Basic Concepts in Pharmacokinetics

Pharmacokinetics is the science that describes the relationship between the dose of a drug administered and the concentrations observed in biologic fluids. Two parameters are of major importance to understand pharmacokinetics: clearance (CL) and volume of distribution (Vd). These parameters are independent but constitute major determinants of drug disposition; in other words, they will not influence each other, but both of them will dictate the time that a drug resides within the organism: the elimination half life (t). From this concept, the following equation is derived:

(1)

Thus, the greater the clearance, the shorter is the elimination half-life. The larger the volume of distribution, the longer is the elimination half-life.

“Clearance” reflects the ability of an organ or of the entire body to get rid of (“clear”) the drug in an irreversible manner. This ability to clear the drug will dictate the mean plasma concentrations observed after a given dose:

(2)

Thus conditions that increase the clearance of a drug (such as enzyme induction) will tend to decrease the mean plasma concentrations; the elimination half-life will also become shorter. Conversely, conditions that decrease the clearance of a drug (such as enzyme inhibition) will increase the mean plasma concentrations of the drug; its elimination half-life will become longer. Finally, the total body clearance of a drug reflects the ability of each organ to clear this drug.

(3)

(4)

When the metabolic or renal clearance of a drug is decreased, the total clearance becomes smaller, the plasma concentrations rise, and the elimination half-life becomes longer. For example, dofetilide and sotalol are cleared primarily by renal excretion. Patients with chronic or acute renal dysfunction will have higher serum concentrations and longer half-life than those with normal renal function. Doses need to be adjusted for renal dysfunction or if renal function changes during therapy. A higher incidence of drug-induced proarrhythmia in older adults receiving these drugs may, in part, be a consequence of failure to adjust doses on the basis of the expected decline in renal function with age, which is not directly reflected in increases in serum creatinine concentration.

The volume of distribution reflects the apparent volume of liquid in which the drug is dissolved (distributed) in the organism. The larger the volume of distribution, the lower are the observed plasma concentrations and the less available the drug for being eliminated by specific organs (the elimination half-life is then longer). For example, the distribution of antiarrhythmic drugs into body tissues will yield, for some drugs such as amiodarone, a very large volume of distribution that results in extremely long half-lives. Conversely, digoxin is distributed in lean body tissues, and the volume of distribution is lower in patients with renal failure, which compounds the effects of decreased renal excretion of digoxin and increasing the likelihood of digoxin toxicity in these patients.

Absorption of drugs can vary with timing of dose in relation to a meal. For example, concentrations of dronedarone (a currently investigational antiarrhythmic drug) are twofold to threefold higher when taken with a meal compared with peak concentrations when taken on an empty stomach.¹

Intersubject Variability in Drug Action

Even though it is obvious that each human being has physiological characteristics that are unique, we are always disconcerted when unexpected effects are observed in a particular patient following administration of a drug. These effects are labeled as unexpected on the basis of “usual” responses observed in the “normal” population. The so-called expected response (which, in fact, reflects the average response) is often derived from selected patients enrolled in clinical trials during drug development under well-controlled conditions. This may not always represent the real-world situation. In everyday practice, patients are treated in settings where concomitant diseases and varying physiological and pathologic conditions are encountered and multiple drugs are administered.

Several factors can modulate the response obtained following the administration of a particular drug to a particular patient at a particular time. This statement argues against the “one size fits all” concept and clearly defines the need for individualized drug therapy. To fully integrate the basic principles underlying clinical pharmacology, the prescriber needs to understand the principles of pharmacokinetics, pharmacodynamics, and drug efficacy. Figure 12-1 depicts the three major principles that define the relationship between drug dose and clinical outcome.

FIGURE 12-1 Principles of clinical pharmacology: factors that affect the relationship between drug dose and clinical outcome for antiarrhythmic drugs. Note that this illustration does not take into account extracardiac (e.g., autonomic) effects of drugs, which further complicate the relationship between the physiological state and the drug effect.

FIGURE 12-2 Illustrations of numerous factors that must be considered in the understanding of a drug’s action on cardiac potassium channels. The drug must be transported inside the myocyte while facing influx and efflux transporters. Once inside, the drug may be metabolized by locally expressed CYP450 and other enzymatic systems. Competition for binding to IKr may occur as well as potentiation through combined binding to IKr and IKs.

As discussed earlier, pharmacokinetics describes the relationship between the dose administered and the observed concentrations of a drug or its metabolites in selected biologic fluids. Concentrations of active or toxic substances at their effector or toxic sites are often of the greatest interest. Pharmacodynamics describes the relationship between the concentration of an active substance at its effector site and the physiological effects observed. Currently, most drugs are aimed at either direct or indirect modulation of a protein function. For most of them, there is a range of concentrations for which changes in protein function are linearly related to drug concentration. Finally, drug efficacy links the physiological effects observed following the administration of a drug to clinical outcome. Several major clinical trials in recent years, such as the Cardiac Arrhythmia Suppression Trial, have demonstrated that achievement of expected pharmacodynamic response is not necessarily related to a desirable clinical outcome (i.e., drug effectiveness).^2,3

Drugs with a Narrow Therapeutic Index: Antiarrhythmic Agents

The notion that monitoring plasma drug concentrations could provide a method for adjusting doses to reduce inter-individual variability in response arose during the development of new antimalarial drugs during World War II. Shortly thereafter, this notion was applied to quinidine therapeutics.⁴ This concept was derived from the well-recognized relationships between “normal” plasma ion concentrations or hormonal levels and a “normal” physiological state. Using such a framework, it was observed in initial trials that plasma concentrations of quinidine below 3 µg/mL were rarely associated with an antiarrhythmic response, whereas concentrations above 8 µg/mL were frequently associated with QRS widening, cinchonism, and hypotension.⁵ Thus, a tentative therapeutic range of 3 to 8 µg/mL was defined.

Using the same approach, relatively well-defined therapeutic ranges were also established for lidocaine (4 to 8 µg/mL), mexiletine (500 to 1000 ng/mL), and procainamide (4 to 8 µg/mL) for patients presenting with ventricular arrhythmias.^6–9 However, as drug assays developed further and experience accumulated, it became evident that the therapeutic concentration window was very wide with these antiarrhythmic agents and that wide intersubject variability existed. Therapeutic ranges, such as the one for quinidine (2 to 5 µg/mL), had to be redefined because of impurities and metabolites interfering with early fluorometric methods.¹⁰ Also, the overlap between effective and toxic concentrations (narrow therapeutic/toxic window) in different patients was significant, and it became almost impossible to predict, for a specific patient, plasma levels associated with efficacy or toxicity.

Subsequently, another important source of intersubject variability was identified in patients treated with the potent class Ic antiarrhythmic agent encainide.¹¹ In a small clinical study, 10 of 11 patients with ventricular arrhythmias responded to the drug (encainide) with arrhythmia suppression and QRS widening, and the eleventh had no response. In the 10 responders, peak plasma encainide ranged from 3 to 200 ng/mL. In the single nonresponder, peak plasma encainide was the highest (300 ng/mL). Further studies demonstrated the importance of active metabolites (O-demethyl encainide [ODE] and 3 methoxy-O-demethyl encainide [MODE]) in accounting for encainide action, but a simple therapeutic range—based solely on the plasma concentrations of the parent compound or in combination with the metabolites—could not be defined.¹²

Propafenone is another class Ic antiarrhythmic agent that shows wide intersubject variability in its response and in the formation of active metabolites.¹³ In addition, the drug exhibits varying electrophysiological (sodium, calcium, and potassium channel block) and pharmacologic (β-blocking) effects depending on the route of administration, the metabolism status, and the plasma concentrations of its enantiomers.^13,14 Several investigators have tried to derive combined therapeutic ranges for the metabolites—the enantiomers—and for the combinations of the parent drug plus metabolites, without success.

The situation with antiarrhythmic agents is not unique and is observed with other drugs that have a narrow therapeutic index. For example, doses and plasma concentrations of warfarin that were required to maintain the international normalized ratio (INR) within acceptable limits (2 to 3) vary widely among individuals.^15–17 There is no rationale to use the plasma concentrations of each warfarin enantiomer, rather than INR values, to adjust warfarin doses.

The notion that the plasma concentrations of a drug should be maintained within a range to guarantee drug response and prevent toxicity is appealing. The problem is that this range most likely needs to be defined for each individual. Several factors must then be considered in addition to the plasma concentrations of the parent compound. A better understanding of the clinical pharmacology of drugs with cardiac electrophysiological effects, including antiarrhythmic and non-antiarrhythmic agents, will be useful for optimal prescribing.

Pharmacogenetics

As discussed earlier, at the same dose, not every individual will have the same plasma concentrations (pharmacokinetics). As well, at the same plasma concentration of a drug, not every individual will exhibit the same physiological response (pharmacodynamics). And with the same physiological response, not every individual will have the same clinical outcome (drug efficacy). Part of this variability can be explained by genetic factors: Pharmacogenetics is the study of inter-individual variability in drug response caused by genetic factors.