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Neuropsychopharmacology: The Fifth Generation of Progress

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Psychotropic Drug Metabolism in Old Age :

Principles and Problems of Assessment

Lisa L. von Moltke, David J. Greenblatt, Jerold S. Harmatz, and Richard I. Shader

INTRODUCTION

As our capacity to understand and treat medical problems of the elderly becomes more refined, the proportion of the American population that is over the age of 65 is increasing. Emotional and psychiatric disorders are commonplace in the elderly population and are disproportionately prevalent in geriatric populations when compared to groups of younger age (9, 53, 66). As such, the appropriate use of psychotropic drugs in the elderly assumes major importance in clinical medicine (11, 46, 47, 61, 64, 77). Elderly individuals may respond uniquely to psychotropic drug treatment as a consequence of alterations in disease characteristics associated with old age or because of intrinsic age-related changes in drug sensitivity occurring at the neuroreceptor site mediating drug action (6). Pharmacologic response may also change in the elderly due to alterations in pharmacokinetics associated with the aging process.

Changes in drug absorption, distribution, elimination, and clearance in elderly populations have been the subject of many studies over the past two decades or more (13, 20, 26, 30, 33, 34, 45, 47, 58, 64, 65, 69, 70). Although many of these studies focus on psychotropic drugs, the quality of the data base is variable, often because the elderly present special problems and constraints. Previous reports have extensively reviewed the status of understanding of age-related changes in psychotropic drug disposition, and we will not present the entire data base again in this chapter. Instead we will focus on theoretical and practical methodological considerations in the design and interpretation of studies of altered psychotropic drug disposition in old age. The first section deals with fundamental pharmacokinetic principles, including the concepts of clearance, distribution, elimination, absorption, and protein-binding. Emphasis is placed on the biologic bases of these concepts, methods of measurement, their relation to physiologic changes in the elderly, and implications for psychotropic drug use in the aging population. The second section outlines options available for the design and implementation of studies of drug disposition in old age, including their benefits and limitations, and implications for the quality of the current data base.

PHARMACOKINETIC PRINCIPLES

Clearance

The concept of clearance is a cornerstone of the understanding of the discipline of pharmacokinetics (22, 24, 25, 28, 72, 73). Clearance is a mathematical construct having units of volume divided by time (i.e., ml/min or liters/hr). It refers to the total amount of blood, serum, or plasma from which a substance is completely removed per unit time. Alternatively, clearance may be viewed as the rate of drug removal per unit of plasma concentration. Physicians usually first encounter the concept of clearance in the context of renal function, whereby creatinine clearance is used as an indirect index of renal function. Under the assumption that the endogenous substance, creatinine, is completely cleared by the kidney, renal clearance of creatinine can be used as an indicator of glomerular filtration rate.

Clearance also applies to the removal of drugs and other foreign chemicals. Clearance is the single most reliable index of the capacity of a given patient to remove a given drug. For most drugs used in clinical practice, the major mechanisms of drug clearance are hepatic biotransformation or renal excretion. For drugs cleared by the kidney, a significant fraction of the administered drug is recovered unchanged in the urine (Fig. 1). For hepatically metabolized drugs, products of biotransformation may ultimately be recovered in the urine, although this does not imply that the intact drug undergoes renal clearance.

Of the drugs encountered in psychopharmacology, lithium is cleared primarily by renal clearance (36, 39), as are the hydroxylated metabolites of the cyclic antidepressants (78). Essentially all other psychotropic drugs are cleared by hepatic biotransformation. The effect of age on renal clearance of drugs excreted intact by the kidney is relatively straightforward to understand and predict, since renal function, as measured by glomerular filtration rate or other functional indexes, on the average declines with age (12, 18, 43, 44, 51, 55). As such, an age-related decline in clearance of lithium can be anticipated (36, 39). The problem is not so straightforward in the case of hepatic biotransformation. Liver metabolism of drugs is mediated by a variety of groups of enzymes and enzyme systems whose activities are not uniformly influenced by age (10, 35, 50, 71, 76).

Hepatic blood flow constitutes an upper limit of clearance for drugs that are metabolized by the liver, since clearance cannot exceed the rate of drug delivery to the clearing organ. In healthy individuals, hepatic blood flow usually falls in the range of 1500-1800 ml/min, although there is considerable individual variation. Some studies suggest a decline in hepatic blood flow with age. Unfortunately, there is no straightforward noninvasive clinical test that can be used routinely to quantitate this parameter.

The numeric value of a drug's clearance relative to hepatic blood flow has important clinical implications (24, 52, 72, 73). Many of the benzodiazepine anxiolytics have low values of hepatic clearance (less than 10% of hepatic blood flow). For such drugs, first-pass metabolism (presystemic extraction) after oral dosage is minimal, and absolute bioavailability after oral dosage is generally greater than 80%. That is, more than 80% of an orally administered dose ultimately reaches the systemic circulation. For these low-clearance drugs, a reduction in hepatic clearance associated with old age will have the effect of prolonging elimination half-life rather than changing the peak plasma concentration after oral dosage. In contrast, many of the cyclic antidepressants and antipsychotic agents have values of hepatic clearance exceeding 50% of hepatic blood flow (4, 8, 14, 19, 57, 68, 70). These drugs undergo substantial presystemic extraction after oral administration, such that a relatively small fraction of an oral dose actually reaches the systemic circulation. Oral doses needed to produce a particular therapeutic endpoint generally will be higher than parenteral doses of the same drug needed for the same endpoint. For these drugs, a reduction in hepatic clearance may lead to a prolongation of half-life but will also be associated with an increase in the peak plasma concentration after oral dosage (24, 52, 72, 73).

For any drug metabolized by the liver, the predicted hepatic extraction ratio (ER) can be calculated as the ratio of clearance after intravenous dosage divided by hepatic blood flow. The maximum systemic availability of an orally administered dose (F) can then be calculated as:

F {ewc MVIMG, MVIMAGE,!lesseq.bmp} 1-ER [1]

Thus, the greater a drug's intravenous clearance relative to hepatic blood flow, the lower the maximum systemic availability after oral dosage (Fig. 2).

Clearance is the major biologic determinant of steady-state plasma concentration (Css) during chronic administration. Assuming that a drug has been administered long enough for the steady state to be reached, Css can be calculated as:

Css = Dosing rate [2]

Clearance

Dosing rate, presumably determined by the health care professional, can be viewed as the "input" determinant: It is the rate at which the drug is given to the patient. If clearance is constant, Css will increase in proportion to dosing rate in any given patient. It is important to remember that actual dosing rate is influenced by patient compliance and therefore does not necessarily correspond to the intended dosing rate as decided upon by the health care professional. The denominator of this equation is clearance, which represents the capacity of that particular patient to eliminate that particular drug.

Clearance then is a biologic variable that cannot be directly measured or predicted without actually giving that particular patient a test dose of the drug in question. Because clearance appears in the denominator, its importance is evident. If drug clearance declines with old age, Css will correspondingly increase unless dosing rate is appropriately reduced (Fig. 3). Increases in Css may be associated with a greater likelihood of drug toxicity. For this reason, clearance is almost always a major focus of studies of altered drug disposition and old age.

Distribution

Drug distribution is not a measure of drug clearance or removal and is completely independent of clearance. Drug distribution is determined by physicochemical properties: the drug's relative solubility in lipid as opposed to water (lipophilicity), its affinity for various body tissues, the blood flow to each of these tissues, and the drug's binding to plasma protein. Only a small fraction of the total amount of a psychotropic drug present in the body interacts with the specific neuroreceptor recognition site in the brain. Uptake of drug by peripheral sites will accordingly influence the amount that is available to the brain.

Body habitus typically changes with age, even if total body weight does not change significantly (5, 16, 28, 60, 62). The amount of adipose tissue relative to total body weight generally will increase as a person ages, while the fraction of lean body mass correspondingly decreases. The same pattern of age-related change will occur in both men and women, but at any age, women have a higher fraction of body weight comprised of adipose tissue than do men. Thus both age and gender influence body habitus, and gender is therefore a potential confounding factor in pharmacokinetic studies in the elderly.

The extent of drug distribution can be quantitated using the pharmacokinetic concept of volume of distribution (Vd). This is a hypothetical quantity having units of volume (liters) that is defined as follows:

Amount of drug in the body

Vd

=

[3]

Concentration in reference compartment

The "reference compartment" in this equation usually refers to blood, serum, or plasma, and therefore Vd represents the amount of drug in the body divided by the blood or plasma concentration. Lipophilic drugs, including most psychotropic agents, have large values of Vd, indicating that the plasma concentration is small relative to the amount of drug in the body. For cyclic antidepressants, for example, the pharmacokinetic Vd may be 10 times the size of the body, or even more. On the other hand, relatively nonlipophilic drugs such as lithium will have smaller Vd, indicating that a larger fraction of what is present in the body is found in blood, serum, or plasma. It must be emphasized that pharmacokinetic Vd is hypothetical, and does not refer to any specific anatomic entity.

Because of age-related changes in body habitus, pharmacokinetic Vd for many drugs will change with increasing age (28, 33). Vd for lipophilic drugs typically will be larger in elderly subjects when compared to young individuals of the same gender, even when total body weight does not differ between groups. This is explained by the greater fraction of total body weight comprised of adipose tissue in the elderly. Conversely, Vd of nonlipophilic drugs may be reduced in the elderly relative to young controls.

Vd itself, and changes in Vd with age, are of importance for two reasons. First, elimination half-life depends on both Vd and clearance, as described below. Second, the duration of action of many lipophilic psychotropic drugs following single doses is dependent mainly on distribution rather than elimination or clearance. This phenomenon is described in detail elsewhere in this volume (see Chapter 84). The duration of action of some psychotropic drugs may be expected to change in the elderly as a consequence of a change in distribution, but this theoretical possibility has not been tested in controlled studies.

Elimination

The rate of drug disappearance in the post-distributive phase after a single dose, or after termination of multiple dose treatment, is quantitated as an elimination half-life. The same half-life applies to the rate of attainment of steady-state after initiation of multiple dose therapy (without a loading dose), or the rate of attainment of a new steady-state condition if the maintenance dose is increased or decreased. Elimination half-life is currently recognized as potentially misleading as a pharmacokinetic variable, because it is a dependent quantity related to Vd and clearance as follows:

0.6930Vd

Elimination half-life

=

Clearance [4]

We ordinarily think of elimination half-life as being inversely related to clearance. That is, low clearance (inefficient drug removal) implies long elimination half-life, and the reverse. This intuitive relationship is correct only in situations when Vd is relatively constant, an untenable assumption when pharmacokinetic properties are being evaluated in relation to age. For any given drug, Vd may increase or decrease as a function of age, depending on lipophilicity and body habitus. Vd also will be influenced by gender. Since either or both Vd and clearance may be affected by aging, elimination half-life should not be used as the sole index of the capacity for drug removal. The relationship of half-life to Vd is most evident in pharmacokinetic studies of lipophilic drugs in obese individuals (1, 2, 29). In such studies, clearance may not be significantly different between obese subjects and normal-weight controls matched for age and sex. Elimination half-life, however, greatly increases in obese individuals only because of their increased Vd.

Absorption

Studies of the pharmacokinetics of drug absorption commonly address questions on the rate and the extent of drug absorption from the gastrointestinal tract. That is, how fast the drug is absorbed, and how much of what is administered actually reaches the systemic circulation. Structural and functional changes in the aging gastrointestinal tract are well-documented (15, 21, 40, 41, 48). Cytochrome P450-3A4 is present in human gastrointestinal tract mucosa and may contribute to presystemic extraction of some drugs, such as cyclosporine (38, 75). It is possible that the apparent activity of gastrointestinal as well as hepatic Cytochrome P450-3A4 may change with age. Observations such as these have led to speculation that absorption of orally administered medications may be reduced and/or delayed in old age. However, systematic studies of drug absorption in the elderly fail to validate this presumption. The rate and extent of absorption of several orally administered psychotropic medications are not importantly changed in elderly subjects when compared to young controls (Table 1).

Protein Binding

Many psychotropic drugs are extensively though reversibly bound to plasma protein. For some drugs, such as diazepam, the extent of binding is very high, with only 1-2% of the total concentration in plasma being in the unbound state (49). Albumin and alpha-1 acid glycoprotein (AAG) are the two plasma proteins usually responsible for drug binding (32, 42, 54, 56, 63, 67, 74).

Old age may be associated with a reduced extent of drug binding to plasma protein (26, 33). This is best documented for drugs bound to plasma albumin. Because albumin concentrations tend to decline with age (23), the extent of drug binding may also be reduced, leaving higher fractions of unbound drug in plasma. The effect of age on plasma binding for drugs bound to AAG is not clearly established (3).

A widely disseminated but incorrect dictum in the medical literature states that reduced plasma binding of psychotropic drugs in the elderly yields increased amounts of unbound drug available for pharmacologic action, and therefore a greater intensity of drug action. The free fraction (FF) of drug in plasma can be calculated as the ratio of free (unbound) concentration divided by total (free plus bound) concentration. This relationship is arithmetically correct but biologically wrong (32). The form of the equation which correctly delineates the dependent and independent biological variables is as follows:

   

Free concentration

Total concentration

=

   

Free fraction [5]

The independent variables are on the right-hand side of the equation. FF is a physicochemical variable determined by the concentration of the binding protein, the concentration of the drug, and the drug's affinity for the binding protein. In the numerator is free concentration, which is completely independent of FF. Free concentration depends on the dosing rate and the liver's capacity to remove the free drug ("free clearance"), as described in Equation 2. The dependent variable, on the left side of the equation, is total concentration. Assume a physiologic situation in which dosing rate and free clearance are constant; therefore, free concentration is constant. If drug protein binding decreases (FF increases), the result will be a reduction in total concentration (32). Thus FF influences total drug concentration, but by itself has no effect on either free concentration or the drug's pharmacologic action (Fig. 4) Since most drug assays measure total rather than free concentration, interpretation of total concentrations may be influenced by changes in FF (17, 32). In studies of clinical situations (such as old age) in which drug binding to plasma protein may be altered, FF must be measured to assure correct interpretation of pharmacokinetic data based on total drug concentrations in plasma.

APPLICATION OF THE PRINCIPLES: OPTIONS FOR STUDY DESIGN

The design and execution of experimental protocols evaluating age-related changes in psychotropic drug disposition requires investigators to integrate an understanding of the principles described above together with the practical and ethical limits of various design options. Two broad categories of design can be applied. Each has benefits and drawbacks, but neither by itself will provide the complete answer. This section considers the two major design options, along with an example of how each can be applied to the same research question.

Controlled Pharmacokinetic Studies

Important data on psychotropic drug disposition in the elderly have been generated through well-controlled clinical pharmacokinetic studies. These studies generally involve healthy volunteers who can be screened to exclude potentially confounding factors such as medical disease, concurrent medications, or extremes of body habitus. The interacting effects of age and gender on pharmacokinetics can be separated by study of separate cohorts of young male, young female, elderly male, and elderly female volunteers.

The study design typically involves administration of a single dose of the medication in question to subjects in all cohorts. Plasma concentrations of the drug are measured at multiple points in time after the dose, and pharmacokinetic methods are used to determine pertinent variables such as clearance, Vd, and elimination half-life. Multiple dosing schemes may be used to verify the relation between the single-dose kinetic profile and plasma concentrations during multiple dosage.

Well-controlled intensive-design studies provide the most complete and accurate description of the pharmacokinetic properties of a given drug in volunteer cohorts. Important confounding factors can be controlled for or eliminated, and the influence of age by itself on drug disposition can be isolated. This approach also has drawbacks. Sample sizes within each cohort generally are limited by the time, patience, and financial resources of the investigators. The representativeness of the study cohorts to the general population can never be determined. If variability within groups is large, the statistical power of comparisons will be reduced, with an increased possibility of failing to detect an important difference that would be demonstrable with a larger sample size. Finally, not all categories of psychotropic drugs are equally suitable for study in healthy volunteers. With proper subject selection and monitoring, and appropriate choice of dosage size, young and elderly volunteers can participate in single-dose kinetic studies of anxiolytics, hypnotics, and most antidepressants. Many such studies are reported in the medical literature (30, 34, 70). Controlled pharmacokinetic studies of neuroleptics, on the other hand, are few in number, owing to the potential hazards and discomfort associated with these agents, particularly in the elderly (14, 19). A further complication is that analytic techniques for quantitation of neuroleptics in plasma following single doses are technically difficult and not widely available.

Population Studies

A second important methodological approach involves the study of plasma concentrations of psychotropic drugs during actual clinical use by larger groups of patients taking the medications for clinical purposes. The prinicpal advantages of this approach are that large numbers of patients can be studied at relatively low cost with essentially no unwarranted risk to the participants. A further benefit is that the study population is "real"; that is, it is precisely the group of patients that actually needs and takes the medication. The population study design also has drawbacks. At most only a few steady-state plasma concentrations are available for any given patient. The only pharmacokinetic variable that can be calculated is clearance. This requires an accurate record of dosing rate, which still can be influenced to an unknown degree by compliance. The time of sampling relative to dosage usually is not controlled and may not even be known. Therefore, steady-state concentrations may be influenced by interdose fluctuation as well as by dosing rate and clearance. Additional confounding factors must be suspected, since real patient populations may have concurrent medical disease, and be taking other medications which could alter plasma concentrations of the drug in question. Finally, drug doses in clinical populations generally are titrated to optimize response, and variations in plasma concentrations will reflect differences in dosage as well as possible effects of age. The statistical analysis must incorporate the effect of dosage when evaluating the influence of age on steady-state plasma concentration.

Application of the Methods

To illustrate the nature of these two approaches, two studies on the benzodiazepine derivative alprazolam are described. An intensive design study evaluated the pharmacokinetics of single 1-mg oral doses of alprazolam in healthy young and elderly male volunteers (27). Age-related differences in alprazolam clearance are shown in Fig. 5. The effect of age was highly significant, with alprazolam clearance reduced an average of 50% in the elderly men compared to the young male controls. A second study evaluated steady-state plasma concentrations of alprazolam in male patients receiving the drug for the treatment of panic disorder in a controlled clinical trial (31). A plasma alprazolam concentration was measured at week 10 of treatment. Daily dosage of alprazolam varied widely among patients, ranging from 1 to 10 mg/day. Because dose was a major determinant of steady-state plasma level, the effect of age could be evaluated only after normalization for dosage. This dose-normalized plasma concentration is shown on the y-axis of Fig. 6, while patient age is shown on the x-axis. Dose-normalized plasma level increased significantly with age (r = 0.24, p< 0.05), but the size of the squared correlation coefficient (r2 = 0.06) indicates that age explains only a small fraction of the variance.

Thus the intensive design pharmacokinetic study in a small group of carefully screened normal volunteers does not yield identical findings as a study of steady-state alprazolam concentrations during actual treatment of panic disorder in a clinical trial. However, the possibility cannot be excluded that confounding factors masked an actual effect of age in the population study. Furthermore, the maximum age in the population study was 59 years, whereas the mean age in the intensive-design study was 70 years (range: 62-77 years).

 

QUALITY OF THE DATA BASE

The effects of age on the pharmacokinetics of psychotropic drugs have been extensively reviewed elsewhere. The quality of the data base is highly variable. It is most solid in the case of benzodiazepine derivaties (30, 34). Reasonable data are also available for a number of cyclic antidepressants and for trazodone, although the antidepressant data base is not nearly as reliable as that for benzodiazepines (70). Some data are available for the serotonin-reuptake-inhibitor antidepressants, although the information has been slow to reach the peer-reviewed medical literature (68). Data on the neuroleptic agents are relatively weak, largely due to ethical problems with studies in volunteers, and difficulties with analytical methodology (14, 19).

Most benzodiazepines are metabolized by microsomal oxidation, with Cytochrome P450-3A4 identified as a major responsible cytochrome (Table 2). The weight of the data indicate impairment of clearance of these drugs in old age, particularly among men (30, 34). For benzodiazepines metabolized by glucuronide conjugation, the weight of the data indicates that age has only a small effect on clearance. A similar conclusion can be drawn for nitrazepam, which is biotransformed by nitroreduction (30). Since clonazepam is metabolized by the same pathway, it can be expected that age would not greatly influence its clearance, but this has not been studied.

Among cyclic antidepressants, clearance of imipramine (also mediated in part by P450-3A4) appears impaired in old age (4, 8, 20, 70). Some data suggest that amitriptyline clearance may also be reduced in the elderly, but this is not a consistent observation (59, 70). Clearance of trazodone appears to be impaired in old age, particularly among men (7, 29). For other antidepressants, study findings of age effects on clearance either are conflicting, or are affected by methodologic drawbacks that preclude definitive interpretation (37, 70).

 

THE FUTURE OF GERIATRIC PHARMACOKINETICS

The pharmacokinetic profile of a new psychotropic medication usually is elucidated in the pre-marketing phase of drug development by studies of healthy young normal male volunteers. Yet the target population of afflicted individuals who ultimately are treated with the drug may consist largely of women and the elderly, about whom little or no pharmacokinetic data are available before the drug reaches the market. This is changing, as women and the elderly are becoming priorities for pre-marketing studies of drug disposition. Understanding age-related alterations in pharmacokinetics is critical to the decision-making by clinicians who must estimate modifications in dosage needed for treatment of elderly patients.

ACKNOWLEDGMENTS

This work was supported by Grant MH-34223 from the Department of Health and Human Services. Dr. von Moltke is the recipient of an Abbott Laboratories Fellowship in Clinical Pharmacology.

 

published 2000