Principles of Clinical Pharmacology

Front cover......Page 1
PRINCIPLES OF CLINICAL PHARMACOLOGY......Page 4
Copyright page......Page 5
Table of contents......Page 6
Preface to the Second Edition......Page 16
Contributors......Page 18
BACKGROUND......Page 22
PHARMACOKINETICS......Page 25
P A R T I: PHARMACOKINETICS......Page 30
THE TARGET CONCENTRATION STRATEGY......Page 32
CONCEPTS UNDERLYING CLINICAL PHARMACOKINETICS......Page 34
MATHEMATICAL BASIS OF CLINICAL PHARMACOKINETICS......Page 39
PHYSIOLOGICAL SIGNIFICANCE OF DRUG DISTRIBUTION VOLUMES......Page 46
PHYSIOLOGICAL BASIS OF MULTICOMPARTMENTAL MODELS OF DRUG DISTRIBUTION......Page 48
CLINICAL CONSEQUENCES OF DIFFERENT DRUG DISTRIBUTION PATTERNS......Page 51
ANALYSIS OF EXPERIMENTAL DATA......Page 52
DRUG ABSORPTION......Page 58
BIOAVAILABILITY......Page 61
KINETICS OF DRUG ABSORPTION AFTER ORAL ADMINISTRATION......Page 65
C H A P T E R 5. Effects of Renal Disease on Pharmacokinetics......Page 72
EFFECTS OF RENAL DISEASE ON DRUG ELIMINATION......Page 73
EFFECTS OF RENAL DISEASE ON DRUG DISTRIBUTION......Page 76
EFFECTS OF RENAL DISEASE ON DRUG ABSORPTION......Page 77
KINETICS OF INTERMITTENT HEMODIALYSIS......Page 80
KINETICS OF CONTINUOUS RENAL REPLACEMENT THERAPY......Page 86
CLINICAL CONSIDERATIONS......Page 88
HEPATIC ELIMINATION OF DRUGS......Page 94
EFFECTS OF LIVER DISEASE ON PHARMACOKINETICS......Page 97
USE OF THERAPEUTIC DRUGS IN PATIENTS WITH LIVER DISEASE......Page 101
INTRODUCTION......Page 110
KINETICS, PHARMACOKINETICS, AND PHARMACOKINETIC PARAMETERS......Page 111
NONCOMPARTMENTAL ANALYSIS......Page 113
COMPARTMENTAL ANALYSIS......Page 118
NONCOMPARTMENTAL VERSUS COMPARTMENTAL MODELS......Page 123
CONCLUSION......Page 126
CENTRAL ISSUES......Page 128
DRUG MODALITY I: DELIVERY ACROSS A PLANAR – TISSUE INTERFACE......Page 129
DRUG MODALITY II: DELIVERY FROM A POINT SOURCE — DIRECT INTERSTITIAL INFUSION......Page 138
SUMMARY......Page 147
ANALYSIS OF PHARMACOKINETIC DATA......Page 150
POPULATION PHARMACOKINETICS......Page 151
MODEL APPLICATIONS......Page 155
CONCLUSIONS......Page 159
P A R T II: DRUG METABOLISM AND TRANSPORT......Page 162
INTRODUCTION......Page 164
PHASE I BIOTRANSFORMATIONS......Page 167
PHASE II BIOTRANSFORMATIONS ( CONJUGATIONS)......Page 177
ADDITIONAL EFFECTS ON DRUG METABOLISM......Page 180
CHOICE OF ANALYTICAL METHODOLOGY......Page 184
CHROMATOGRAPHIC SEPARATIONS......Page 185
ABSORPTION AND EMISSION SPECTROSCOPY......Page 186
IMMUNOAFFINITY ASSAYS......Page 187
MASS SPECTROMETRY......Page 188
EXAMPLES OF CURRENT ASSAY METHODS......Page 191
INTRODUCTION......Page 200
HIERARCHY OF PHARMACOGENETIC INFORMATION......Page 201
IDENTIFICATION AND SELECTION OF OUTLIERS IN A POPULATION......Page 202
EXAMPLES OF IMPORTANT GENETIC POLYMORPHISMS......Page 204
CONCLUSIONS AND FUTURE DIRECTIONS......Page 212
MECHANISMS OF TRANSPORT ACROSS BIOLOGICAL MEMBRANES......Page 218
DESCRIPTION OF SELECTED MEMBRANE PROTEIN TRANSPORTERS......Page 225
ROLE OF TRANSPORTERS IN PHARMACOKINETICS AND DRUG ACTION......Page 230
PHARMACOGENETICS AND PHARMACOGENOMICS OF TRANSPORTERS......Page 236
FUTURE DIRECTIONS......Page 241
INTRODUCTION......Page 250
MECHANISMS OF DRUG INTERACTIONS......Page 251
PREDICTION AND CLINICAL MANAGEMENT OF DRUG INTERACTIONS......Page 263
INTRODUCTION......Page 270
DRUG-INDUCED LIVER TOXICITY......Page 274
MECHANISMS OF OTHER DRUG TOXICITIES......Page 280
P A R T III: ASSESSMENT OF DRUG EFFECTS......Page 294
BIOLOGICAL MARKERS OF DRUG EFFECT......Page 296
IDENTIFICATION AND EVALUATION OF BIOMARKERS......Page 298
USES OF BIOMARKERS AND SURROGATE ENDPOINTS......Page 300
FUTURE DEVELOPMENT OF BIOMARKERS......Page 304
BACKGROUND......Page 310
DRUG–RECEPTOR INTERACTIONS......Page 311
GRADED DOSE-EFFECT RELATIONSHIP......Page 313
QUANTAL DOSE-EFFECT RELATIONSHIP......Page 316
PHARMACODYNAMIC MODELS......Page 319
CONCLUSION......Page 320
C H A P T E R 19. Time Course of Drug Response......Page 322
PHARMACOKINETICS AND DELAYED PHARMACOLOGIC EFFECTS......Page 323
PHYSIOKINETICS — TIME COURSE OF EFFECTS DUE TO PHYSIOLOGICAL TURNOVER PROCESSES......Page 328
THERAPEUTIC RESPONSE, CUMULATIVE DRUG EFFECTS, AND SCHEDULE DEPENDENCE......Page 329
DISEASE PROGRESS MODELS......Page 334
CONCLUSION......Page 341
P A R T IV: OPTIMIZING AND EVALUATING PATIENT THERAPHY......Page 344
PHARMACOKINETICS......Page 346
PHARMACODYNAMICS......Page 352
SUMMARY......Page 355
C H A P T E R 22. Drug Therapy in Pregnant and Nursing Women......Page 360
PREGNANCY PHYSIOLOGY AND ITS EFFECTS ON PHARMACOKINETICS......Page 361
PHARMACOKINETIC STUDIES DURING PREGNANCY......Page 365
PLACENTAL TRANSFER OF DRUGS......Page 369
TERATOGENESIS......Page 370
DRUG THERAPY IN NURSING MOTHERS......Page 373
BACKGROUND......Page 380
ONTOGENY AND PHARMACOLOGY......Page 383
THERAPEUTIC IMPLICATIONS OF GROWTH AND DEVELOPMENT......Page 387
CONCLUSIONS......Page 392
PATHOPHYSIOLOGY OF AGING......Page 396
AGE-RELATED CHANGES IN PHARMACOKINETICS......Page 398
AGE-RELATED CHANGES IN EFFECTOR SYSTEM FUNCTION......Page 400
DRUG GROUPS FOR WHICH AGE CONFERS INCREASED RISK FOR TOXICITY......Page 404
CONCLUSIONS......Page 406
INTRODUCTION......Page 410
CLASSIFICATION......Page 411
CLINICAL DETECTION......Page 412
ADR DETECTION IN CLINICAL TRIALS......Page 419
INFORMATION SOURCES......Page 420
INTRODUCTION......Page 424
ORGANIZATIONAL INFLUENCES ON MEDICATION USE QUALITY......Page 427
SUMMARY......Page 438
P A R T V: DRUG DISCOVERY AND DEVELOPMENT......Page 442
INTRODUCTION......Page 444
PORTFOLIO DESIGN, PLANNING, AND MANAGEMENT......Page 445
PROJECT PLANNING AND MANAGEMENT......Page 450
PROJECT PLANNING AND MANAGEMENT TOOLS......Page 452
PROJECT TEAM MANAGEMENT AND DECISION- MAKING......Page 455
DEFINITION OF DRUG TARGETS......Page 460
GENERATING DIVERSITY......Page 464
DEFINITION OF LEAD STRUCTURES......Page 465
QUALIFYING LEADS FOR TRANSITION TO EARLY TRIALS......Page 466
INTRODUCTION......Page 470
COMPONENTS OF PRECLINICAL DRUG DEVELOPMENT......Page 471
DRUG DEVELOPMENT PROGRAMS AT THE NCI......Page 477
THE CHALLENGE — MOLECULARLY TARGETED THERAPIES AND NEW PARADIGMS FOR CLINICAL TRIALS......Page 480
ALLOMETRY......Page 484
PHYSIOLOGICAL PHARMACOKINETICS......Page 488
IN VITRO-IN VIVO CORRELATION OF HEPATIC METABOLISM......Page 490
DISEASE-SPECIFIC CONSIDERATIONS......Page 494
STARTING DOSE AND DOSE ESCALATION......Page 495
BEYOND TOXICITY......Page 498
INTRODUCTION......Page 500
PHARMACOKINETIC CHARACTERISTICS OF MACROMOLECULES......Page 504
PHARMACODYNAMICS......Page 515
PHASES, SIZE, AND SCOPE OF CLINICAL DEVELOPMENT PROGRAMS......Page 522
GOAL AND OBJECTIVES OF CLINICAL DRUG DEVELOPMENT......Page 526
CRITICAL DRUG DEVELOPMENT PARADIGMS......Page 528
CRITICAL CLINICAL DRUG DEVELOPMENT DECISION POINTS......Page 530
LEARNING CONTEMPORARY CLINICAL DRUG DEVELOPMENT......Page 535
C H A P T E R 34. Role of the FDA in Guiding Drug Development......Page 540
WHEN DOES THE FDA GET INVOLVED IN DRUG DEVELOPMENT?......Page 541
HOW DOES THE FDA GUIDE DRUG DEVELOPMENT?......Page 542
WHAT ARE FDA GUIDANCES?......Page 544
A P P E N D I X I. Abbreviated Tables of Laplace Transforms......Page 548
A P P E N D I X II. Answers to Study Problems......Page 550
Index......Page 558