Atkinson Jr. / Abernethy / Jr. Principles of Clinical Pharmacology

2. Auflage 2011
ISBN: 978-0-08-046642-2
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 568 Seiten

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

Zielgruppe

Academic/professional/technical: Research and professional

Autoren/Hrsg.

Jr.,

Atkinson Jr., Arthur J.

Abernethy, Darrell R.

Daniels, Charles E.

Dedrick, Robert

Markey, Sanford P.

Inhaltsverzeichnis

1;Front cover;1
2;Title page;4
3;Copyright page;5
4;Table of contents;6
5;Preface to the First Edition;16
6;Preface to the Second Edition;16
7;Contributors;18
8;CHAPTER 1. Introduction to Clinical Pharmacology;22
8.1;BACKGROUND;22
8.2;PHARMACOKINETICS;25
9;PART I: PHARMACOKINETICS;30
9.1;CHAPTER 2. Clinical Pharmacokinetics;32
9.1.1;THE TARGET CONCENTRATION STRATEGY;32
9.1.2;CONCEPTS UNDERLYING CLINICAL PHARMACOKINETICS;34
9.1.3;MATHEMATICAL BASIS OF CLINICAL PHARMACOKINETICS;39
9.2;CHAPTER 3. Compartmental Analysis of Drug Distribution;46
9.2.1;PHYSIOLOGICAL SIGNIFICANCE OF DRUG DISTRIBUTION VOLUMES;46
9.2.2;PHYSIOLOGICAL BASIS OF MULTICOMPARTMENTAL MODELS OF DRUG DISTRIBUTION;48
9.2.3;CLINICAL CONSEQUENCES OF DIFFERENT DRUG DISTRIBUTION PATTERNS;51
9.2.4;ANALYSIS OF EXPERIMENTAL DATA;52
9.3;CHAPTER 4. Drug Absorption and Bioavailability;58
9.3.1;DRUG ABSORPTION;58
9.3.2;BIOAVAILABILITY;61
9.3.3;KINETICS OF DRUG ABSORPTION AFTER ORAL ADMINISTRATION;65
9.4;CHAPTER 5. Effects of Renal Disease on Pharmacokinetics;72
9.4.1;EFFECTS OF RENAL DISEASE ON DRUG ELIMINATION;73
9.4.2;EFFECTS OF RENAL DISEASE ON DRUG DISTRIBUTION;76
9.4.3;EFFECTS OF RENAL DISEASE ON DRUG ABSORPTION;77
9.5;CHAPTER 6. Pharmacokinetics in Patients Requiring Renal Replacement Therapy;80
9.5.1;KINETICS OF INTERMITTENT HEMODIALYSIS;80
9.5.2;KINETICS OF CONTINUOUS RENAL REPLACEMENT THERAPY;86
9.5.3;CLINICAL CONSIDERATIONS;88
9.6;CHAPTER 7. Effect of Liver Disease on Pharmacokinetics;94
9.6.1;HEPATIC ELIMINATION OF DRUGS;94
9.6.2;EFFECTS OF LIVER DISEASE ON PHARMACOKINETICS;97
9.6.3;USE OF THERAPEUTIC DRUGS IN PATIENTS WITH LIVER DISEASE;101
9.7;CHAPTER 8. Noncompartmental versus Compartmental Approaches to Pharmacokinetic Analysis;110
9.7.1;INTRODUCTION;110
9.7.2;KINETICS, PHARMACOKINETICS, AND PHARMACOKINETIC PARAMETERS;111
9.7.3;NONCOMPARTMENTAL ANALYSIS;113
9.7.4;COMPARTMENTAL ANALYSIS;118
9.7.5;NONCOMPARTMENTAL VERSUS COMPARTMENTAL MODELS;123
9.7.6;CONCLUSION;126
9.8;CHAPTER 9. Distributed Models of Drug Kinetics;128
9.8.1;INTRODUCTION;128
9.8.2;CENTRAL ISSUES;128
9.8.3;DRUG MODALITY I: DELIVERY ACROSS A PLANAR – TISSUE INTERFACE;129
9.8.4;DRUG MODALITY II: DELIVERY FROM A POINT SOURCE — DIRECT INTERSTITIAL INFUSION;138
9.8.5;SUMMARY;147
9.9;CHAPTER 10. Population Pharmacokinetics;150
9.9.1;INTRODUCTION;150
9.9.2;ANALYSIS OF PHARMACOKINETIC DATA;150
9.9.3;POPULATION PHARMACOKINETICS;151
9.9.4;MODEL APPLICATIONS;155
9.9.5;CONCLUSIONS;159
10;PART II: DRUG METABOLISM AND TRANSPORT;162
10.1;CHAPTER 11. Pathways of Drug Metabolism;164
10.1.1;INTRODUCTION;164
10.1.2;PHASE I BIOTRANSFORMATIONS;167
10.1.3;PHASE II BIOTRANSFORMATIONS (CONJUGATIONS);177
10.1.4;ADDITIONAL EFFECTS ON DRUG METABOLISM;180
10.2;CHAPTER 12. Methods of Analysis of Drugs and Drug Metabolites;184
10.2.1;INTRODUCTION;184
10.2.2;CHOICE OF ANALYTICAL METHODOLOGY;184
10.2.3;CHROMATOGRAPHIC SEPARATIONS;185
10.2.4;ABSORPTION AND EMISSION SPECTROSCOPY;186
10.2.5;IMMUNOAFFINITY ASSAYS;187
10.2.6;MASS SPECTROMETRY;188
10.2.7;EXAMPLES OF CURRENT ASSAY METHODS;191
10.3;CHAPTER 13. Clinical Pharmacogenetics;200
10.3.1;INTRODUCTION;200
10.3.2;HIERARCHY OF PHARMACOGENETIC INFORMATION;201
10.3.3;IDENTIFICATION AND SELECTION OF OUTLIERS IN A POPULATION;202
10.3.4;EXAMPLES OF IMPORTANT GENETIC POLYMORPHISMS;204
10.3.5;CONCLUSIONS AND FUTURE DIRECTIONS;212
10.4;CHAPTER 14. Equilibrative and Concentrative Transport Mechanisms;218
10.4.1;INTRODUCTION;218
10.4.2;MECHANISMS OF TRANSPORT ACROSS BIOLOGICAL MEMBRANES;218
10.4.3;DESCRIPTION OF SELECTED MEMBRANE PROTEIN TRANSPORTERS;225
10.4.4;ROLE OF TRANSPORTERS IN PHARMACOKINETICS AND DRUG ACTION;230
10.4.5;PHARMACOGENETICS AND PHARMACOGENOMICS OF TRANSPORTERS;236
10.4.6;FUTURE DIRECTIONS;241
10.5;CHAPTER 15. Drug Interactions;250
10.5.1;INTRODUCTION;250
10.5.2;MECHANISMS OF DRUG INTERACTIONS;251
10.5.3;PREDICTION AND CLINICAL MANAGEMENT OF DRUG INTERACTIONS;263
10.6;CHAPTER 16. Biochemical Mechanisms of Drug Toxicity;270
10.6.1;INTRODUCTION;270
10.6.2;DRUG-INDUCED LIVER TOXICITY;274
10.6.3;MECHANISMS OF OTHER DRUG TOXICITIES;280
11;PART III: ASSESSMENT OF DRUG EFFECTS;294
11.1;CHAPTER 17. Physiological and Laboratory Markers of Drug Effect;296
11.1.1;BIOLOGICAL MARKERS OF DRUG EFFECT;296
11.1.2;IDENTIFICATION AND EVALUATION OF BIOMARKERS;298
11.1.3;USES OF BIOMARKERS AND SURROGATE ENDPOINTS;300
11.1.4;FUTURE DEVELOPMENT OF BIOMARKERS;304
11.2;CHAPTER 18. Dose-Effect and Concentration-Effect Analysis;310
11.2.1;BACKGROUND;310
11.2.2;DRUG–RECEPTOR INTERACTIONS;311
11.2.3;GRADED DOSE-EFFECT RELATIONSHIP;313
11.2.4;QUANTAL DOSE-EFFECT RELATIONSHIP;316
11.2.5;PHARMACODYNAMIC MODELS;319
11.2.6;CONCLUSION;320
11.3;CHAPTER 19. Time Course of Drug Response;322
11.3.1;PHARMACOKINETICS AND DELAYED PHARMACOLOGIC EFFECTS;323
11.3.2;PHYSIOKINETICS — TIME COURSE OF EFFECTS DUE TO PHYSIOLOGICAL TURNOVER PROCESSES;328
11.3.3;THERAPEUTIC RESPONSE, CUMULATIVE DRUG EFFECTS, AND SCHEDULE DEPENDENCE;329
11.4;CHAPTER 20. Disease Progress Models;334
11.4.1;CLINICAL PHARMACOLOGY AND DISEASE PROGRESS;334
11.4.2;DISEASE PROGRESS MODELS;334
11.4.3;CONCLUSION;341
12;PART IV: OPTIMIZING AND EVALUATING PATIENT THERAPHY;344
12.1;CHAPTER 21. Pharmacological Differences between Men and Women;346
12.1.1;PHARMACOKINETICS;346
12.1.2;PHARMACODYNAMICS;352
12.1.3;SUMMARY;355
12.2;CHAPTER 22. Drug Therapy in Pregnant and Nursing Women;360
12.2.1;PREGNANCY PHYSIOLOGY AND ITS EFFECTS ON PHARMACOKINETICS;361
12.2.2;PHARMACOKINETIC STUDIES DURING PREGNANCY;365
12.2.3;PLACENTAL TRANSFER OF DRUGS;369
12.2.4;TERATOGENESIS;370
12.2.5;DRUG THERAPY IN NURSING MOTHERS;373
12.3;CHAPTER 23. Drug Therapy in Neonates and Pediatric Patients;380
12.3.1;BACKGROUND;380
12.3.2;ONTOGENY AND PHARMACOLOGY;383
12.3.3;THERAPEUTIC IMPLICATIONS OF GROWTH AND DEVELOPMENT;387
12.3.4;CONCLUSIONS;392
12.4;CHAPTER 24. Drug Therapy in the Elderly;396
12.4.1;INTRODUCTION;396
12.4.2;PATHOPHYSIOLOGY OF AGING;396
12.4.3;AGE-RELATED CHANGES IN PHARMACOKINETICS;398
12.4.4;AGE-RELATED CHANGES IN EFFECTOR SYSTEM FUNCTION;400
12.4.5;DRUG GROUPS FOR WHICH AGE CONFERS INCREASED RISK FOR TOXICITY;404
12.4.6;CONCLUSIONS;406
12.5;CHAPTER 25. Clinical Analysis of Adverse Drug Reactions;410
12.5.1;INTRODUCTION;410
12.5.2;CLASSIFICATION;411
12.5.3;CLINICAL DETECTION;412
12.5.4;ADR DETECTION IN CLINICAL TRIALS;419
12.5.5;INFORMATION SOURCES;420
12.6;CHAPTER 26. Quality Assessment of Drug Therapy;424
12.6.1;INTRODUCTION;424
12.6.2;ORGANIZATIONAL INFLUENCES ON MEDICATION USE QUALITY;427
12.6.3;SUMMARY;438
13;PART V: DRUG DISCOVERY AND DEVELOPMENT;442
13.1;CHAPTER 27. Portfolio and Project Planning and Management in the Drug Discovery, Development, and Review Process;444
13.1.1;INTRODUCTION;444
13.1.2;PORTFOLIO DESIGN, PLANNING, AND MANAGEMENT;445
13.1.3;PROJECT PLANNING AND MANAGEMENT;450
13.1.4;PROJECT PLANNING AND MANAGEMENT TOOLS;452
13.1.5;PROJECT TEAM MANAGEMENT AND DECISION-MAKING;455
13.2;CHAPTER 28. Drug Discovery;460
13.2.1;INTRODUCTION;460
13.2.2;DEFINITION OF DRUG TARGETS;460
13.2.3;GENERATING DIVERSITY;464
13.2.4;DEFINITION OF LEAD STRUCTURES;465
13.2.5;QUALIFYING LEADS FOR TRANSITION TO EARLY TRIALS;466
13.3;CHAPTER 29. Preclinical Drug Development;470
13.3.1;INTRODUCTION;470
13.3.2;COMPONENTS OF PRECLINICAL DRUG DEVELOPMENT;471
13.3.3;DRUG DEVELOPMENT PROGRAMS AT THE NCI;477
13.3.4;THE CHALLENGE — MOLECULARLY TARGETED THERAPIES AND NEW PARADIGMS FOR CLINICAL TRIALS;480
13.4;CHAPTER 30. Animal Scale-Up;484
13.4.1;INTRODUCTION;484
13.4.2;ALLOMETRY;484
13.4.3;PHYSIOLOGICAL PHARMACOKINETICS;488
13.4.4;IN VITRO-IN VIVO CORRELATION OF HEPATIC METABOLISM;490
13.5;CHAPTER 31. Phase I Clinical Studies;494
13.5.1;INTRODUCTION;494
13.5.2;DISEASE-SPECIFIC CONSIDERATIONS;494
13.5.3;STARTING DOSE AND DOSE ESCALATION;495
13.5.4;BEYOND TOXICITY;498
13.6;CHAPTER 32. Development of Biotechnology Products and Large Molecules;500
13.6.1;INTRODUCTION;500
13.6.2;PHARMACOKINETIC CHARACTERISTICS OF MACROMOLECULES;504
13.6.3;PHARMACODYNAMICS;515
13.7;CHAPTER 33. Design of Clinical Development Programs;522
13.7.1;INTRODUCTION;522
13.7.2;PHASES, SIZE, AND SCOPE OF CLINICAL DEVELOPMENT PROGRAMS;522
13.7.3;GOAL AND OBJECTIVES OF CLINICAL DRUG DEVELOPMENT;526
13.7.4;CRITICAL DRUG DEVELOPMENT PARADIGMS;528
13.7.5;CRITICAL CLINICAL DRUG DEVELOPMENT DECISION POINTS;530
13.7.6;LEARNING CONTEMPORARY CLINICAL DRUG DEVELOPMENT;535
13.8;CHAPTER 34. Role of the FDA in Guiding Drug Development;540
13.8.1;WHY DOES THE FDA GET INVOLVED IN DRUG DEVELOPMENT?;541
13.8.2;WHEN DOES THE FDA GET INVOLVED IN DRUG DEVELOPMENT?;541
13.8.3;HOW DOES THE FDA GUIDE DRUG DEVELOPMENT?;542
13.8.4;WHAT ARE FDA GUIDANCES?;544
14;APPENDIX I. Abbreviated Tables of Laplace Transforms;548
15;APPENDIX II. Answers to Study Problems;550
16;Index;558

Leseproben

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: The relationship between dose and biological effect. The localization of the site of action of a drug. The mechanism(s) of action of a drug. The absorption, distribution, metabolism, and excretion of a drug. 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: Inappropriate polypharmacy. Failure of prescribing physicians to establish and adhere to clear therapeutic goals. Failure of medical personnel to attribute new symptoms or changes in laboratory test results to drug therapy. Lack of priority given to the scientific study of adverse drug reaction mechanisms. 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...