Principles of Pharmacokinetics and Pharmacodynamics


Pharmacokinetics is defined as the study of the time course of drugs and their metabolites through the body. Pharmacodynamics is defined as the study of the time course and intensity of pharmacological effects of drugs. A convenient lay description of these terms is that pharmacokinetics describes what the body's physiology does to a drug, and pharmacodynamics describes what a drug does to the body. Although clinicians are more interested in drug effects than drug concentrations, these disciplines are closely connected. Pharmacokinetic and pharmacodynamic variability is a major determinant of the dose-effect relationship in patients (Figure 8-1). There is increasing recognition that genetic variability—in the form of polymorphic genes controlling the transcription of proteins involved in drug-metabolizing enzymes, drug transporters, and drug targets—is a substantial determinant of pharmacokinetic and pharmacodynamic variability. An integrated knowledge of these areas is essential in the drug development process and can be instrumental in individualizing dosage regimens for specific patients.

FIGURE 8-1. Pharmacokinetic and pharmacodynamic variability as determinants of the dose-effect relationship.

FIGURE 8-1. Pharmacokinetic and pharmacodynamic variability as determinants of the dose-effect relationship.

The dose and the frequency of dosing necessary to produce the desired pharmacological response from psychoactive drugs differ widely among patients. This variability in the drug dose-effect relationship is not surprising, given the large differences in patients' physiology, ages, range of severity of illness, activity of drug metabolizing enzymes and transporters, renal function, and other variables. Thus, a rational approach to drug dosage regimens, based on scientific principles, is needed to reach therapeutic objectives without either underdosing (and obtaining an unsatisfactory response) or overdosing (and risking intolerability or toxicity).

The interface between pharmacokinetics and pharmacodynamics, where drugs interact with molecular targets at an effect site (see Figure 8-1), is increasingly becoming the focus of research. The ability to link drug concentrations with pharmacodynamic effects using mathematical models has improved greatly in recent years with the availability of new computer software. Population pharmacokinetic/pharmacodynamic modeling enables definition of the relationship between drug concentration and effect in individuals from vulnerable populations such as children, pregnant women, and the elderly where only sparse data may be available (Bies et al. 2004). Covariants such as age, gender, genotype of drug-metabolizing enzymes, and concomitant treatment with other drugs can be easily incorporated into these models and tested for their significance in influencing drug concentration and effects

(DeVane et al. 2006). Measurements of plasma drug concentration are easily performed with sensitive analytical methods including gas and liquid chromatography and mass spectrometry.

In recent years, our understanding of the role of drug transporters and of gene expression of intestinal and hepatic enzymes in influencing drug movement within the body has increased considerably. Extensive contributions to our understanding of the sources of variability in pharmacokinetic/pharmacodynamic response have come from the field of pharmacogenetics. Genetic polymorphisms in drug-metabolizing enzymes enhance or diminish the body's ability to biotransform a variety of substrate drugs. A large number of defective alleles have been discovered, some of which have functional significance. On the pharmacodynamic side of the dose-effect relationship, the significance of polymorphisms in drug targets is an intense area of investigation. One of the most studied polymorphisms is in the promoter region of the gene encoding the serotonin transporter (5-HTT) and consists of the insertion or deletion of a 44-base pair sequence, giving rise to two variants: long (l) and short (s). A meta-analysis of 15 studies representing 1,435 patients concluded that patients with the ss genotype are less likely to reach remission during selective serotonin reuptake inhibitor (SSRI) therapy and require a longer treatment period for 50% symptom improvement (Serretti et al. 2007).

Although the discipline of pharmacokinetics relies heavily on mathematical description and prediction of the time course of drugs in the body, the purpose of this chapter is to explain basic principles of pharmacokinetics and how they interface with pharmacodynamics to provide insight into observed dose-effect relationships that can aid in developing drug dosage regimens. The fundamental concepts of pharmacokinetics have not changed since the initial publication of this chapter. These principles are reviewed here, and the interface of pharmacokinetics with the discipline of pharmacogenetics—the study of the genetic basis for differences in drug effects—is discussed as a essential component of variability in drug dose-effect relationships in psychopharmacology (see Figure 8-1).

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