Verfügbarkeit: Principles of clinical pharmacology

Principles of clinical pharmacology:

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Format:	Buch
Sprache:	English
Veröffentlicht:	San Diego [u.a.] Elsevier, Acad. Press 2012
Ausgabe:	3. ed.
Schlagworte:	Farmacologie Pharmacologie clinique Clinical pharmacology Pharmacology, Clinical Pharmakologie Lehrbuch
Online-Zugang:	Inhaltsverzeichnis
Beschreibung:	XXI, 626 S. Ill., graph. Darst.
ISBN:	9780123854711 0123854717

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Datensatz im Suchindex

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adam_text	Contents Preface to the First Edition xvii Preface to the Third Edition xvii Contributors xix CHAPTER Introduction to Clinical Pharmacology ARTHUR ]. ATKINSON, JR Background 1 Optimizing Use of Existing Medicines 1 Evaluation and Development of Medicines 3 Pharmacokinetics 5 The Concept of Clearance 5 Clinical Estimation of Renal Function 6 Dose-Related Toxicity Often Occurs When Impaired Renal Function is Unrecognized 7 References 8 Additional Sources of Information 8 PART I PHARMACOKINETICS CHAPTER Clinical Pharmacokinetics ARTHUR J. ATKINSON, JR The Target Concentration Strategy 13 Monitoring Serum Concentrations of Digoxin as an Example 13 General Indications for Drug Concentration Monitoring 15 Concepts Underlying Clinical Pharmacokinetics 16 Initiation of Drug Therapy (Concept of Apparent Distribution Volume) 16 Continuation of Drug Therapy (Concepts of Elimination Half-Life and Clearance) 17 Drugs Not Eliminated by First-Order Kinetics 19 Mathematical Basis of Clinical Pharmacokinetics 20 First-Order Elimination Kinetics 20 Concept of Elimination Half-Life 21 Relationship of к to Elimination Clearance 21 Cumulation Factor 22 The Plateau Principle 22 Application of Laplace Transforms to Pharmacokinetics 23 References 24 Study Problems 24 CHAPTER Compartmental Analysis of Drug Distribution ARTHUR J. ATKINSON, JR Fit-for-Purpose Modeling of Drug Distribution 27 Physiological Significance of Drug Distribution Volumes 28 Physiological Basis of Multicompartmental Models of Drug Distribution 30 Formulation of Muiticompartmental Models 30 Basis of Multicompartmental Structure 30 Mechanisms of Transcapillary Exchange 31 Clinical Consequences of Different Drug Distribution Patterns 33 VI Contents Estimating Model Parameters from Experimental Data 34 Derivation of Equations for a Two-Compartment Model 34 Calculation of Rate Constants and Compartment Volumes from Data 37 Different Estimates of Apparent Volume of Distribution 37 References 38 Study Problems 39 Computer-Based Tutorials 39 CHAPTER Drug Absorption and Bioavailability ARTHUR J. ATKINSON, JR Drug Absorption 41 Bioavailability 44 Absolute Bioavailability 45 Relative Bioavailability 47 In Vitro Prediction of Bioavailability 47 Kinetics of Drug Absorption After Oral Administration 49 Time to Peak Level 51 Value of Peak Level 51 Use of Convolution/Deconvolution to Assess in Vitro-in Vivo Correlations 51 References 52 Study Problems 53 Computer-Based Tutorials 53 CHAPTER Plasma Protein Binding of Acidic Drugs 60 Plasma Protein Binding of Basic and Neutral Drugs 61 Tissue Binding of Drugs 61 Effects of Renal Disease on Drug Absorption 62 References 62 Study Problem 63 CHAPTER Pharmacokinetics in Patients Requiring Renal Replacement Therapy ARTHUR J. ATKINSON, JR AND GREGORY M. SULSA Kinetics of Intermittent Hemodialysis 66 Solute Transfer across Dialyzing Membranes 66 Calculation of Dialysis Clearance 67 Patient Factors Affecting Hemodialysis of Drugs 69 Kinetics of Continuous and Sustained Renal Replacement Therapy 70 Clearance by Continuous Hemofiltration 70 Clearance by Continuous Hemodialysis and SLED 72 Extracorporeal Clearance during Continuous Renal Replacement Therapy 73 Clinical Considerations 73 Drug Dosing Guidelines for Patients Requiring Renal Replacement Therapy 74 Extracorporeal Therapy of Patients with Drug Toxicity 76 References 77 Computer-Based Tutorial 79 CHAPTER Effect of Renal Disease on Pharmacokinetics ARTHUR J. ATKINSON, JR AND JUAN J.L. LERTORA Drug Dosing in Patients with Impaired Renal Function 56 Effects of Renal Disease on Renal Drug Excretion Mechanisms 57 Excretion Mechanisms 57 Reabsorption Mechanisms 58 Renal Metabolism 58 Analysis and interpretation of Renal Excretion Data 58 Effects of Impaired Renal Function on Non-Renal Metabolism 59 Effects of Renal Disease on Drag Distribution 60 Effect of Liver Disease on Pharmacokinetics GREGORY M. SUSLA AND JUAN J.L. LERTORA Hepatic Elimination of Drugs 81 Restrictively Metabolized Drags (ER < 0.3) 82 Drugs with an Intermediate Extraction Ratio (0.3 <ER< 0.7) 83 Non-Restrictively Metabolized Drags (ER > 0.70) 83 Biliary Excretion of Drugs 84 Effects of Liver Disease on Pharmacokinetics 84 Acute Hepatitis 85 Chronic Liver Disease and Cirrhosis 86 Pharmacokinetic Consequences of Liver Cirrhosis 87 Use of Therapeutic Drugs in Patients with Liver Disease 88 Contents Vil Effects of Liver Disease on the Hepatic Elimination of Drugs 89 Effects of Liver Disease on the Renal Elimination of Drugs 91 Effects of Liver Disease on Patient Response 92 Modification of Drug Therapy in Patients with Liver Disease 93 References 94 CHAPTER 8 Non-Compartmental and Compartmental Approaches to Pharmacokinetic Data Analysis DAVID M. FOSTER AND PAOLO VICINI Introduction 97 Kinetics, Pharmacokinetics and Pharmacokinetic Parameters 98 Kinetics and the Link to Mathematics 98 The Pharmacokinetic Parameters 99 Non-Compartmental Analysis 101 Non-Compartmental Model 101 Kinetic Parameters of the Non-Compartmental Model 102 Estimating the Kinetic Parameters of the Non-Compartmental Model 104 Compartmental Analysis 107 Definitions and Assumptions 107 Linear, Constant Coefficient Compartmental Models 109 Parameters Estimated from Compartmental Models 109 Non-Compartmental vs Compartmental Models 113 Models of Data vs Models of System 113 The Equivalent Sink and Source Constraints Linearity and Time-Invariance 114 Recovering Pharmacokinetic Parameters from Compartmental Models 114 Conclusion 115 References 116 114 CHAPTER Distributed Models of Drag Kinetics PAUL F. MORRISON Introduction 117 Central Issues 117 Drug Modality I: Delivery Across a Planar-Tissue Interface 118 General Principles 118 Differences between the Delivery of Small Molecules and Macromolecules across a Planar Interface 124 Drug Modality II: Delivery from a Point Source, Direct Interstitial Infusion 127 General Principles 127 Low-Flow Microinfusion Case 127 High-Flow Microinfusion Case 128 Summary 136 References 137 CHAPTER 10 Population Pharmacokinetics RAYMOND MILLER Introduction 139 Analysis of Pharmacokinetic Data 140 Structure of Pharmacokinetic Models 140 Fitting Individual Data 140 Population Pharmacokinetics 141 Population Analysis Methods 141 Model Applications 144 Mixture Models 144 Exposure-Response Models 147 Conclusions 148 References 149 Suggested Additional Reading 149 PART II DRUG METABOLISM AND TRANSPORT CHAPTER 11 Pathways of Drug Metabolism SANFORD P. MARKEY Introduction 153 Phase I Biotransformations 156 Liver Microsomal Cytochrome P450 Monooxygenases 156 CYP-Mediated Chemical Transformations 158 VIU Contents Non-CYP Biotransformations 162 Phase II Biotransformations (Conjugations) 166 Glucuronidation 166 Sulfonation 166 Acetylation 167 Additional Effects on Drug Metabolism 169 Enzyme Induction and Inhibition 169 Species 169 Sex 170 Age 170 References 171 Examples of Important Genetic Polymorphisms 200 Drug Absorption 200 Drug Distribution 200 Drug Elimination 200 Mutations that Influence Drug Receptors 209 Combined Variants in Drug Metabolism and Receptor Genes: The Value of Drug Pathway Analysis 210 Conclusions and Future Directions 211 References 212 CHAPTER CHAPTER 12 Methods of Analysis of Drugs and Drug Metabolites SANFORD P. MARKEY Introduction 173 Choice of Analytical Methodology 173 Principles of Analysis 174 Chromatographie Separations 174 Absorption and Emission Spectroscopy 175 Immunoaffinity Assays 176 Mass Spectrometry 177 Accelerator Mass Spectrometry 181 Examples of Current Assay Methods 182 UHPLC-UV Assays of New Chemical Entities 182 UHPLC-MS/MS Assays of New Chemical Entities 183 HPLC/MS/MS Quantitative Assays of Cytochrome P450 Enzyme Activity 184 HPLC/UV and Immunoassays of Cyclosporine: Assays for Therapeutic Drug Monitoring 185 Dried Blood Spot Analyses: New Chemical Entities and Cyclosporine 189 Accelerator Mass Spectrometry Assay: Microdosing in Early Drug Development 189 Imaging Mass Spectrometry 191 Assay Selection 192 References 193 14 Mechanisms and Genetics of Drug Transport JOSEPH A. WARE, LEI ZHANG AND SHIEW-MEI HUANG Introduction 217 Mechanisms of Transport Across Biological Membranes 217 Nomenclature, Genetic Classification, and Function of Selected Membrane Transporters 219 The ATP-Binding Cassette (ABC) Superfamily 219 Solute Carriers (SLCs) 223 Role of Transporters in Pharmacokinetics and Drug Action 224 Role of Membrane Transport in the Intestine 224 Metabolism and Transport Interplay 225 Role of Membrane Transporters in Drug Distribution 226 Role of Membrane Transporters in Renal Drug Elimination 228 Transporter-Mediated Drug-Drug Interactions 229 Pharmacogenetics and Pharmacogenomics of Membrane Transport 230 Race/Ethnic Differences in Transporter Genes 232 Conclusions and Future Perspectives 232 References 233 CHAPTER 13 Clinical Pharmacogenetics DAVID A. FLOCKHART AND SHIEW-MEI HUANG Introduction 195 Hierarchy of Pharmacogenetic Information 196 Identification and Selection of Outliers in a Population 199 CHAPTER 15 Drug Interactions SARAH ROBERTSON, SCOTT R. PENZAK AND SHIEW-MEI HUANG Introduction 239 Mechanisms of Drug Interactions 239 Contents їх Interactions Affecting Drug Absorption 239 Interactions Affecting Drug Distribution 240 Interactions Affecting Drug Metabolism 240 Interactions Involving Drug Transport Proteins 244 Influence of pH and Renal Blood Flow on Drug Interactions in the Kidney 249 Predicting Drug Interactions and Product Labeling 250 In Vitro Screening Methods 250 Utility of Physiologically Based Pharmacokinetic (PBPK) Modeling 250 Drug Interactions Involving Therapeutic Proteins 251 Genetic Variation 252 Drug Interactions in Product Labeling 252 References 253 CHAPTER 16 Biochemical Mechanisms of Drug Toxicity ARTHUR J. ATKINSON, JR AND SANFORD P. MARKEY Introduction 259 Drug-Induced Methemoglobinemia 259 The Role of Covalent Binding in Drug Toxicity 262 Drug-Induced Liver Toxicity 263 Hepatotoxic Reactions Resulting from Covalent Binding of Reactive Metabolites 263 Immunologically Mediated Hepatotoxic Reactions 266 Mechanisms of Other Drug Toxicities 268 Systemic Reactions Resulting from Drug Allergy 269 Carcinogenic Reactions to Drugs 273 Teratogenic Reactions to Drugs 277 References 280 CHAPTER 17 Pharmacogenomic Mechanisms of Drug Toxicity SHIEVV-MEI HUANG, LIGONG CHEN, AND KATHLEEN M. GIACOMINI Introduction 285 ADRs with a Pharmacogenomic Basis 285 Drug Metabolizing Enzyme-Mediated Pharmacogenomic Mechanisms of Drug Toxicity 286 Transporter- Mediated Pharmacogenomic Mechanisms of Drug Toxicity 290 Genetic Mechanisms for Drug-Induced Hypersensitivity Reactions 296 Haptens Interact with HLA Molecules in a Polymorphic-Specific Manner 297 Abacavir-Indticed Hypersensitivity Reactions 298 Granulysin Produced by CD8+ T-Cells is a Key Determinant of Disseminated Keratinocyte Death in Patients with SJS and TEN 298 FDA Labeling of Drugs for Pharmacogenomic Information 300 The Role of Simulation in Elucidating Pharmacogenomic ADR Mechanisms 301 The Role of Consortia in Elucidating Pharmacogenomic ADR Mechanisms 303 Acknowledgement 303 References 303 PART III ASSESSMENT OF DRUG EFFECTS CHAPTER 18 Physiological and Laboratory Markers of Drag Effect JANET WOODCOCK, ARTHUR J. ATKINSON, JR AND PAUL ROLAN Conceptual Framework 309 Identification and Evaluation of Biomarkers 310 Biomarker Discovery 311 Analytical Validation 311 Qualification 312 Surrogate Endpoints 312 Uses of Biomarkers 315 Application of Blood Pressure in Hypertension 315 Use of Biomarkers in Contemporary Drug Development 317 Contents Case Study: Development and Use of Serum Cholesterol as a Biomarker and Surrogate Endpoint 318 Role of Serum Cholesterol in the Simvastatin Development Program 319 Unanticipated Therapeutic Benefit from HMG-CoA Reducíase Inhibitors 320 Cholesterol-Lowering Disappointments 320 Future Development of Biomarkers 321 References 323 CHAPTER 19 Imaging in Drug Development RICHARD J. HARGREAVES AND MICHAEL KLIMAS Introduction 327 The Case for Molecular Imaging 328 Enabling Clinical Proof of Concept Testing 328 Accelerating Drug Development 328 Improving the Efficiency of Drug Development 329 Challenges to Using Imaging in Drug Development 329 Molecular Imaging Technologies 330 Imaging Biomarker Examples 331 Selecting and Monitoring the Right Patients 331 Target Engagement Imaging 331 Imaging Biology and Predicting Response 333 Imaging Therapeutic Drug Effects 335 Respiratory Imaging 335 Cardiovascular Imaging 336 Bone Imaging 337 Functional CNS Imaging 337 Conclusion 339 References 339 CHAPTER 20 Dose-Effect and Concentration-Effect Analysis ELIZABETH S. LOWE AND JUAN J.L. LERTORA Background 343 Drug-Receptor Interactions 344 Receptor Occupation Theory 345 Receptor-Mediated Effects 345 The Graded Dose-Effect Relationship 346 Dose-Effect Parameters 347 Dose Effect and Site of Drag Action 348 Biphasic Dose-Response Relationships (Hormesis) 349 The Quantal Dose-Effect Relationship 350 Therapeutic Indices 351 Dose-Effect and Defining Optimal Dose 352 FDA Guidance on Exposure-Response Relationships 353 Pharmacodynamic Models 353 Fixed-Effect Model 354 Maximum-Effect (Emax and Sigmoid Emax) Models 354 Linear and Log-Linear Model 355 Conclusion 356 References 356 CHAPTER 21 Time Course of Drug Response NICHOLAS H.G. HOLFORD AND ARTHUR J. ATKINSON, JR Pharmacokinetics and Delayed Pharmacologie Effects 358 The Biophase Compartment 358 Incorporation of Pharmacodynamic Models 360 Sigmoid Emax Models 361 Physiokinetics - the Time Course of Effects Due to Physiological Turnover Processes 362 Time-Varying Changes in the Relationship between Concentration and Drug Effect 364 Therapeutic Response, Cumulative Drug Effects, and Schedule Dependence 364 References 366 CHAPTER 22 Disease Progress Models NICHOLAS H.G. HOLFORD, DIANE R. MOULD AND CARL G PECK Clinical Pharmacology and Disease Progress 369 Disease Progress Models 369 No Progress Model 370 Linear Progression Model 370 Asymptotic Progress Model 372 Non-Zero Asymptote 373 Physiological Turnover Models 374 Growth and Decay Models 374 Contents Xl Design of Trials to Study Disease Progress 377 Conclusion 378 References 378 PART IV OPTIMIZING AND EVALUATING PATIENT THERAPY CHAPTER 23 Pharmacological Differences between Men and Women AMEF.TA I AREKH Introduction 383 Pharmacokinetics 384 Drug Transport 384 Absorption 384 Distribution 385 Drug Metabolism 386 Renal Excretion 387 Effects of Menstrual Cycle and Menopause on Pharmacokinetics 388 Pharmacodynamics 388 Cardiovascular Effects 388 Pain 389 Immunology and Inimunosuppression 391) Effects of Extraneous Factors 390 Summary 391 Acknowledgement 391 References 391 CHAPTER 24 Drug Therapy in Pregnant and Nursing Women CATHERINE S, STÍKA AND MARILYXN С FREDERIKSEX Pregnancy Physiology and its Effects on Pharmacokinetics 396 Gastrointestinal Changes 396 Cardiovascular Effects 397 Blood Composition Changes 398 Renal Changes 399 Hepatic Drug Metabolizing Changes 399 Peripartum Changes 401 Postpartum Changes 401 Pharmacokinetic Studies During Pregnancy 401 Results of Selected Pharmacokinetic Studies in Pregnant Women 401 Guidelines for the Conduct of Drug Studies in Pregnant Women 405 Placerttal Transfer of Drugs 405 Teratogenesis 408 Principles of Teratology 408 Measures to Minimize Teratogenic Risk 410 Drug Therapy of Nursing Mothers 411 References 412 CHAPTER 25 Pediatric Clinical Pharmacology and Therapeutics BRIDGRTTE L. JONES, JOHN N. VAN DEN ANKER AND GREGORY L. KEARNS Introduction 417 History of Pediatric Clinical Pharmacology 417 Developmental Clinical Pharmacology 419 Ontogeny of Pharmacokinetics in Children 420 Oral Absorption 420 Extravascular Absorption 420 Distribution 421 Drug Transport 421 Drug Metabolism 422 Drug Elimination 424 Developmental Pharmacodynamics 425 Drug Receptors 425 Immune Function 427 Pharmacodynamic Biomarkers 427 Therapeutic Considerations 428 Formulation 428 Adherence (Compliance) 429 Adverse Drug Reactions in Children 430 Special Therapeutic Considerations in the Neonate 430 Therapeutic Hypothermia 432 Pediatrie Dose and Regimen Selection 432 Application oi Pediatric Pharmacology to Clinical Study Design 433 References 433 Xli Contents CHAPTER 26 Drug Therapy in the Elderly S.W. JOHNNY LAU AND DARRELL R. ABERNETHY Introduction 437 Pathophysiology of Aging 437 Age-Related Changes in Pharmacokinetics 438 Age-Related Changes in Drug Distribution 438 Age-Related Changes in Renal Clearance 440 Age-Related Changes in Hepatic and Extrahepatic Drug Biotransformations 440 Age-Related Changes in Effector System Function 442 Central Nervous System 442 Autonomie Nervous System 443 Cardiovascular Function 444 Renal Function 445 Hematopoietic System and the Treatment of Cancer 446 Musculoskeletal System and the Treatment of Osteoporosis 446 Drug Groups for Which Age Confers Increased Risk for Toxicity 448 Conclusions 449 References 449 CHAPTER 27 Clinical Analysis of Adverse Drug Reactions MICHAEL FOTIS AND WILLIAM BUDRIS Introduction 455 Definitions and Classification 455 Classification by Severity 456 Classification by Type 456 ADR Detection 457 Determining Causality 458 Assessing ADR Risk 458 Evaluating Drug Labels for ADR Risk 458 Safety Alerts from FDA and International Regulators 460 Evaluating Publications for ADR Risk 461 Risk Associated with Recently Approved Drugs 461 Risk Associated with Off-Label Prescribing 462 Minimizing and Managing ADRS 462 Risk Evaluation and Mitigation Strategy (REMS) 462 Managing ADRs 463 References 464 CHAPTER 28 Quality Assessment of Drug Therapy CHARLES E. DANIELS Introduction 467 Adverse Drug Events 467 Medication-Use Process 468 Improving the Quality of Medication Use 470 Organizational Influences on Medication-Use Quality 470 Medication Policy Issues 471 Formulary Management 471 Analysis and Prevention of Medication Errors 474 Medication-Use Evaluation 478 Summary 481 References 481 PART V DRUG DISCOVERY AND DEVELOPMENT CHAPTER 29 Portfolio and Project Planning and Management in the Drug Discovery, Evaluation, Development, and Regulatory Review Process CHARLES GRUDZINSKAS AND CHARLES T. GOMBAR Introduction 487 What Is R&D Portfolio Design, Planning and Management? 488 What Is Project Planning and Management? 489 PORTFOLIO DESIGN, PLANNING, AND MANAGEMENT 489 Maximizing Portfolio Value 490 Portfolio Design 491 Portfolio Planning 493 Portfolio Management 493 Portfolio Optimization Using Sensitivity Analysis 494 Contents Xllí Project Planning and Management 495 Defining a Project 495 The Project Cycle 498 Project Planning and Management Tools 498 Milestone Tables 499 Work Breakdown Structures 499 PERT/CPM Charts 499 Gantt Charts 500 Financial Tracking 501 Risk Registers 501 Project Team Management and Decision- Making 501 Industry Project Teams 501 FDA Project Teams 502 Effective PDT Meetings 503 Resource Allocation 503 Effective Project Decision-Making 503 Process Leadership and Benchmarking 504 References 505 In Vitro Assessment of Pharmacologie Efficacy 518 In Vivo Assessment of Pharmacologie Efficacy 519 Non-Clinical Pharmacokinetics 522 Assessment of Pharmacologie Safety 523 Non-Clinical Toxicology 523 Starting Dose Selection for FIH Studies in Oncology 524 Translational Research in Oncology Drug Development 525 Molecularly Targeted Therapies 525 Biomarker-Guided Drug Development 525 Model-Based Drug Development and the Pharmacological Audit Trail 526 The Challenge: Molecularly Targeted Therapies and Translational Research in Drug Development 527 References 527 CHAPTER CHAPTER 30 Drug Discovery EDWARD A. SAUSVILLE Introduction 507 Drug Discovery Philosophies and Definition of Drug Targets 507 Empirical Drug Discovery 508 Rational Drug Discovery 509 Generating Diversity 510 Natural Products 510 Chemical Compound Libraries 511 Definition of Lead Structures 511 Structure-Based Drug Design 511 Biochemical Screens 512 Cell-Based Screens 512 Qualifying Leads for Transition to Early Trials 513 Acknowledgement 514 References 514 CHAPTER 31 Non-Clinical Drag Development CHRIS H. TAKIMOTO AND MICHAEL J. WICK Introduction 517 Components of Non-Clinical Drug Development 518 32 Preclinical Prediction of Human Pharmacokinetics MALCOLM ROWLAND AND ROBERT L. DEDRICK Introduction 531 Allometry 531 Use of Allometry to Predict Human Pharmacokinetic Parameters 532 Deviation from Expectation 533 Microdosing 535 Physiologic Pharmacokinetics 535 References 540 CHAPTER 33 Phase I Clinical Studies JERRY M. COLLINS Introduction 541 Disease-Specific Considerations 541 Starting Dose and Dose Escalation 542 Modified Fibonacci Escalation Scheme 542 Pharmacologically-Guided Dose Escalation 543 Interspecies Differences in Drug Metabolism 543 Active Metabolites 544 Beyond Toxicity 545 References 546 XIV Contents CHAPTER 34 Pharmacokinetic and Pharmacodynamic Considerations in the Development of Biotechnology Products and Large Molecules PAMELA D. GARZONE Introduction 547 Monoclonal Antibodies 547 Antibody Structure and Production 547 Pharmacokinetic Properties of Monoclonal Antibodies 549 Assay of Macromolecules 550 Interspecies Scaling of Macromolecules: Predictions in Humans 551 Safe Starting Doses of Monoclonal Antibodies in First-in-Human (FIH) Studies 553 Pharmacokinetic Characteristics of Macromolecules 553 Endogenous Concentrations 553 Absorption 555 Distribution 557 Metabolism 559 Elimination 561 Application of Sparse Sampling and Population Kinetic Methods 563 Pharmacodynamics of Macromolecules 564 Models 564 Regimen Dependency 565 References 566 CHAPTER 35 Design of Clinical Development Programs STEVEN W. RYDER AND ETHAN S. WEINER Introduction 571 Principles of Clinical Development 572 Proper Scientific Conduct 572 Ethical Principles 572 Legal and Regulatory Requirements 572 Regulatory Guidance 573 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 574 Good Clinical Practice 574 International (outside EU, US, Japan) and US State Regulation 575 Business Regulation 575 Data Privacy 575 Evidence-Based, Goal-Directed Clinical Development 576 Exponential Growth of Resource Requirements as a Clinical Development Program Progresses 576 High Attrition at All Phases of Clinical Development 577 Key Milestones: Proof of Mechanism, Proof of Concept, and Confirmation 577 Specific Design Issues in Clinical Development Programs 580 Ethical Design Considerations 580 Study Populations 580 Study Design Paradigms 580 Statistical Considerations Underlying the Number of Study Subjects 582 The Impact of Safety Assessment on Development Programs 583 Conduct of Clinical Development 585 Number and Location of Study Sites for Global Clinical Development Programs 585 Data Flow and Data Quality 585 Use of Independent Data Monitoring Committees (IDMCs) and Adjudication Committees 586 Special Topics 587 Personalized Medicine 587 Elderly and Pediatrie Populations 587 Orphan Drugs 588 Comparative Effectiveness 589 Combination Treatments 589 Transparency 590 References 591 CHAPTER 36 The Role of the FDA in Guiding Drug Development CHANDRAHAS G. SAHAJWALLA, LAWRENCE J. LESKO AND SHIEW-MEI HUANG Why does the FDA Get Involved in Drug Development? 596 When does the FDA Get Involved in Drug Development? 597 How does the FDA Guide Drug Development? 598 What are FDA Guidances? 599 The Role of the FDA Office of Clinical Pharmacology 600 Contents xv Future Development of Regulatory Science at the Appendix II FDA 601 ARTHUR J. ATKINSON, JR. Disclaimer 601 Answers to Study Problems 605 References 601 Subject Index 613 Appendix I Abbreviated Tables of Laplace Transforms 603
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spelling	Principles of clinical pharmacology Arthur J. Atkinson ... 3. ed. San Diego [u.a.] Elsevier, Acad. Press 2012 XXI, 626 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Farmacologie gtt Pharmacologie clinique Clinical pharmacology Pharmacology, Clinical Pharmakologie (DE-588)4045687-0 gnd rswk-swf (DE-588)4123623-3 Lehrbuch gnd-content Pharmakologie (DE-588)4045687-0 s DE-604 Atkinson, Arthur J. Sonstige oth Digitalisierung UB Regensburg application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=025485523&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis
spellingShingle	Principles of clinical pharmacology Farmacologie gtt Pharmacologie clinique Clinical pharmacology Pharmacology, Clinical Pharmakologie (DE-588)4045687-0 gnd
subject_GND	(DE-588)4045687-0 (DE-588)4123623-3
title	Principles of clinical pharmacology
title_auth	Principles of clinical pharmacology
title_exact_search	Principles of clinical pharmacology
title_full	Principles of clinical pharmacology Arthur J. Atkinson ...
title_fullStr	Principles of clinical pharmacology Arthur J. Atkinson ...
title_full_unstemmed	Principles of clinical pharmacology Arthur J. Atkinson ...
title_short	Principles of clinical pharmacology
title_sort	principles of clinical pharmacology
topic	Farmacologie gtt Pharmacologie clinique Clinical pharmacology Pharmacology, Clinical Pharmakologie (DE-588)4045687-0 gnd
topic_facet	Farmacologie Pharmacologie clinique Clinical pharmacology Pharmacology, Clinical Pharmakologie Lehrbuch
url	http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=025485523&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
work_keys_str_mv	AT atkinsonarthurj principlesofclinicalpharmacology

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