Principles of Clinical Pharmacology (eBook)

Darrell R. Abernethy, Charles E. Daniels, Robert Dedrick, Arthur J. Atkinson Jr., Sanford P. Markey (Herausgeber)

eBook Download: EPUB

2011 | 2. Auflage
568 Seiten
Elsevier Science (Verlag)
978-0-08-046642-2 (ISBN)

Infos

This revised second edition covers the pharmacologic principles underlying the individualization of patient therapy and contemporary drug development, focusing on the fundamentals that underlie the clinical use and contemporary development of pharmaceuticals. Authors drawn from academia, the pharmaceutical industry and government agencies cover the spectrum of material, including pharmacokinetic practice questions, covered by the basic science section of the certifying examination offered by the American Board of Clinical Pharmacology. This unique reference is recommended by the Board as a study text and includes modules on drug discovery and development to assist students as well as practicing pharmacologists.
* Unique breadth of coverage ranging from drug discovery and development to individualization and quality assessment of drug therapy.
* Unusual cohesive of presentation that stems from author participation in an ongoing popular NIH course.
* Instructive linkage of pharmacokinetic theory and applications with provision of sample problems for self-study.
* Wide-ranging perspective of authors drawn from the ranks of Federal agencies, academia and the pharmaceutical industry.
* Expanded coverage of pharmacogenetics
* Expanded coverage of drug transporters and their role in interactions
* Inclusion of new material on enzyme induction mechanisms in chapters on drug metabolism and drug interactions
* A new chapter on drug discovery that focuses on oncologic agents
* Inclusion of therapeutic antibodies in chapter on biotechnology products

Inhalt

Front cover 1
Title page 4
Copyright page 5
Table of contents 6
Preface to the First Edition 16
Preface to the Second Edition 16
Contributors 18
CHAPTER 1. Introduction to Clinical Pharmacology 22
BACKGROUND 22
PHARMACOKINETICS 25
PART I: PHARMACOKINETICS 30
CHAPTER 2. Clinical Pharmacokinetics 32
THE TARGET CONCENTRATION STRATEGY 32
CONCEPTS UNDERLYING CLINICAL PHARMACOKINETICS 34
MATHEMATICAL BASIS OF CLINICAL PHARMACOKINETICS 39
CHAPTER 3. Compartmental Analysis of Drug Distribution 46
PHYSIOLOGICAL SIGNIFICANCE OF DRUG DISTRIBUTION VOLUMES 46
PHYSIOLOGICAL BASIS OF MULTICOMPARTMENTAL MODELS OF DRUG DISTRIBUTION 48
CLINICAL CONSEQUENCES OF DIFFERENT DRUG DISTRIBUTION PATTERNS 51
ANALYSIS OF EXPERIMENTAL DATA 52
CHAPTER 4. Drug Absorption and Bioavailability 58
DRUG ABSORPTION 58
BIOAVAILABILITY 61
KINETICS OF DRUG ABSORPTION AFTER ORAL ADMINISTRATION 65
CHAPTER 5. Effects of Renal Disease on Pharmacokinetics 72
EFFECTS OF RENAL DISEASE ON DRUG ELIMINATION 73
EFFECTS OF RENAL DISEASE ON DRUG DISTRIBUTION 76
EFFECTS OF RENAL DISEASE ON DRUG ABSORPTION 77
CHAPTER 6. Pharmacokinetics in Patients Requiring Renal Replacement Therapy 80
KINETICS OF INTERMITTENT HEMODIALYSIS 80
KINETICS OF CONTINUOUS RENAL REPLACEMENT THERAPY 86
CLINICAL CONSIDERATIONS 88
CHAPTER 7. Effect of Liver Disease on Pharmacokinetics 94
HEPATIC ELIMINATION OF DRUGS 94
EFFECTS OF LIVER DISEASE ON PHARMACOKINETICS 97
USE OF THERAPEUTIC DRUGS IN PATIENTS WITH LIVER DISEASE 101
CHAPTER 8. Noncompartmental versus Compartmental Approaches to Pharmacokinetic Analysis 110
INTRODUCTION 110
KINETICS, PHARMACOKINETICS, AND PHARMACOKINETIC PARAMETERS 111
NONCOMPARTMENTAL ANALYSIS 113
COMPARTMENTAL ANALYSIS 118
NONCOMPARTMENTAL VERSUS COMPARTMENTAL MODELS 123
CONCLUSION 126
CHAPTER 9. Distributed Models of Drug Kinetics 128
INTRODUCTION 128
CENTRAL ISSUES 128
DRUG MODALITY I: DELIVERY ACROSS A PLANAR – TISSUE INTERFACE 129
DRUG MODALITY II: DELIVERY FROM A POINT SOURCE — DIRECT INTERSTITIAL INFUSION 138
SUMMARY 147
CHAPTER 10. Population Pharmacokinetics 150
INTRODUCTION 150
ANALYSIS OF PHARMACOKINETIC DATA 150
POPULATION PHARMACOKINETICS 151
MODEL APPLICATIONS 155
CONCLUSIONS 159
PART II: DRUG METABOLISM AND TRANSPORT 162
CHAPTER 11. Pathways of Drug Metabolism 164
INTRODUCTION 164
PHASE I BIOTRANSFORMATIONS 167
PHASE II BIOTRANSFORMATIONS (CONJUGATIONS) 177
ADDITIONAL EFFECTS ON DRUG METABOLISM 180
CHAPTER 12. Methods of Analysis of Drugs and Drug Metabolites 184
INTRODUCTION 184
CHOICE OF ANALYTICAL METHODOLOGY 184
CHROMATOGRAPHIC SEPARATIONS 185
ABSORPTION AND EMISSION SPECTROSCOPY 186
IMMUNOAFFINITY ASSAYS 187
MASS SPECTROMETRY 188
EXAMPLES OF CURRENT ASSAY METHODS 191
CHAPTER 13. Clinical Pharmacogenetics 200
INTRODUCTION 200
HIERARCHY OF PHARMACOGENETIC INFORMATION 201
IDENTIFICATION AND SELECTION OF OUTLIERS IN A POPULATION 202
EXAMPLES OF IMPORTANT GENETIC POLYMORPHISMS 204
CONCLUSIONS AND FUTURE DIRECTIONS 212
CHAPTER 14. Equilibrative and Concentrative Transport Mechanisms 218
INTRODUCTION 218
MECHANISMS OF TRANSPORT ACROSS BIOLOGICAL MEMBRANES 218
DESCRIPTION OF SELECTED MEMBRANE PROTEIN TRANSPORTERS 225
ROLE OF TRANSPORTERS IN PHARMACOKINETICS AND DRUG ACTION 230
PHARMACOGENETICS AND PHARMACOGENOMICS OF TRANSPORTERS 236
FUTURE DIRECTIONS 241
CHAPTER 15. Drug Interactions 250
INTRODUCTION 250
MECHANISMS OF DRUG INTERACTIONS 251
PREDICTION AND CLINICAL MANAGEMENT OF DRUG INTERACTIONS 263
CHAPTER 16. Biochemical Mechanisms of Drug Toxicity 270
INTRODUCTION 270
DRUG-INDUCED LIVER TOXICITY 274
MECHANISMS OF OTHER DRUG TOXICITIES 280
PART III: ASSESSMENT OF DRUG EFFECTS 294
CHAPTER 17. Physiological and Laboratory Markers of Drug Effect 296
BIOLOGICAL MARKERS OF DRUG EFFECT 296
IDENTIFICATION AND EVALUATION OF BIOMARKERS 298
USES OF BIOMARKERS AND SURROGATE ENDPOINTS 300
FUTURE DEVELOPMENT OF BIOMARKERS 304
CHAPTER 18. Dose-Effect and Concentration-Effect Analysis 310
BACKGROUND 310
DRUG–RECEPTOR INTERACTIONS 311
GRADED DOSE-EFFECT RELATIONSHIP 313
QUANTAL DOSE-EFFECT RELATIONSHIP 316
PHARMACODYNAMIC MODELS 319
CONCLUSION 320
CHAPTER 19. Time Course of Drug Response 322
PHARMACOKINETICS AND DELAYED PHARMACOLOGIC EFFECTS 323
PHYSIOKINETICS — TIME COURSE OF EFFECTS DUE TO PHYSIOLOGICAL TURNOVER PROCESSES 328
THERAPEUTIC RESPONSE, CUMULATIVE DRUG EFFECTS, AND SCHEDULE DEPENDENCE 329
CHAPTER 20. Disease Progress Models 334
CLINICAL PHARMACOLOGY AND DISEASE PROGRESS 334
DISEASE PROGRESS MODELS 334
CONCLUSION 341
PART IV: OPTIMIZING AND EVALUATING PATIENT THERAPHY 344
CHAPTER 21. Pharmacological Differences between Men and Women 346
PHARMACOKINETICS 346
PHARMACODYNAMICS 352
SUMMARY 355
CHAPTER 22. Drug Therapy in Pregnant and Nursing Women 360
PREGNANCY PHYSIOLOGY AND ITS EFFECTS ON PHARMACOKINETICS 361
PHARMACOKINETIC STUDIES DURING PREGNANCY 365
PLACENTAL TRANSFER OF DRUGS 369
TERATOGENESIS 370
DRUG THERAPY IN NURSING MOTHERS 373
CHAPTER 23. Drug Therapy in Neonates and Pediatric Patients 380
BACKGROUND 380
ONTOGENY AND PHARMACOLOGY 383
THERAPEUTIC IMPLICATIONS OF GROWTH AND DEVELOPMENT 387
CONCLUSIONS 392
CHAPTER 24. Drug Therapy in the Elderly 396
INTRODUCTION 396
PATHOPHYSIOLOGY OF AGING 396
AGE-RELATED CHANGES IN PHARMACOKINETICS 398
AGE-RELATED CHANGES IN EFFECTOR SYSTEM FUNCTION 400
DRUG GROUPS FOR WHICH AGE CONFERS INCREASED RISK FOR TOXICITY 404
CONCLUSIONS 406
CHAPTER 25. Clinical Analysis of Adverse Drug Reactions 410
INTRODUCTION 410
CLASSIFICATION 411
CLINICAL DETECTION 412
ADR DETECTION IN CLINICAL TRIALS 419
INFORMATION SOURCES 420
CHAPTER 26. Quality Assessment of Drug Therapy 424
INTRODUCTION 424
ORGANIZATIONAL INFLUENCES ON MEDICATION USE QUALITY 427
SUMMARY 438
PART V: DRUG DISCOVERY AND DEVELOPMENT 442
CHAPTER 27. Portfolio and Project Planning and Management in the Drug Discovery, Development, and Review Process 444
INTRODUCTION 444
PORTFOLIO DESIGN, PLANNING, AND MANAGEMENT 445
PROJECT PLANNING AND MANAGEMENT 450
PROJECT PLANNING AND MANAGEMENT TOOLS 452
PROJECT TEAM MANAGEMENT AND DECISION-MAKING 455
CHAPTER 28. Drug Discovery 460
INTRODUCTION 460
DEFINITION OF DRUG TARGETS 460
GENERATING DIVERSITY 464
DEFINITION OF LEAD STRUCTURES 465
QUALIFYING LEADS FOR TRANSITION TO EARLY TRIALS 466
CHAPTER 29. Preclinical Drug Development 470
INTRODUCTION 470
COMPONENTS OF PRECLINICAL DRUG DEVELOPMENT 471
DRUG DEVELOPMENT PROGRAMS AT THE NCI 477
THE CHALLENGE — MOLECULARLY TARGETED THERAPIES AND NEW PARADIGMS FOR CLINICAL TRIALS 480
CHAPTER 30. Animal Scale-Up 484
INTRODUCTION 484
ALLOMETRY 484
PHYSIOLOGICAL PHARMACOKINETICS 488
IN VITRO-IN VIVO CORRELATION OF HEPATIC METABOLISM 490
CHAPTER 31. Phase I Clinical Studies 494
INTRODUCTION 494
DISEASE-SPECIFIC CONSIDERATIONS 494
STARTING DOSE AND DOSE ESCALATION 495
BEYOND TOXICITY 498
CHAPTER 32. Development of Biotechnology Products and Large Molecules 500
INTRODUCTION 500
PHARMACOKINETIC CHARACTERISTICS OF MACROMOLECULES 504
PHARMACODYNAMICS 515
CHAPTER 33. Design of Clinical Development Programs 522
INTRODUCTION 522
PHASES, SIZE, AND SCOPE OF CLINICAL DEVELOPMENT PROGRAMS 522
GOAL AND OBJECTIVES OF CLINICAL DRUG DEVELOPMENT 526
CRITICAL DRUG DEVELOPMENT PARADIGMS 528
CRITICAL CLINICAL DRUG DEVELOPMENT DECISION POINTS 530
LEARNING CONTEMPORARY CLINICAL DRUG DEVELOPMENT 535
CHAPTER 34. Role of the FDA in Guiding Drug Development 540
WHY DOES THE FDA GET INVOLVED IN DRUG DEVELOPMENT? 541
WHEN DOES THE FDA GET INVOLVED IN DRUG DEVELOPMENT? 541
HOW DOES THE FDA GUIDE DRUG DEVELOPMENT? 542
WHAT ARE FDA GUIDANCES? 544
APPENDIX I. Abbreviated Tables of Laplace Transforms 548
APPENDIX II. Answers to Study Problems 550
Index 558

Textauszug

CHAPTER 1 Introduction to Clinical Pharmacology

ARTHUR J. ATKINSON, JR.

Clinical Center, National Institutes of Health, Bethesda, Maryland

Fortunately a surgeon who uses the wrong side of the scalpel cuts his own fingers and not the patient; if the same applied to drugs they would have been investigated very carefully a long time ago.

Rudolph Bucheim

Beitrage zur Arzneimittellehre, 1849 (1)

BACKGROUND

Clinical pharmacology can be defined as the study of drugs in humans. Clinical pharmacology often is contrasted with basic pharmacology. Yet applied is a more appropriate antonym for basic (2). In fact, many basic problems in pharmacology can only be studied in humans. This text will focus on the basic principles of clinical pharmacology. Selected applications will be used to illustrate these principles, but no attempt will be made to provide an exhaustive coverage of applied therapeutics. Other useful supplementary sources of information are listed at the end of this chapter.

Leake (3) has pointed out that pharmacology is a subject of ancient interest but is a relatively new science. Reidenberg (4) subsequently restated Leake’s listing of the fundamental problems with which the science of pharmacology is concerned:

1. The relationship between dose and biological effect.
2. The localization of the site of action of a drug.
3. The mechanism(s) of action of a drug.
4. The absorption, distribution, metabolism, and excretion of a drug.
5. The relationship between chemical structure and biological activity.

These authors agree that pharmacology could not evolve as a scientific discipline until modern chemistry provided the chemically pure pharmaceutical products that are needed to establish a quantitative relationship between drug dosage and biological effect.

Clinical pharmacology has been termed a bridging discipline because it combines elements of classical pharmacology with clinical medicine. The special competencies of individuals trained in clinical pharmacology have equipped them for productive careers in academia, the pharmaceutical industry, and governmental agencies, such as the National Institutes of Health (NIH) and the Food and Drug Administration (FDA). Reidenberg (4) has pointed out that clinical pharmacologists are concerned both with the optimal use of existing medications and with the scientific study of drugs in humans. The latter area includes both evaluation of the safety and efficacy of currently available drugs and development of new and improved pharmacotherapy.

Optimizing Use of Existing Medicines

As the opening quote indicates, the concern of pharmacologists for the safe and effective use of medicine can be traced back at least to Rudolph Bucheim (1820–1879), who has been credited with establishing pharmacology as a laboratory-based discipline (1). In the United States, Harry Gold and Walter Modell began in the 1930s to provide the foundation for the modern discipline of clinical pharmacology (5). Their accomplishments include the invention of the double-blind design for clinical trials (6), the use of effect kinetics to measure the absolute bioavailability of digoxin and characterize the time course of its chronotropic effects (7), and the founding of Clinical Pharmacology and Therapeutics.

Few drugs have focused as much public attention on the problem of adverse drug reactions as did thalidomide, which was first linked in 1961 to catastrophic outbreaks of phocomelia by Lenz in Germany and McBride in Australia (8). Although thalidomide had not been approved at that time for use in the United States, this tragedy prompted passage in 1962 of the Harris–Kefauver Amendments to the Food, Drug, and Cosmetic Act. This act greatly expanded the scope of the FDA’s mandate to protect the public health. The thalidomide tragedy also provided the major impetus for developing a number of NIH-funded academic centers of excellence that have shaped contemporary clinical pharmacology in this country. These U.S. centers were founded by a generation of vigorous leaders, including Ken Melmon, Jan Koch-Weser, Lou Lasagna, John Oates, Leon Goldberg, Dan Azarnoff, Tom Gaffney, and Leigh Thompson. Collin Dollery and Folke Sjöqvist established similar programs in Europe. In response to the public mandate generated by the thalidomide catastrophe, these leaders quickly reached consensus on a number of theoretically preventable causes that contribute to the high incidence of adverse drug reactions (5). These causes include the following failures of approach:

1. Inappropriate polypharmacy.
2. Failure of prescribing physicians to establish and adhere to clear therapeutic goals.
3. Failure of medical personnel to attribute new symptoms or changes in laboratory test results to drug therapy.
4. Lack of priority given to the scientific study of adverse drug reaction mechanisms.
5. General ignorance of basic and applied pharmacology and therapeutic principles.

The important observations also were made that, unlike the teratogenic reactions caused by thalidomide, most adverse reactions encountered in clinical practice occurred with commonly used, rather than newly introduced, drugs, and were dose related, rather than idiosyncratic (9, 10).

Recognition of the considerable variation in response of patients treated with standard drug doses provided the impetus for the development of laboratory methods to measure drug concentrations in patient blood samples (10). The availability of these measurements also made it possible to apply pharmacokinetic principles to routine patient care. Despite these advances, serious adverse drug reactions (defined as those adverse drug reactions that require or prolong hospitalization, are permanently disabling, or result in death) have been estimated to occur in 6.7% of hospitalized patients (11). Although this figure has been disputed, the incidence of adverse drug reactions probably is still higher than is generally recognized (12). In addition, the majority of these adverse reactions continue to be caused by drugs that have been in clinical use for a substantial period of time (5).

The fact that most adverse drug reactions occur with commonly used drugs focuses attention on the last of the preventable causes of these reactions: the training that prescribing physicians receive in pharmacology and therapeutics. Bucheim’s comparison of surgery and medicine is particularly apt in this regard (5). Most U.S. medical schools provide their students with only a single course in pharmacology that traditionally is part of the second-year curriculum, when students lack the clinical background that is needed to support detailed instruction in therapeutics. In addition, Sjöqvist (13) has observed that most academic pharmacology departments have lost contact with drug development and pharmacotherapy. As a result, students and residents acquire most of their information about drug therapy in a haphazard manner from colleagues, supervisory house staff and attending physicians, pharmaceutical sales representatives, and whatever independent reading they happen to do on the subject. This unstructured process of learning pharmacotherapeutic technique stands in marked contrast to the rigorously supervised training that is an accepted part of surgical training, in which instantaneous feedback is provided whenever a retractor, let alone a scalpel, is held improperly.

Evaluation and Development of Medicines

Clinical pharmacologists have made noteworthy contributions to the evaluation of existing medicines and development of new drugs. In 1932, Paul Martini published a monograph entitled Methodology of Therapeutic Investigation that summarized his experience in scientific drug evaluation and probably entitles him to be considered the “first clinical pharmacologist” (14). Martini described the use of placebos, control groups, stratification, rating scales, and the “n of 1” trial design, and emphasized the need to estimate the adequacy of sample size and to establish baseline conditions before beginning a trial. He also introduced the term “clinical pharmacology.” Gold (6) and other academic clinical pharmacologists also have made important contributions to the design of clinical trials. More recently, Sheiner (15) outlined a number of improvements that continue to be needed in the use of statistical methods for drug evaluation, and asserted that clinicians must regain control over clinical trials in order to ensure that the important questions are being addressed.

Contemporary drug development is a complex process that is conventionally divided into preclinical research and development and a number of clinical development phases, as shown in Figure 1.1 for drugs licensed by the United States Food and Drug Administration (16). After a drug candidate is identified and put through in vitro screens and animal testing, an Investigational New Drug application (IND) is submitted to the FDA. When the IND is approved, Phase I clinical development begins with a limited number of studies in healthy volunteers or patients. The goal of these studies is to establish a range of tolerated doses and to characterize the drug candidate’s pharmacokinetic properties and initial toxicity profile. If these results warrant further development of the compound, short-term Phase II studies are conducted in a selected...

Produkt-Details

• Erscheint lt. Verlag: 28.4.2011
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Gesundheitsfachberufe
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie
• Themenwelt: Technik ► Umwelttechnik / Biotechnologie
• ISBN-10: 0-08-046642-7 / 0080466427
• ISBN-13: 978-0-08-046642-2 / 9780080466422