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Workshop on Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations

This chapter summarizes the presentations made at the IOM workshop and the discussions that took place among the speakers, committee, and participants (see the Appendix for the workshop agenda and lists of the speakers and participants). Each speaker was asked by the committee to address issues related to the effect of age, gender, race, ethnicity, and the environment on the topic of his or her presentation.

PHYSIOLOGY OF AGING1

Multiple parameters at the cellular and system levels change with age (Table 2.1), and many of these changes have pharmacokinetic and pharmacodynamic implications. Although it is thought that drug absorption is not markedly altered by age, drug distribution, excretion, and metabolism can be affected by a number of the physiological changes associated with aging. For example, age-related changes in body composition with loss of lean body mass and decreased total body water can lead to decreased volume for the distribution of some drugs. These changes can be exaggerated in the presence of disease. The most consistent age-related change affecting drug excretion is the decrease in renal drug clearance resulting from decreased blood flow to the kidneys and decreased renal mass. Data on age-related changes in hepatic drug clearance have been less consistent and may be more complex.

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This section is based on workshop presentations by Drs. Jane Cauley, Keith Ferdinand, Jeffrey Halter, and Fran Kaiser.



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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary 2 Workshop on Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations This chapter summarizes the presentations made at the IOM workshop and the discussions that took place among the speakers, committee, and participants (see the Appendix for the workshop agenda and lists of the speakers and participants). Each speaker was asked by the committee to address issues related to the effect of age, gender, race, ethnicity, and the environment on the topic of his or her presentation. PHYSIOLOGY OF AGING1 Multiple parameters at the cellular and system levels change with age (Table 2.1), and many of these changes have pharmacokinetic and pharmacodynamic implications. Although it is thought that drug absorption is not markedly altered by age, drug distribution, excretion, and metabolism can be affected by a number of the physiological changes associated with aging. For example, age-related changes in body composition with loss of lean body mass and decreased total body water can lead to decreased volume for the distribution of some drugs. These changes can be exaggerated in the presence of disease. The most consistent age-related change affecting drug excretion is the decrease in renal drug clearance resulting from decreased blood flow to the kidneys and decreased renal mass. Data on age-related changes in hepatic drug clearance have been less consistent and may be more complex. 1   This section is based on workshop presentations by Drs. Jane Cauley, Keith Ferdinand, Jeffrey Halter, and Fran Kaiser.

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary TABLE 2.1 Selected Physiological Age-Related Changes in Body Function and Composition Autonomic nervous system   Peripheral     ↓ Baroreflex responses ↓ Beta-adrenergic responsiveness, ↓ receptors ↓ Signal transduction ↓ Muscarinic parasympathetic responses Preserved alpha responses Central     ↓ Dopamine receptors ↑ Alpha responses ↑ Muscarinic parasympathetic responses Body composition ↓ Lean body mass ↓ Muscular mass, ↓ creatinine production ↓ Skeletal mass ↓ Total body water ↑ Percent adipose tissue (until age 60, then ↓) Cellular DNA damage and ↓ DNA repair capacity ↓ Oxidative capacity ↑ Fibrosis Lipofuscin accumulation Ears Loss of high frequency hearing Endocrine Menopause, ↓ estrogen and progesterone secretion ↓ Testosterone secretion ↓ Growth hormone secretion ↓ Vitamin D absorption and activation ↑ Incidence of thyroid abnormalities ↑ Incidence of diabetes (decreased insulin sensitivity or increased insulin resistance) ↑ Bone mineral loss Eyes ↓ Lens flexibility ↑ Time for pupillary reflexes (constriction, dilation) ↑ Incidence of cataracts Gastrointestinal ↓ Hepatic mass ↓ Hepatic blood flow ↓ Splanchnic blood flow ↑ Transit time

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary Heart ↓ Intrinsic heart rate and maximal heart rate ↓ Diastolic relaxation ↑ AV conduction time ↑ Atrial and ventricular ectopy Immune system ↓ T-cell function Joints Degeneration of cartilaginous tissues Fibrosis, ↓ elasticity Nose ↓ Smell Pulmonary ↓ Vital capacity ↓ Lung elasticity Renal ↓ Renal blood flow ↓ Renal mass ↓ Glomerular filtration ↓ Renal tubular secretion and reabsorption ↓ Ability to excrete a free-water load Vasculature ↓ Endothelin-dependent vasodilation ↑ Peripheral resistance ↑ Systolic pressure Researchers still do not fully understand the physiological mechanisms of aging or the interaction of age-related changes with drug actions (see, e.g., Box 2.1). Moreover, investigators are only beginning to explore variations among individuals and the role of numerous environmental and genetic factors including gender, race, socioeconomic status, physical activity, and other modifiers that interact with the physiological aging process and affect pharmacology. Research on the physiology of aging is complicated by difficulties in distinguishing the effects of normal aging from the consequences of coexisting diseases. There is significant variability among individuals (in physical and mental health status and a number of other parameters) that increases with age, and researchers must determine whether the variability is due primarily to disease or to an effect associated with normal aging. At the cellular level, changes due to aging may appear distinct (e.g., increased collagen cross-linkage, decreased elasticity, and alteration in DNA degradation) while in the whole organism, changes due to normal aging are often difficult to separate from disease processes.

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary BOX 2.1: Homeostatic Control Systems Age-related changes in homeostatic control systems present a challenge to the study of the physiological effects of drug therapy. For example, aging has a number of effects on the autonomic nervous system including increased circulating adrenergic catecholamines, decreased resting parasympathetic nervous system tone, and downregulation of peripheral adrenergic receptor function and vasomotor responsiveness, all of which may contribute to the age-related impairment of baroreceptor function. Because the autonomic nervous system plays an adaptive role in modulating the overall body response to a variety of medications, the interaction of age-related changes with drug effects must be considered. An example of this interaction is the use of diuretics or potent alpha-blocking vasodilators for hypertension. Because diuretics can decrease fluid volume, people with baroreceptor dysfunction, such as elderly persons, may be at increased risk for developing postural hypotension during diuretic therapy. Similarly, blockade of alpha-constrictor effects in the presence of blunted heart rate responses (and decreased intravascular volumes) may predispose to postural hypotension. In fact, most symptomatic orthostatic hypotension occurring in older adults can be directly traced to medication use. In addition, there are a number of areas in which research is beginning to challenge previous assumptions about aging. For example, osteoporosis, long thought of primarily as a disease risk for Caucasian and Asian women, has become a concern for African-American women as well (with the onset occurring approximately 10 years later than in other elderly female populations). Elderly men are also at risk for osteoporosis, although little is known about the extent of this risk. Research on changes in the endocrine system has in the past primarily focused on women and the relationship between loss of estrogen and bone disease, and more recently, cardiovascular disease. There is still much to be learned about changes in the level of testosterone in men during the aging process (Kaiser and Morley, 1994). Preliminary intervention studies show positive benefits for testosterone replacement (Morley et al., 1993). Studies are ongoing to compare the effects of endogenous versus exogenous hormones (Box 2.2). The significance of distribution of body weight is of increasing research interest, and the implications of poor nutrition and weight loss are only beginning to be explored in elderly populations (Clarkston et al., 1997). It has been noted that high waist-to-hip ratios are associated with a higher prevalence of diabetes, hypertension, and coronary artery disease. The Baltimore Longitudinal Study on Aging found that, with aging, there is an increase both in upper and central body fat distribution, with most men having a higher waist-to-hip ratio than most women of comparable age (Shimokata et al., 1989).

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary BOX 2.2 Biological Effects of Endogenous and Exogenous Hormones Hormone replacement therapy is widely used in the United States, particularly for its protective effects in reducing the incidence of osteoporosis in postmenopausal women (Cauley et al., 1995). One area of ongoing research is a comparison of the physiological effects associated with endogenous hormones versus exogenous hormone administration. For example, blood concentrations of serum estrogens after estrogen replacement therapy at currently recommended doses are in the range of 153 pg/mL of estrone and 40 pg/mL of estradiol. This contrasts to physiological levels among postmenopausal women, not on hormone replacement therapy, in the range of 30 pg/mL of estrone and 8 pg/mL of estradiol. Estrogen replacement therapy also appears to be associated with significant reductions in the risk of coronary death and death due to stroke. The mechanism of this protective action has not been fully elucidated or separated completely from the selection bias of socioeconomic status found in retrospective studies to date, but potential mechanisms include effects on metabolic processes that produce beneficial changes in lipids and lipoproteins, as well as direct effects on the arteries themselves to improve arterial function. Although there is a strong association of exogenous estrogen administration with reduced cardiovascular disease in women, preliminary research has found no association between endogenous estrogen levels and heart disease in women (Cauley et al., 1994). Studies of the relationship of breast cancer and uterine cancer with endogenous or exogenous estrogens are ongoing. This area of research is one example of the numerous avenues for research on pharmacotherapy in the elderly. Pharmacotherapies such as hormone replacement therapy, raise a number of important questions including the consequences of long-term exposure to medications and the most appropriate methodologies for studying the effects of these drugs on older persons. Observational studies are an appropriate design to use in evaluating long-term exposures, since randomized clinical trials over 10–15 years are inappropriate for this age group. Issues in Elderly Minority Populations Although the disease burden falls heavily on elderly minority populations, researchers have not fully explored the pathophysiology of disease processes in various minority populations. Health-seeking behavior, socioeconomic status, nutrition, physical and economic access to medications, adherence to prescription regimens, and access to medical care all play a significant role in the prevalence and treatment of diseases in the minority elderly (Figure 2.1). Research is needed to more fully understand the variations between ethnic and racial groups in the time of appearance of disease, the disease processes that dominate, and the effectiveness of treatment interventions.

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary FIGURE 2.1 A framework for understanding the relationship between race and health. SOURCE: King and Williams (1995). Reprinted by permission of Oxford University Press. 12

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary Hypertension, diabetes, renal disease, and their complications are generally more prevalent in elderly African Americans than in elderly Caucasians. In addition, African Americans frequently have more severe sequelae of hypertension, with higher rates of cardiovascular morbidity and mortality. Isolated systolic hypertension is disproportionately prevalent in African-American women. The cardiovascular risks associated with systolic hypertension have only recently been recognized. The Systolic Hypertension in the Elderly Program (SHEP), a multicenter study of community-based ambulatory elderly patients, has shown that treatment of isolated systolic hypertension can significantly improve cardiovascular survival and decrease risk of stroke in elderly patients (SHEP Cooperative Research Group, 1991). However, as in many studies, there was not significant representation from minority patients. Studies indicate an earlier onset of hypertension in African Americans and suggest differing responses to antihypertensive medications. Recent studies have shown that African-American hypertensive cohorts had a higher response rate to treatment with calcium channel antagonists and diuretics and a lower response rate to treatment with ACE (angiotensin-converting enzyme) inhibitors and beta-blockers (reviewed in Jamerson, 1993). Possible physiological explanations include variations in the regulation of salt and water balance, variations in the angiotensin–renin system, differing sensitivities to the vasodilator bradykinin, or angiotensin-converting enzyme polymorphism. Thus, further research is needed to optimize the development of effective clinical therapeutic regimens. INTRACELLULAR RESPONSES2 Pharmacokinetics The therapeutic effect of a drug will be produced only when the appropriate concentration of the drug is present at its site(s) of action. Many medications act by binding to receptors at the cell surface; other medications require intercellular transport. Transport across cell membranes may occur through passive diffusion or facilitated diffusion (i.e., carrier-mediated transport in which there is no input of energy) or active transport through carrier-mediated membrane transport. At this time there are few data that examine the effects of age, sex, or ethnicity on transport mechanisms. 2   This section is based on workshop presentations by Drs. Darrell Abernethy, Grant Wilkinson, and Kurt Rasmussen.

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary In addition to the transport of the drug to the site of action, drug concentration also depends upon the extent and rate of drug absorption, distribution, protein binding, and elimination. Important age-related changes in body composition and functioning (see Table 2.1) are relevant to drug disposition and, in turn, affect drug concentration. These changes have significant implications for clinical therapeutics in the elderly (Scharf and Christophidis, 1993). The absorption of drugs (which affects the duration and intensity of drug action) does not generally appear to be significantly impaired in the elderly; however, the distribution of drugs may be affected. Certain physiological and physiochemical properties including cardiac output and regional blood flow will determine how a drug is distributed through the body. The drug is distributed to the heart, liver, kidney, brain, and other highly perfused organs during the first few minutes after absorption. Delivery to muscle, viscera, skin, and fat occurs later and at a lower level (Benet et al., 1996). In addition, distribution may be limited to the vascular compartment by the drug binding to plasma proteins, particularly albumin and alpha1-acid glycoprotein. As the production of albumin by the liver generally declines with age, there may be an age-related rise in the free fraction of any highly albumin-bound drug. Although this change does not by itself cause an increase in the drug concentration, it may be a marker for other alterations that may be associated with increased drug sensitivity. As lean body mass falls and total body water falls, both in absolute terms and as a percentage of body weight, the volume of distribution of highly lipid- or water-soluble drugs will be affected. Altered drug elimination is also a consideration in the elderly. Drugs are eliminated from the body either by metabolism (primarily by the liver) or by excretion (primarily by the kidney). Drug metabolism in the liver occurs by a variety of reactions such as oxidations, reductions, or hydrolytic processes. In addition, drugs may be metabolized by conjugation reactions, such as acetylation, glucuronidation, or sulfation. There is evidence to suggest that oxidative metabolism decreases with age, whereas conjugative metabolism appears to be less affected by aging (Scharf and Christophidis, 1993). It is known that liver mass decreases with age, as does hepatic blood flow (see Table 2.1). Additionally, oxidative metabolism may also be influenced by smoking, genetics, gender, concurrent diseases, and frailty.3 Renal function also declines with age, as reflected by declines in creatinine clearance. When creatinine clearance falls below 30mL/minute, 4 the excretion of drugs that are eliminated mainly by the kidneys decreases significantly and 3   In general, frailty is the term used by health professionals to describe elderly persons who require assistance with mobility and activities of daily living, have abnormal laboratory findings, and suffer with co-occurring medical conditions including Alzheimer' s disease, multi-infarct cerebrovascular disease, Parkinsonism, osteoporosis, or healed fractures (Scharf and Christophidis, 1993). 4   Normal creatinine clearance in a young adult is 100–120 mL/minute. After age 40, creatinine clearance on average falls by 10 percent for every decade of life (Lee, 1996).

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary the risk of accumulation of the drug and its metabolites increases (Lee, 1996). Although measures of creatinine clearance provide dosing guidelines for drugs that are excreted exclusively by the kidneys, changes in hepatic metabolism with age and pathology are more difficult to estimate quantitatively. Inter- and intraindividual variability in the pharmacokinetics of many drugs is largely determined by variations in hepatic drug clearance as described by the parameters of hepatic blood flow and metabolic capacity. These parameters may be altered as a result of liver disease, genetic differences in enzyme content, and drug interactions. Several metabolizing enzymes have been identified and characterized at the gene, mRNA, and protein level, as have their substrate specificities, including N-acetyltransferase (NAT) and isoforms of cytochrome P450 5 (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A). Some of these isoforms (e.g., NAT2, CYP2C19, and CYP2D6) exhibit genetic polymorphism such that there are subpopulations that may include a small group of people (3 percent–10 percent) who are homozygous and have the poor metabolizing phenotype (i.e., they have an impaired ability to metabolize specific chemicals or drugs) or the extensive metabolizing phenotype, which consists of both the homozygous and the heterozygous genotypes. In many different ethnic and racial groups (e.g., African Americans, Caucasians, Asians, Native Alaskans, and North Africans) there are differences in the frequency of the deficient alleles. For example, in African Americans, the frequency of the poor metabolizing allele for debrisoquine sulfate (an antihypertensive drug that is a specific substrate for CYP2D6) and for over 40 cardiovascular and central nervous system drugs is lower than in Caucasians. Thus, in populations of African Americans the proportion of people who cannot metabolize these drugs extensively is smaller. Asians also exhibit a significantly lower frequency of the poor metabolizing characteristic (~1 percent) than Caucasians (~7 percent) for CYP2D6 substrates. Studies of the effects of physiological aging on the distribution and elimination of drugs in representative populations of the elderly are complex. Multiple confounding variables (e.g., gender, race, ethnicity, body weight, and exposure to caffeine, nicotine, and alcohol) and concomitant diseases, increase the difficulty of understanding the implications of age-related changes on clinical therapeutics in the elderly population. 5   Cytochrome P450 (CYP) is a primary component of the oxidative enzyme system. Individual differences in enzyme activity and susceptibility to induction are genetically determined. Rates of biotransformation (which fosters elimination of drugs) may vary significantly among individuals.

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary Cardiovascular Physiology Cardiovascular disease is the single largest cause of death in the elderly. Although basal cardiac output is maintained in the elderly by an increase in ventricular size and greater stroke volume than in the young, maximal- and stress-related responses are decreased. With regard to cardiac and arterial function, the following changes are also characteristic of aging: decreased intrinsic heart rate, impaired diastolic function (e.g., slowed cardiac diastolic relaxation), increased atrial and ventricular ectopy, prolonged AV conduction times and increased repolarization times, decreased elasticity of the aorta and large vessels, impaired baroflex function, and impaired vascular endothelium-mediated function (Stolarek et al., 1991; Lakatta, 1993; Lakatta et al., 1987, 1993; Craft and Schwartz, 1995). The physiology and pharmacology of the autonomic nervous system and the sympathetic regulation of the cardiovascular system are clearly affected by aging. Normally, stretch receptors in the systemic and pulmonary arteries and veins monitor intravascular pressures; the resulting afferent impulses alter sympathetic activity. An increase in blood pressure stimulates arterial baroreceptors, which results in the inhibition of central sympathetic outflow. In the opposite manner, when blood pressure falls, decreased afferent impulses diminish central inhibition, resulting in an increase in sympathetic outflow, withdrawal of parasympathetic tone, and a rise in arterial pressure. Thus, baroreceptors play an important role in blood pressure regulation. However, baroreceptor reflex activity appears to decline with age. There appear to be significant age-related changes in adrenergic receptors.6 Although circulating norepinephrine levels increase in the elderly, there is no change in the sensitivity to the vasoconstrictor alpha1-adrenoceptor while there is evidence for both a decline in peripheral beta-adrenoreceptor numbers and decreased activity of the G-coupled protein complex and related intracellular second messengers. Age-related changes in central nervous system adrenoreceptor responses are less clear (White et al., 1994). 6   Alpha-adrenergic receptors (there are distinct alpha1- and alpha2-receptor subtypes) mediate vasoconstriction, intestinal relaxation, and pupillary dilation. Beta-adrenergic receptors (the three distinct subtypes are beta1, beta2, and beta3) stimulate heart rate and increase contractility, vasodilation, bronchodilation, and lipolysis.

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary Neurotransmitter Receptors The brain is one of the most complex organ systems in terms of drug actions and disease. Research on the mechanisms of signal transduction, or intercellular communication, in the brain over the past two decades has shown that simple models of synaptic transmission (involving the release of neurotransmitters, which bind to specific receptors and either stimulate or inhibit neural activity) are not sufficient to explain all of the effects of neurotransmitters on neurons. It has been observed that a medication that acts at one or more neuronal receptors may also change neuronal activity by more than one mechanism depending on prevailing conditions at the receptor site.7 However, the biological significance of having varied mechanisms of intracellular communication among neurons in the brain also depends on the part of the brain involved and its complex connections and pathways to other brain regions, as well as on the composition of neurotransmitters and receptors present in specific brain regions. These varied mechanisms of neural activity underly both long- and short-term responses of neurons. For example, short-term effects may include inhibition or excitation of neuronal activity affecting the release of neurotransmitters along brain pathways (chains of neurons comprising subsystems with specific functions). However, research has identified a variety of subtypes of many neurotransmitter receptors (e.g., dopamine and serotonin receptors) that function differently and exhibit different pharmacological responses. In addition, some neurotransmitters exert effects by binding to receptors coupled to ion channels (proteins that regulate the flow of specific ions, e.g., chloride and sodium), and many neurotransmitters affect a cascade of intracellular chemical reactions that, eventually, lead to changes in gene expression in the neural cells. Such long-term effects of neural transmission are often mediated by proteins in neuronal membranes coupled to receptors and a variety of so-called “second messenger ” molecules that act inside cells to regulate many cell processes including changes in gene expression. All of these reactions may be affected by aging; however, they also provide targets for therapeutic interventions. Neurological diseases present important challenges to medication development and use in the elderly. Two neurological disorders often associated with aging are Alzheimer's and Parkinson's disease. Alzheimer's disease is clearly age related (it is uncommon in young or middle-aged persons) with a prevalence as high as 47 percent in people over 85 years, and this disease is the leading cause of cognitive impairment in the elderly population. The pathological features of Alzheimer's disease include neuritic plaques, neurofibrillary tangles, and the death and disappearance of nerve cells in the cerebral cortex. The densities of forebrain 7   Similarly, it is by means of different receptors that norepinephrine can cause constriction in vessels of the skin and dilation of those in muscles. Acetylcholine too has an excitatory function, but it can also be inhibitory, depending on prevailing conditions at the receptor site.

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary utilization and health outcomes. The unintended result of that would be to limit studies on pharmacotherapy in elderly populations. CLINICAL TRIAL RECRUITMENT11 Clinical trials are conducted to establish the safety and efficacy of drugs. There are several phases of clinical development of a drug. Phase I studies are usually conducted to establish a drug's safety. These are small trials that typically involve only healthy volunteers to determine pharmacokinetics and overall safety. Phase II studies establish a drug's pharmacological actions and note adverse reactions in individuals affected by the disease or condition for which the drug is targeted. Phase III studies evaluate a drug's benefits and risks in larger numbers of patients and in special populations. The data collected in Phase III studies help to better define safety and efficacy and provide important information to enable physicians to use the drug effectively. Phase IV postmarketing studies generally evaluate the drug under normal use conditions (OTA, 1993). Until recently, most of the volunteers who have enrolled in clinical trials have been young Caucasian men. It is only in the past few years that citizen groups have pointed out this deficiency and ground rules for participation by women of child-bearing potential have been established, allowing their rather common inclusion in clinical studies. The elderly typically have not been recruited for clinical trials because of their multiple comorbidities, high prevalence of chronic illness, and chronic medication use (Wenger, 1993). As a consequence many studies have age-based exclusions (Gurwitz et al., 1992). However, the systematic exclusion of elderly populations from clinical trials leaves many questions unanswered with regard to age –disease interactions, disease– disease interactions, disease–drug interactions, and age–drug interactions. These questions remain unanswered for elderly minority populations as well. Yet, increases in the size of the elderly population, increases in the range and extent of health problems associated with aging, and subsequent increase in the use of medications by the elderly (Chapter 1) make it imperative to study the safety and efficacy of drugs in this population. It has been estimated, for example, that if an effective medication could be developed to produce a 5-year delay in the age of onset of Alzheimer's disease, it would reduce the prevalence of this disease by 50 percent in one generation. If, for all diseases, the postponement of dependency for 1 month could be achieved for all people over 65 years of age, the cost savings would be approximately $5 billion per month, or $60 billion per year. 11   This section is based on the workshop presentations by Drs. Richard Corriveau, Gregory Sachs, Nanette Wenger, and Jackson Wright.

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary A few additional demographic points that make pharmacotherapeutic research for the elderly imperative include the size of the population of the oldest old is increasing markedly; health status will decline and comorbidity will increase progressively with aging; and almost one half of the current U.S. population can anticipate living to age 80. Given the statistics and demographics regarding the elderly, the FDA issued a guideline in 1989 for testing drugs in the elderly. The guideline was intended to encourage routine and thorough evaluation of the elderly in an effort to provide physicians with sufficient information regarding the use of drugs in older patients. The guideline states that, “there is no good basis for the exclusion of patients on the basis of advanced age alone, or because of the presence of any concomitant illness or medication, unless there is reason to believe that the concomitant illness or medication will endanger the patient or lead to confusion in interpreting the results of the study. Attempts should therefore be made to include patients over 75 years of age and those with concomitant illness and treatments, if they are stable and willing to participate (FDA, 1989).” Although the FDA guideline is useful in providing a message that exclusion from a trial because of chronologic age is not appropriate, researchers are not legally required to follow the guideline (Gurwitz, 1993). Nevertheless, there remain significant barriers to the inclusion of the elderly in clinical trials. Paradoxically, however, the barriers to their inclusion in trials are also the reasons to study this population. The barriers include the complexity of the elderly population, which can confound the study interpretation because of multiple diseases and therapies and coexisting psychological and social problems; differing physiology and pathophysiology in the elderly as compared to younger populations; problems with obtaining proper informed consent in those elderly patients who are confused,who are demented or become so during the study, or who have declining or fluctuating cognition; and the costs associated with recruitment and surveillance of the elderly, and the need for a larger sample size. There are methodological issues, however, that can be utilized to overcome some of the barriers. With regard to the effects of heterogeneity and the associated increase in variability in response, trials can be stratified by clinically meaningful parameters such as the number of co-occurring illnesses, the number of drugs, measures of health status, and general measures of disability. Stratifying by those parameters can limit the effects of heterogeneity. Stratification may

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary include groups that age successfully, groups that demonstrate typical aging (with illness and disability), and the frail elderly (i.e., those with multiple illnesses and severe disability). Outcomes that either maintain or enhance independence and functional status may be assessed, and outcomes that address prevention or complications of existing disease may be considered. In addition, a variety of endpoints should be examined other than mortality. More appropriate endpoints to consider in this population may include morbidity and functional status, quality of life, impact on coexisting illnesses, and cost-effectiveness. Other aspects of methodology that need to be explored include the selection of a subpopulation of older persons for a trial based on the purpose of that trial (e.g., a drug intervention trial may more appropriately involve a heterogeneous group of elderly to test efficacy in a broad sample, whereas targeted interventions may involve a more homogeneous subpopulation). Selection of the subpopulation of elderly persons may condition the intervention (e.g., the specific design of an exercise intervention is unlikely to be similar for healthy and ill older persons). Finally, selection of the subpopulation may affect the generalizability of the results (Harris, 1993). Ethical considerations may need to be broadened with regard to the participation of elderly persons in clinical trials. Whereas previously the emphasis was on symptomatic relief, it may be important to include quality of life and prolongation of life as issues that should be considered in future studies. In addition, there may be a need to identify population subsets with the greatest potential for benefit or for harm from an intervention. Complicating the ethical issues related to this group is the number of elderly persons with dementia. The capacity to make decisions and give informed consent is a difficult issue. Statistically, the elderly are more likely than the young to be affected by dementia or to be cognitively impaired. Furthermore, this population more frequently suffers from delirium and psychiatric illnesses than do younger cohorts. All of these conditions raise questions about the ability to give consent to participate in studies. There is also a concern about nursing home residents and their ability to give consent free from coercion. Further, elderly persons may be subject to abuse by others and are more likely to be impaired by the toxic metabolic effects of illness. Nonetheless, research with elderly persons who are capable of making decisions is governed by exactly the same principles and processes as clinical research with other age cohorts. The researcher clearly has an obligation to investigate and determine the cognitive capacity of each potential study participant (Dubler, 1993). The recruitment of elderly minority populations into clinical trials, especially African Americans, has proved to be difficult. A variety of factors have contributed to this situation:

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary occurrences of research exploitation of minority populations (e.g. sickle-cell screening programs, involuntary sterilization, and the Tuskegee syphilis experiments); the limited access of many minority persons to health care (including high-technology and costly interventions); a lack of trust placed in the medical community (e.g., the view of AIDS as being a genocidal plot); frustration over an inability to have access to costly pharmacotherapeutic interventions once medications are chosen as the therapy of choice; a poor understanding of the need for clinical trials; a poor understanding of the safeguards in place in human subject research; and difficulty in getting to the site of a trial. Yet it is important to include minorities in drug trials, as there may be significant differences in drug metabolism and therapeutic outcomes between ethnic groups. Cross-cultural validation of quality-of-life measures and utility measures (i.e., patient preferences and values) are also important in assessing the efficacy of drug therapies. Several mechanisms have been suggested to overcome some of these difficulties. It is important to obtain the endorsement of community physicians and leaders within the African-American community. Additionally, clinical trials should be advertised at cultural events and community gathering places (e.g., churches, barber shops). Ensuring that study participants are treated with dignity and respect is another critical factor. Other mechanisms to increase African-American participation in clinical trials include the association and collaboration of universities and historically African-American colleges in administering trials; educating individuals and communities about the benefits of participation in trials and about the safeguards in place for human subject research; recruiting minority researchers and staff to enlist patients into clinical trials; educating and disseminating information to the community about the knowledge that will be gained from the study and its potential impact on disease prevalence within the minority community; and providing transportation (or reimbursement for travel) to the study site. The ability and commitment of researchers to accommodate the study population will affect success in minority recruitment. This issue is important both to ensure equal generalizability in populations that may demonstrate differences in drug metabolism from those seen in other ethnic groups and to validate cross-cultural quality-of-life measures.

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary INFORMATION DISSEMINATION12 Disseminating the immense amount of frequently changing and technically detailed information about pharmacotherapeutic interventions in a timely manner presents an ongoing challenge. The targets for this information—physicians, pharmacists, other health professionals, and patients—each have their own set of information needs and ways they access information. Physicians and Pharmacists Information on new medications and on drug interactions changes rapidly. As a result, some of the biggest challenges facing physicians and pharmacists concern updating existing information and accessing new information. Health professionals are trained to remember large amounts of information, unfortunately, they find it difficult to forget outdated information. Having an efficient way of delivering information so that it reaches health professionals at the time they are making decisions about drug therapy and writing or filling a prescription is a key need. Information is also critically needed when patients are being monitored for compliance and intended outcomes. Determining a patient's current and prior drug profile is another challenge. Many elderly persons have several diseases and take numerous medications, and they frequently see several health care professionals and obtain their medications in a variety of locations. All of these factors make it difficult to individualize drug information and to track prescriptions. The disparate nature of the health care system and the inadequacies of medical records place the information burden on patients by requiring them to remember each of their numerous medications. Additionally, it is important for information dissemination to flow in two directions—i.e., health care professionals need to educate patients on appropriate medication use and drug interactions, and they also need to receive information from their patients regarding their medication use, adverse effects, and other negative and positive outcomes. Patients The elderly population varies with regard to their knowledge and understanding of drug-related information. At one end of the spectrum are elderly patients who are extremely knowledgeable about their health and their medica- 12   This section is based on the workshop presentations by Dr. Stephen Pauker and Dr. Jeffrey Halter.

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary tions. Pharmaceutical advertisements, direct mail information, and the growth of consumer health information and the Internet all assist patients who want to be well informed and want to discuss this information with their health care professional. Addressing the questions of well-informed patients raises a number of issues including the need for high-quality data and an increased length of time for patient-health professional interaction. Toward the other end of the spectrum are those older persons who may have decreased cognitive function primarily related to the speed with which they process information (Park and Halter, In press). Older patients may have less working memory capacity, may experience visual and hearing limitations, and may have problems sorting out critical information. Although they generally have more experience with the medical system, they tend to seek out less information when making medical decisions than do younger persons. Drug-related information is often presented using complex terminology, and older patients can get overloaded with the extensive amounts of information that are not provided in an accessible or coherent way. Thus, the challenge is to present drug-related information in a manner that is comprehensible to the entire spectrum of the elderly patient population and that will assist them in making informed decisions about their medical treatment. In addition, attempts to overcome challenges in the elderly population such as impaired vision, poor manual manipulation skills, and memory lapses may be assisted by devising new methods for distributing medications, such as by automating pillboxes or other medication delivery systems. Cultural differences and disparate ethnic backgrounds between health care providers and elderly patients from minority populations may interfere with the effective transfer of information about drug use and potential side effects. Further, health care providers may not be aware of the community groups and service resources that are available to provide information to patients of different ethnic backgrounds regarding their medication use. INVESTIGATORS13 There are serious shortfalls in the number of primary care physicians and internists trained in geriatrics, the number of physicians trained in geriatrics, and the number of geriatricians involved in research and education, including geriatric pharmacology research. As with many other fields of medical research, funding is increasingly scarce and more time-consuming to secure, and the economic realities resulting from changes in the health care system are diverting funds away from research training. Moreover, the applied nature of much of 13   This section is based on the workshop presentations by Drs. Jesse Roth and John Ruffin.

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary geriatric pharmacotherapy research puts it outside the mandate of funding agencies such as NIH. In addition, geriatric medicine fellowships have been shortened from 2 or 3 years to 1 year which has resulted in inadequate time for research and an almost exclusive focus on clinical training. Another problem in attracting geriatricians to research endeavors is the need for clinical geriatricians to treat the increasing numbers of elderly patients. Thus, there is a need to develop mechanisms for attracting and retaining researchers in geriatrics. There are many decision points along a typical career path that may be addressed to reach this goal. First, it is important to attract young people who are in college or recently graduated. New approaches suggested by the workshop speakers included a 1- or 2-year postbaccalaureate program that would provide research assistant positions in geriatric medicine programs linked to pharmacology and clinical therapeutics. Such a postbaccalaureate program offered by schools of medicine or pharmacy could provide exposure to research and clinical activities and to a series of role models including geriatric physicians, clinical pharmacists, and investigators evaluating drugs used with the elderly. The predoctoral Intramural Research Training Award fellowship at NIH was suggested as a model for a postbaccalaureate program in geriatric pharmacology and clinical therapeutics. The latter program would include schools of pharmacy and pharmacy clinicians. The post-baccalaureate program, in addition to providing inspiration and role models for nascent researchers, would also provide much needed assistance to their mentors, young investigators in the field. The beginning years of the research track are often difficult due to an increasing gap between the availability of initial funding and the assurance of long-term funding. As originally conceived, there was continuing support from fellowship training to first awards to independent grant support. However, the gap has widened between fellowship training and independent support. This issue needs to be addressed in order to assure continuity of support for young investigators. Loan-forgiveness programs could be developed modeled on the NIH loan-forgiveness program for researchers in AIDS. Stipends that are competitive with salaries for people with similar experience are needed. Potential sources for such stipends include the FDA, the Department of Veterans Affairs, the Department of Defense, pharmaceutical companies (models include the programs sponsored by Merck in partnership with the American Federation for Aging Research or the program sponsored by Pfizer in partnership with the American Geriatrics Society), foundations (e.g., the Hartford and Brookdale Foundation programs), or insurance companies. Another potential mechanism is the NIH R03 grant, a one-time research award available to young investigators so they can garner the preliminary data needed to apply for more definitive funding such as an NIH First Independent Research Support and Transition Award (R29) or an NIH Independent Investigator Award (R01). It is equally important to retain midcareer professionals in this field. Mechanisms for support

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Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in Elderly African-American Populations: Workshop Summary at this stage of the career include merit awards at the midcareer level and research sabbaticals to retrain midcareer geriatricians in research methodologies. Recruiting minority students into the field of geriatrics, and specifically geriatric pharmacology and clinical therapeutics, is of importance. Collaborations and true partnerships are needed between minority institutions (e.g., historically black colleges and universities) and academic health sciences centers to provide minority students with extensive research training in this field. The National Institute of General Medical Sciences and the NIH Office of Research on Minority Health have initiated model programs to build these partnerships through an M.S.–Ph.D. program. Students at minority institutions who are accepted into a master's program at the minority institution are simultaneously accepted into the Ph.D. program at the affiliated academic health sciences center. The student can choose his or her research subject from either institution and have research mentors at both. Programs that are truly collaborative will benefit the entire community and will increase the number and diversity of motivated, well-trained investigators. SUMMARY OF THE WORKSHOP14 The topics presented in this workshop fall into two main categories: approaches to research issues and the resources needed to carry out research. The research issues that need to be addressed in this field are numerous and can overwhelm the resources available for investigator-initiated research. It is crucial to overcome the traditional linear way of thinking about sciences moving exclusively from the laboratory bench to the bedside and instead recognize that research ideas need to be exchanged between the laboratory, clinical, and social sciences. Future research should emphasize interdisciplinary efforts and should not overlook the role of the social sciences in studying pharmacotherapy in elderly populations. The broad scope of important research questions will have to be addressed by encompassing a range of methodologies including observational as well as traditional experimental studies. Ensuring adequate, sustained research funding is of critical importance —without that, it will be impossible to pursue answers to the research questions identified for this field. As discussed throughout the workshop, there are a number of innovative methods that could be implemented to increase recruitment of minority elderly populations in clinical trials. In addition, the maintenance of professional career paths will require new and expanded approaches and funding mechanisms. Finally, the changes taking place in the health care system will continue to present challenges and will require a reassessment of the optimal way to answer the numerous questions on pharmacokinetics and drug interactions in elderly populations. 14   This section is based on the summary presentation by Dr. Marcus Reidenberg.

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