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INTRODUCTION

Drugs are the cornerstone of modern therapeutics. Nevertheless, it is well recognized among health care providers and the lay community that the outcome of drug therapy varies widely among individuals. While this variability has been perceived as an unpredictable, and therefore inevitable, accompaniment of drug therapy, this is not the case.

Drugs interact with specific target molecules to produce their beneficial and adverse effects. The chain of events between administration of a drug and production of these effects in the body can be divided into two components, both of which contribute to variability in drug actions. The first component comprises the processes that determine drug delivery to, and removal from, molecular targets. The resulting description of the relationship between drug concentration and time is termed pharmacokinetics. The second component of variability in drug action comprises the processes that determine variability in drug actions independent of variability in drug delivery to effector drug sites. This description of the relationship between drug concentration and effect is termed pharmacodynamics. As discussed further below, pharmacodynamic variability can arise as a result of variability in function of the target molecule itself or of variability in the broad biologic context in which the drug-target interaction occurs to achieve drug effects. The principles described below were developed by studying small drug molecules but are equally useful in describing the effects of very large molecules, such as the therapeutic antibodies increasingly applied to autoimmune diseases and cancer.

Two important goals of clinical pharmacology are (1) to provide a description of conditions under which drug actions vary among human subjects; and (2) to determine mechanisms underlying this variability, with the goal of improving therapy with available drugs as well as pointing to mechanisms whose targeting by new drugs may be effective in the treatment of human disease. The drug development process is briefly described at the end of this chapter.

The first steps in the discipline of clinical pharmacology were empirical descriptions of the influence of disease on drug actions and of individuals or families with unusual sensitivities to adverse drug reactions (ADRs). These important descriptive findings are now being replaced by an understanding of the molecular mechanisms underlying variability in drug actions. Importantly, it is often the personal interaction of the patient with the physician or other health care provider that first identifies unusual variability in drug actions; maintained alertness to unusual drug responses continues to be a key component of improving drug safety.

One useful unifying framework is to consider that the effects of disease, drug coadministration, or familial factors in modulating drug action reflect variability in expression or function of specific genes whose products determine pharmacokinetics and pharmacodynamics. This idea forms the basis for pharmacogenomic science; a few examples are cited in this chapter, and further details are addressed in Chap. 68.

GLOBAL CONSIDERATIONS

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