PKPD analysis is an alternative to conventional dose-effect analysis of in vivo drug effects, and it focuses on the relationship of drug-induced behavioral or physiological effects to drug and metabolite concentrations in the body rather than to drug dose. Hysteresis loops are one manifestation of PKPD analysis, and these loops describe the time course of the potentially variable relationship between drug/metabolite concentration and drug effect over time. PKPD analysis, including analysis of hysteresis loops, can play a valuable role in interpretation of drug effects and PKPD relationships for the purposes of drug assessment and translational research in pharmacology. This chapter provided examples of the application of PKPD analysis to studies of the discriminative stimulus effects of drugs.
Introduction
Drugs produce their effects by interacting with receptor targets, and drug discrimination is one behavioral procedure that is useful for investigating determinants of this interaction. In conceptualizing drug-receptor interactions in whole organisms, it is convenient to think of the receptors as relatively fixed in anatomical space, whereas each dug molecule embarks on a journey from its site of administration, through the body to the receptor upon which it acts, and then back out of the body. Pharmacokinetics and pharmacodynamics are subdisciplines within the field of pharmacology that address two facets of this journey. Pharmacokinetics (PK) is concerned with the processes that govern a drug’s path through the body and its resulting concentration in different body compartments. Pharmacodynamics (PD), in contrast, is concerned with the physiological and behavioral consequences produced by that subset of drug molecules that find and occupy receptors during their journey through the body.
The relationship between PK and PD is described by PKPD analysis that relates drug concentration to drug effect. This type of analysis provides an alternative to conventional “dose-effect” analysis of drug effects, and they have value for at least three reasons [1]. First, drug effects are ultimately determined by drug concentration at the receptors upon which the drug acts, and that concentration is determined not only by the drug dose administered, but also by the PK processes that deliver that dose to and from the receptors. “Dose” is a measure of the amount of drug determined prior to its delivery, often in units of drug mass relative to the mass of the organism (e.g., mg/kg). Dose is precisely controlled by the experimenter, and it often serves as the principal independent variable in analysis of data from in vivo studies. For example, the “dose-effect curve” is a common mode of data presentation used to estimate critical drug features such as potency and efficacy. However, after a dose is administered, the drug must be absorbed into the body from the site of its administration (e.g., absorbed from gastrointestinal tract into the blood stream after oral delivery) and distributed from that site to the sites where receptors are located (e.g., distributed by the circulatory system from the gastrointestinal tract to brain). Moreover, drug molecules are subject to degradation via metabolism by enzymes and to removal from the body via excretion by routes such as urine, feces, or exhaled air. Together, these PK processes of absorption, distribution, metabolism, and excretion convert a drug dose administered at a single anatomical site and a single point in time into a dynamic tide of drug concentrations that rises and then falls throughout the body over time. These changing drug concentrations through time can then be related to changing drug effects through time to yield a richer data set than can be achieved by a reference to only a single drug dose administered at the beginning of an experiment. The most precise assessment of this relationship between drug concentration and drug effect would ideally measure drug concentrations at the site of receptors that mediate the measured effect. In practice, measurement of drug concentration at the receptor is often difficult, and the site of receptors might be unknown or broadly distributed. Accordingly, a common compromise is to measure drug concentrations in more accessible compartments (e.g., venous blood or cerebrospinal fluid) that usefully approximate drug concentrations across broad areas within the organism.
A second advantage of PKPD analysis is that it permits evaluation of the relationship between drug effect and concentrations not only of the administered drug, but also of drug metabolites. All drugs are subject to at least some degree of metabolism in the body, and in many cases, these metabolites are active and may contribute to the overall effect produced by an administered drug dose. An extreme example of this phenomenon is prodrugs, which are compounds designed to be metabolized in the body to active metabolites that then produce the drug’s intended effect [2]. When samples of blood or cerebrospinal fluid are collected and analyzed for concentrations of the administered drug, they can also be analyzed for concentrations of known or suspected metabolites, and changing drug effects over time can be related to changing concentrations of the metabolites as well as of the parent drug.
A third advantage of PKPD analysis is that it provides a basis not only for evaluating changing drug effects over time within an organism, but also for evaluating variable drug effects between organisms [3]. Thus, the administration of a given drug dose in mg/kg units often produces different effects across subjects within a species or across subjects of different species in translational studies. One factor that may contribute to such between-subject or between-species variability in drug effect is variability in PK processes. For example, metabolism may proceed at different rates or yield different metabolites in different subjects, and these differences in metabolism will result in different temporal profiles of drug and metabolite concentrations and associated behavioral and physiological effects despite use of the same administered dose. Use of drug and metabolite concentration, rather than drug dose, as the primary independent variable can reveal PK differences across subjects or species and provide a basis for integrating these differences into interpretation of drug effects.
The remainder of this chapter will illustrate strategies for using PKPD analysis in drug discrimination research using results from studies in rhesus monkeys trained to discriminate cocaine from saline.
What is PK and what is PD?
Pharmacokinetics vs. Pharmacodynamics. The difference between pharmacokinetics (PK) and pharmacodynamics (PD) is that pharmacokinetics is the movement of drugs through the body, whereas pharmacodynamics is the body’s biological response to drugs.
What does PK mean for clinical trial?
A study that measures what happens to a drug in a person’s body over time.
