Principles of Clinical Pharmacology

Shiew-Mei Huang, Juan J.L. Lertora, Arthur J. Atkinson Jr., Sanford P. Markey, Arthur J. Atkinson, Jr.

• Publisher: Academic Press
• Year: 2012
• eBook ISBN: 9780123854728
• Edition: 3
• Topic: Medicine
• Subtopic: Pharmacology

Principles of Clinical Pharmacology is a successful survey covering the pharmacologic principles underlying the individualization of patient therapy and contemporary drug development. This essential reference continues to focus on the basics of clinical pharmacology for the development, evaluation, and clinical use of pharmaceutical products while also addressing the most recent advances in the field. Written by leading experts in academia, industry, clinical and regulatory settings, the third edition has been thoroughly updated to provide readers with an ideal reference covering the wide range of important topics impacting clinical pharmacology as the discipline plays an increasingly significant role in drug development and regulatory science.The Third Edition has been endorsed by the American Society for Clinical Pharmacology and Therapeutics- Includes new chapters on imaging and the pharmacogenetic basis of adverse drug reactions- Offers an expanded regulatory section that addresses US and international issues and guidelines- Provides extended coverage of earlier chapters on transporters, pharmacogenetics and biomarkers and also illustrates the impact of gender on drug response- Presents a broadened discussion of clinical trials from Phase 1 to incorporate Phases II and III

Chapter 1

Introduction to Clinical Pharmacology

Arthur J. Atkinson Jr.

Department of Molecular Pharmacology & Biochemistry, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

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 quotation 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 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 US 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 include:

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 drugs that have been in clinical use for a substantial period of time rather than newly introduced drugs, and were dose related rather than idiosyncratic [5, 9, 10].

Recognition of the considerable variation in response of different patients treated with standard drug doses has provided the impetus for the development of what is currently called “personalized medicine” [11]. Despite the recent introduction of this term, it actually describes a continuing story that can be divided into three chapters in which different complementary technologies were developed and are being applied to cope with this variability. In the earliest chapter, laboratory methods were developed to measure drug concentrations in patient blood samples and to guide therapy – an approach now termed “therapeutic drug monitoring” [10]. The routine availability of these measurements then made it possible to apply pharmacokinetic principles in routine patient care to achieve and maintain these drug concentrations within a prespecified therapeutic range. 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) continue to pose a severe problem and recently have been estimated to occur in 6.7% of hospitalized patients [12]. Although this figure has been disputed, the incidence of adverse drug reactions probably is still higher than is generally recognized [13]. In the third chapter, which is still being written, genetic approaches are being developed and applied both to meet this challenge and to improve the efficacy and safety of drug therapy [11]. Thus, pharmacogenetics is being used to identify slow drug-metabolizing patients who might be at increased risk for drug toxicity and rapid metabolizers who might not respond when standard drug doses are prescribed. In a parallel development, pharmacogenomic methods are increasingly used to identify subsets of patients who will either respond satisfactorily or be at increased risk of an adverse reaction to a particular drug.

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 US 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 [14] 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” [15]. 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 [16] 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 ar...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Preface to the First Edition
• Preface to the Third Edition
• Contributors
• Chapter 1. Introduction to Clinical Pharmacology
• Part I: Pharmacokinetics
• Part II: Drug Metabolism and Transport
• Part III: Assessment of Drug Effects
• Part IV: Optimizing and Evaluating Patient therapy
• Part V: Drug Discovery and Development
• Appendix I. Abbreviated Tables of Laplace Transforms
• Appendix II. Answers to Study Problems
• Subject Index