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.

Genetically Determined Pharmacokinetic Factors

Genetically determined abnormalities in the ability to biotransform drugs range from apparently benign conditions such as Gilbert’s syndrome (a deficiency in glucuronyl transferase activity) to the rare but potentially fatal syndrome of pseudo-cholinesterase deficiency. This most widely studied polymorphic drug oxidation trait is a deficiency in the cytochrome P450 isozyme (CYP2D6) responsible, among others, for the biotransformation of the antihypertensive drug debrisoquine to its inactive 4-hydroxy metabolite.^18,19 Following the oral administration of a single 10-mg dose of debrisoquine, a metabolic ratio (debrisoquine/4-hydroxydebrisoquine), established from an 8-hour urinary excretion profile, can discriminate between two distinct phenotypes.²⁰ Individuals with a ratio greater than 12.6 are defined as poor metabolizers (PMs), whereas a value less than this antimode reflects the ability to extensively metabolize (EM) the probe drug. Family studies indicated that the deficient trait is inherited as an autosomal recessive character.¹⁸ Regardless of geographic location, about 5% to 10% of whites are PMs. At the other end of the spectrum, 2% to 5% are known as ultra-rapid metabolizers (UM), since they exhibit very high expression levels and activity of CYP2D6.

The CYP2D6 gene is located on the long arm of chromosome 22 (q11.2-qter).²¹ Deletion or transition mutations in the gene lead to splicing errors during messenger ribonucleic acid (mRNA) processing and result in unstable proteins.^22,23 Therefore, the CYP2D6 protein is functionally absent in PMs. Deoxyribonucleic acid (DNA) assays based on allele-specific amplification with the polymerase chain reaction (PCR) allow identification of approximately 95% of all PMs.^23–25

CYP2D6 activity can also be inhibited by drugs, including quinidine, some tricyclic antidepressants, and some selective serotonin reuptake inhibitors (SSRIs; fluoxetine and paroxetine).²⁶

CYP2D6 can metabolize substances via various C-oxidations, including aromatic, alicyclic, and aliphatic hydroxylation; N- and S-oxidation; as well as O-dealkylation. For example, the metabolism of several classes of cardiovascular drugs such as β-blockers and class I antiarrhythmic drugs, as well as the metabolism of neuroleptics and antidepressants, co-segregates with the debrisoquine 4-hydroxylase polymorphism.²⁷ The clinical consequences of genetically determined polymorphic drug metabolism depend on the pharmacologic activity or toxicity of the parent compound compared with that of the metabolites formed by CYP2D6. Clinically important variations can be encountered in the following four situations:

1. Pharmacologic effects are mediated by the parent compound alone.

2. A metabolite is more active than the parent compound.

3. The parent compound and the metabolite have different pharmacologic effects.

4. Toxicity resides within the metabolite.

The following examples for the four situations listed above are provided only for illustrative purposes, since some drugs are no longer or rarely used. The principles underlying these examples are, nevertheless, important to consider while prescribing antiarrhythmic agents.

Pharmacologic Effects Are Mediated by the Parent Compound Alone

Mexiletine is a class Ib antiarrhythmic agent that undergoes stereoselective disposition because of an extensive metabolism; less than 10% of an administered oral dose is recovered unchanged in urine.^28,29 The major metabolites formed by carbon and nitrogen oxidation are hydroxymethylmexiletine, p-hydroxymexiletine, m-hydroxymexiletine, and N-hydroxymexiletine.^28–31 Antiarrhythmic activity resides solely in mexiletine, and all metabolites are inactive. The formation of hydroxymethylmexiletine, p-hydroxymexiletine, and m-hydroxymexiletine is genetically determined and co-segregates with polymorphic debrisoquine 4-hydroxylase (CYP2D6) activity.³² Hence, subjects with the EM phenotype form large amounts of these metabolites. Conversely, clearance of mexiletine is twofold smaller and elimination half-life is longer in subjects with the PM phenotype. Consequently, at the same dose, mean plasma concentrations of mexiletine are higher, and drug accumulation is expected to occur in PM patients during chronic therapy.³² This may lead to side effects such as ataxia and muscle weakness because of the increased block of sodium channels in peripheral nerves.

Combined administration of low-dose quinidine, which is a selective and potent inhibitor of CYP2D6, inhibits mexiletine metabolism through its three CYP2D6 major oxidative pathways and alters mexiletine disposition to such an extent that the pharmacokinetic parameters of the drug are no longer different between EMs and PMs.³² Mexiletine and quinidine have been used in combination to improve antiarrhythmic efficacy and to decrease the incidence of gastrointestinal side effects.³³ Because of decreased clearance and increased elimination half-life during quinidine coadministration, EM patients undergoing combined therapy should exhibit higher trough concentrations and lesser peak-to-trough fluctuations in mexiletine plasma concentrations. Drug accumulation and long-term side effects remain a risk if dosage adjustments are not made.

Some β-blockers are metabolized by CYP2D6 (metoprolol and timolol, for example). As for mexiletine, the parent compound itself is responsible for drug action. Hence, PMs of CYP2D6 exhibit an increased ratio of peak plasma concentrations–dose compared with EMs or UMs and are very sensitive to the drugs. Conversely, UMs are resistant to β-blocking effects, and this necessitates administration of higher doses of the drugs; caution should be exercised in patients receiving high doses of β-blockers under conditions of drug-drug interactions with CYP2D6. Indeed, combined use of high-affinity CYP2D6 substrates (fluoxetine, paroxetine) or inhibitors (quinidine, terbinafine) with β-blockers in EMs or UMs is associated with increased β-blocking effects because of inhibition of CYP2D6-mediated metabolism. Bradycardia and Raynaud syndrome are not uncommon in PMs, EMs, or UMs under these conditions.

Specific genotypes are associated with metabolic bio-inactivation and, hence, the dose requirement or efficacy of certain drugs. For example, a specific genetic profile (activity of CYP2C9) is associated with higher or lower than average doses required to maintain the INR in the desired range for patients receiving warfarin therapy, and dose prediction based on a pharmacogenetic algorithm is superior to empiric dosing in rapidly achieving the desired target INR.³⁴

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