Pharmacokinetics is typically discussed in terms of the four major activities it includes, absorption, distribution, metabolism, and elimination.

Absorption of a drug into the body’s systemic circulation usually occurs from the stomach or intestines for orally administered drugs. It can also occur from under the tongue, anal area, skin applications, lungs, and nasal passages. Intravenously administered drugs bypass the absorption phase of pharmacokinetics as they are given directly into the circulation. Other parenteral dosage forms such as depots and intramuscular injections release their drug into the circulation over time so that absorption must be assessed for those dosage forms. The process of how the drug dissolves and enters into the body is part of the study of absorption.

After the drug is absorbed into the body, it will diffuse through the blood and tissues and distribution is the study of these processes. Different drugs will distribute differently in tissues depending on their fat or lipid affinity and other factors. The volume of distribution relates to the amount of drug in the body to the concentration of drug in the blood.

As the drug is being distributed in the body to certain tissues or blood fractions, it is also being metabolized into other substances. These are the metabolites and they may be active or inactive biologically. In some cases, the drug given is inactive until it is converted into an active form. Those parent drugs are referred as pro-drugs. This conversion (i.e., metabolism) may occur in the intestines prior to absorption, in the blood, in tissues at receptors on cell surfaces, in the interior of cells or elsewhere. The majority of metabolites are less active than the drug given.

The fourth stage is elimination (sometimes called excretion) and covers the processes by which the body rids itself of the drug and its metabolites (i.e., breakdown products). This is most typically via urine or feces, but can be via the breath or through sweating although they are minor routes of elimination.

The reasons for studying pharmacokinetics cannot be viewed in isolation from those of pharmacodynamics (i.e., what the drug does to the body, as opposed to what the body does to the drug, which is a shorthand summary of pharmacokinetic processes). The major objectives of studying a compound’s pharmacokinetics in the preclinical discovery period are to assist in the design of new
drugs by determining the magnitude and rate of absorption, as well as the duration of effect in animals and other characteristics. In addition, pharmacokinetic principles are used to interpret both toxicology and pharmacology data. In the clinical period, the data on the amount of drug absorbed is often used to optimize the formulation and dosage form (e.g., should a tablet be enteric coated).

Various patient groups such as children, the elderly, women, renally impaired individuals, hepatic impaired individuals, immunocompromised individuals, and individuals with certain genetic characteristics (e.g., slow or fast acetylators of some drugs) are studied for their own pharmacokinetic parameters to understand which factors influence these in a significant way (e.g., decrease the rate of metabolism and, therefore, prolong the clinical effect, interactions with another drug which may change the primary drug’s efficacy or safety). Other factors such as the severity of a patient’s disease, the subtype of a disease, other diseases, the timing of meals relative to drug administration, and types of meals may also be studied to better learn about a drug’s profile.

One way to think of the parameters or characteristics studied is to think of the process that occurs when one takes an oral drug. After it is swallowed and dissolves in the stomach, it is often absorbed from the duodenum into the bloodstream. The time it takes for the maximal amount of drug to be absorbed into the bloodstream as measured by the concentration in the blood is referred to as the “Tmax” or time to achieve the maximal drug concentration in the plasma (usually). The “T₉₀” is the time by which 90% of the administered dose has been absorbed. The amount of the drug that is present in the plasma at the peak concentration is the “Cmax” or maximal or peak drug concentration. When measured at the trough of the plasma concentration the term used is “Cmin.” The volume of distribution “V” was previously mentioned as the amount of drug in the body compared to the concentration of drug in the plasma.

Over time, the body eliminates the drug and it eventually disappears from the plasma. The time it takes for half of the drug concentration to decrease from the plasma is referred to as the “t_1/2” or half-life of the drug. The ability of the body to eliminate the drug is measured in terms of volume of drug eliminated per unit of time. This is referred to as systemic clearance or “Cl.” Finally, the concentration of drug in the plasma is measured over time and the area under this curve is referred to as the “AUC” (area under the curve). The official terminology for AUC is the empirical area under the steady-state plasma concentration-time curve by the log-trapezoidal method over one dose administration interval of 24 hours. When the period that the AUC is calculated is 24 hours after the drug is given, the term used is “AUC_24h.” Various other pharmacokinetic terms are used that include several that are derived as ratios from these or other pharmacokinetic terms.

Over the past decade, pharmacokinetics has been increasingly viewed as a scientific area that interacts with numerous others, and in that sense, is widely considered as a translational science. A few examples are as follows:

Thus, pharmacokinetic assessments are more widely used than heretofore and are used in a variety of important ways that have expanded over the past decade.

An increased emphasis on population pharmacokinetics has been quite apparent over the past decade. Population pharmacokinetics simply means that instead of evaluating pharmacokinetics in a group of normal individuals who are studied for a short time, actual patients with the disease being treated who are taking the drug for its beneficial results have their pharmacokinetic parameters studied (generally at steady-state) during the course of an efficacy trial. Population pharmacokinetics may also be used to evaluate drug-drug interactions (Zhou 2006).

This methodology is now more widely used, even though some skeptics believe the amount of emphasis in this area is more than can be justified, based on the value of the data obtained. Nevertheless, there is greater acceptability of these data than in the past by regulatory agencies worldwide. One way to view a population analysis is that it is basically a subgroup analysis, using plasma samples of Phase 2 and 3 clinical trials, that is performed to identify covariates that may have an impact of the plasma levels of the new chemical entity. Population based trials do not require
the usual requirements for multiple sampling of blood for creating “area under the curve” and to determine various other pharmacokinetic characteristics. Instead these trials provide clinically relevant data for specific patient populations based on results from multiple studies or multiple patients of specific types. Population based assessments can confirm reported drug-drug interactions or characterize suspected interactions. Zhou (2006) discusses drug-drug interactions in greater detail.

There is an increased number and emphasis on simulations, both of clinical pharmacokinetic parameters as well as other forms of simulations. Uses of computer simulations for high-throughput screening in drug metabolism and pharmacokinetics is discussed by van de Waterbeemd (2002); high throughput screening to learn about pharmacokinetic parameters is discussed by Balani et al. (2005); and, use of in silico tools for predicting pharmacokinetic properties as well as others (e.g., human therapeutica-go-go related gene, drug transport proteins) are discussed by Beresford, Segall, and Tarbit (2004). Other types of simulations are briefly discussed later in this chapter.