3 Phase 2 Activities: First Results in Different Indications......Page 566
D.2.4 Phase 1/2/3 and Adaptive Trial Designs......Page 567
D.2.6 Phase 4......Page 568
Index......Page 572
