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)

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.

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,

1. Introduction

PART 1: PHARMACOKINETICS 2. Clinical pharmacokinetics 3. Compartmental analysis of drug distribution 4. Drug absorption and bioavailability 5. Effects of renal disease on pharmacokinetics 6. Kinetics of hemodialysis and hemofiltration 7. Effects of liver disease on pharmacokinetics 8. Noncompartmental vs. compartmental approaches to pharmacokinetic analysis 9. Distributed models of drug kinetics 10. Population pharmacokinetics

PART 2: DRUG METABOLISM AND TRANSPORT 11. Pathways of drug metabolism 12. Biochemical mechanisms of drug toxicity 13. Chemical assay of drugs and drug metabolites 14. Equilibrative and concentrative transport 15. Pharmacogenetics 16. Drug interactions

PART 3: ASSESSMENT OF DRUG EFFECTS 17. Physiological and laboratory markers of drug effect 18. Dose response and concentration response analysis 19. Kinetics of pharmacologic effect 20. Disease progression models

PART 4: OPTIMIZING AND EVALUATING PATIENT THERAPY 21. Sex differences in pharmacokinetics and pharmacodynamics 22. Drug therapy in pregnant and nursing women 23. Drug therapy in neonates and pediatric patients 24. Drug therapy in the elderly 25. Clinical analysis of adverse drug reactions 26. Quality assessment of drug therapy

PART 5: DRUG DISCOVERY AND DEVELOPMENT 27. Project management 28. Drug discovery 29. Pre-clinical development 30. Animal scale up 31. Phase I studies 32. PK and PD considerations in the development of biotechnology products and large molecules 33. Design of clinical development programs 34. Good design practices for clinical trials 35. Role of the FDA in guiding drug development

Appendix I. Table of Laplace Transforms II. Answers to Study Problems