Alterations in drug disposition in older adults.

Review

Alterations in drug disposition in older adults

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Nyu Medical Center on 02/17/15 For personal use only.

Emily Reeve†, Michael D Wiese & Arduino A Mangoni 1.

Introduction

2.

Absorption

3.

Distribution

4.

Metabolism

5.

Elimination

6.

Conclusion

7.

Expert opinion

†

University of Sydney, Kolling Institute for Medical Research, School of Medicine, Cognitive Decline Partnership Centre, Ageing and Pharmacology, New South Wales, Australia

Introduction: The worldwide population is aging, and several age-associated physiological and pathophysiological changes can affect drug disposition. This is particularly important in view of the extensive medication prescribing and exposure in older adults. Areas covered: Using a framework of the four primary pharmacokinetic processes (Absorption, Distribution, Metabolism and Elimination), this review discusses the current evidence of the pharmacokinetic changes that occur with aging, particularly ‘healthy aging,’ focusing on developments in this field over the last 10 years. Expert opinion: A substantial amount of work has been conducted to address whether advancing age significantly affects drug disposition in humans. Despite significant advances in the field, particularly regarding drug metabolism and elimination, a number of issues remain unsolved. In particular, lack of inclusion of older adults with multimorbidity and those aged > 80 and minimal evidence in relation to new drugs limits the applicability of findings to current clinical practice. Keywords: absorption, aging, distribution, elimination, metabolism, pharmacokinetics Expert Opin. Drug Metab. Toxicol. [Early Online]

1.

Introduction

The worldwide population is aging. In 2013, ~ 10% of the population was aged > 60, and this is expected to increase to 25% by 2050 [1]. Understanding the physiologic changes of tissues, organs and systems, and consequently the changes in medication pharmacokinetics that occurs with aging, will enable better use of medications. This, in turn, has the potential to greatly impact (and hopefully reduce) the unintended consequences of medication use, ensuring at the same time therapeutic efficacy. There is no all-encompassing definition of aging from a biological or clinical standpoint. It is a term normally used to describe the outcomes of accumulated changes at the molecular, cellular and tissue levels. The process of aging is generally characterized by impaired adaptive and homeostatic mechanisms, which result in diminished ability to deal with external stressors [2]. The exact mechanisms involved remain largely unknown. Several changes that occur on the cellular level are thought to be responsible, including damage to mitochondrial and nuclear DNA due to oxidative stress, increased lipid peroxidation, telomere shortening, altered gene expression and upregulation of cell apoptosis [3-5]. The aging process results in changes in body composition and organ or system function. The latter is associated with increased risk of mortality and acute and long-term disability [2,6,7]. Examples of age-related changes involve the cardiovascular system (e.g., increased systolic blood pressure and stiffening of the arteries), reduced kidney and liver mass, weakening of bladder muscles and degeneration of the brain and spinal cord [8,9]. These changes are not consistent across different people of the same chronological age, and even within an individual, the function of 10.1517/17425255.2015.1004310 © 2015 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

1

E. Reeve et al.

Article highlights. .


.

.

.

.

.

While advancing age is associated with physiological changes to the gastrointestinal tract, the effect on absorption is unlikely to be clinically significant with the possible exception of drugs with high first-pass metabolism. In older adults with atrophic gastritis, or those taking acid-suppressive medications, basic compounds may have impaired dissolution resulting in reduced bioavailability. Changes in pharmacokinetics must be considered for medications with non-oral administration as well as for medications administered via enteral feeding tubes. Changes in body composition and specific plasma proteins can affect the volume of distribution of medications; however, this does not appear to have major clinical implications for the vast majority of drugs. The most clinically significant age-associated alterations in pharmacokinetics are those affecting drug clearance. Clearance via Phase I metabolism or renal clearance is generally decreased in older adults, with possible increased total drug exposure. Reduced hepatic blood flow is mostly responsible for reduced Phase I metabolism. However, changes in the structure of the liver parenchyma, reducing transfer of oxygen into hepatocytes, may be responsible for reduced metabolism of capacity-limited drugs. Not all older adults will experience significant renal impairment with aging, but due to the high prevalence of comorbidities and medications affecting renal function, renally cleared drugs should be reviewed regularly. Chronic kidney disease can affect all stages of drug disposition due to accumulation of uremic toxins including increased bioavailability through downregulation of enzymes (decreasing first-pass metabolism) and downregulation of efflux transporters (e.g., P-glycoprotein), altered distribution due to conformational changes in plasma albumin and decreased hepatic metabolism due to downregulation of enzymes.

This box summarizes key points contained in the article.

one organ may be maintained (e.g., the liver) while another (e.g., the lungs) is compromised [10]. Importantly, interindividual variability increases with advancing age, and as such older adults (those aged > 65) cannot be considered a homogeneous group [11-13]. Age-related changes in physiology can influence the pharmacokinetics of medications, and the overall effect is dependent on the individual drug characteristics (e.g., lipophilicity, degree of protein binding), mechanism of elimination, intercurrent disease states and concomitantly taken drugs [14]. These will influence the effective dose, frequency of administration, treatment duration and in fact choice of medication [15]. Internationally, increasing age is associated with increased prevalence of multiple disease states and consequently increased medication use [16]. In Australia, people aged > 65 make up 13% of the total population but account for > 50% of medication expenditure [17]. In the UK, the average number of yearly 2

prescriptions doubled over the decade of 1996 -- 2006 from 21.2 to 40.8 items per person [18]. Older adults are more susceptible to adverse drug reactions and other medication-related errors, a common cause of mortality and morbidity in this population [19]. Given that the older adult population is heterogenous and often characterized by multimorbidity, determining what changes are purely due to aging is difficult to establish. For example, diseases of the liver and kidney, the organs primarily responsible for drug metabolism and elimination, are more common in older adults than younger ones. Another major determinant of the pharmacokinetics of a medication is the other medications that the individual is taking, so-called drug--drug interactions [20]. The increased prevalence of polypharmacy and therefore increased potential for drug--drug interactions also make it difficult to determine whether the altered pharmacokinetics are purely due to aging. The potential effect of age on pharmacokinetics was first discussed at the end of the 1970s [21] and there has been much attention paid to the topic since then. However, despite increased knowledge and advances in technology and techniques that are used to investigate the aging process in experimental models as well as in humans, much is still unknown. For example, the knowledge of the role of P-glycoprotein (P-gp) in different body tissues and its interactions with medications is increasing, though whether these interactions are affected by aging is still mostly unknown [22]. Using a framework of the four primary pharmacokinetic processes (Absorption, Distribution, Metabolism and Elimination), this review discusses the current evidence of the pharmacokinetic changes that occur with aging, focusing mainly on developments in this field over the last 10 years (Table 1). A literature search was conducted in Medline and Embase using the terms ‘pharmacokinetics,’ ‘medication’ and ‘age’ and variations on these, with the results restricted to January 2004--May 2014. Review articles identified had their reference lists searched for relevant articles. This search was supplemented with searches using the terms absorption, distribution, metabolism and elimination where insufficient literature had been identified from the first search strategy. Where appropriate, original research articles were obtained, however, due to the breadth of this research topic, key review articles are also discussed. 2.

Absorption

Absorption after oral administration After a medication is administered orally, it may undergo some or all of dissolution, absorption (which may be passive or active) and metabolism in the gastrointestinal tract and/or liver (so-called first-pass metabolism) before it reaches the systemic circulation. The fraction of an orally administered dose that reaches the systemic circulation (i.e., the oral bioavailability) may therefore be influenced by several factors including gastric pH, gastrointestinal motility, intestinal permeability and integrity of the mucosa, drug transporter function and 2.1

Expert Opin. Drug Metab. Toxicol. (2015) 11(5)


Table 1. Summary of the changes in drug disposition associated with aging according to the four primary pharmacokinetic processes.


Absorption Gastric acidity

Transit time

Permeability Passive Carrier mediated P-glycoprotein activity First-pass metabolism

Overall Distribution Body composition

Plasma protein binding

Overall Metabolism Hepatic blood flow

Transfer of substances into hepatocytes Metabolizing capacity Phase I

Phase II Overall Elimination Renal function

Overall

Change in older adults

Clinical significance

Example drugs

Hypochlorhydria due to gastric mucosal atrophy more common in older adults Reduced gastric acidity may also be caused by medication use, for example, proton pump inhibitors and histamine-2 receptor antagonists, in this group May be unchanged -- reduced due to certain comorbidities (e.g., diabetes, Parkinson’s Disease) and certain medications (e.g., anticholinergics and opioids)

Potential reduced absorption of weakly basic drugs, enhanced absorption of weakly acid drugs where increased pH is present

Ketoconazole has impaired absorption in older adults with pH > 5

Unlikely to have a clinical significance

--

-Reduced absorption of certain nutrients Unclear

-Glucose, calcium, Vitamin B12

Unchanged May be reduced Both increased and decreased activities have been reported Reduced first-pass metabolism due to reduced liver blood flow and mass

--

May or may not be clinically Nifedipine, labetalol and significant depending on extent verapamil have all increased of first-pass metabolism and bioavailability in older adults therapeutic indices (clinical significance uncertain) Reported changes due to aging alone are unlikely to be clinically significant

Relative reduction in total body Uncertain -water Reduction in muscle mass Relative increase in body fat Small reduction in plasma albumin Unlikely -(further reduction may be due to age-related chronic conditions) a1-acid glycoprotein may be increased (usually due to acute illness or chronic inflammatory disease states) Reported changes due to aging alone are unlikely to be clinically significant Reduced by 20 -- 50% Pseudocapillarization may impede the transfer of substances into hepatocytes

Drugs with high extraction ratios will have reduced clearance Unclear

Amitriptyline, fentanyl, morphine, verapamil Most likely to affect large molecules and those highly protein bound

Reduced (mostly due to reduced hepatic blood flow and mass and reduced oxygen availability)

Reduction in metabolism of Ibuprofen, warfarin, temazepam drugs that undergo Phase I metabolism can be clinically significant No change --Reduced Phase I metabolism and potentially higher plasma drug concentrations Depending on the renal function Digoxin of the individual, the effect may be clinically significant Renally cleared drugs will have reduced elimination with consequential increase in half-life and plasma concentration

Reduced renal function is common in older adults


3

E. Reeve et al.

expression and gastrointestinal blood flow and metabolism. Reductions in gastric emptying, gastrointestinal motility, gastric acid secretions (increased gastric pH), gastrointestinal blood flow and intestinal surface area have all been observed with aging [23], but the overall effect of these changes does not appear to significantly change the total absorption for most medications. The potential impact of these changes is discussed below. Gastric acidity It was originally proposed that a decline in gastric acid secretion was a normal part of the aging process. However, more recent studies have challenged this, noting that in healthy older adults, levels of fasting and stimulated gastric acid secretion were not significantly reduced compared to younger counterparts [24,25]. The earlier findings of reduced acid secretion may be due to the relatively high prevalence of hypochlorhydria secondary to gastric mucosal atrophy in older adults (5 -- 10%) compared to < 1% in younger subjects [24-26]. A recent study looking into the effect of age on acid secretion enrolled 47 relatively healthy participants (adults scheduled for surgery, without upper gastrointestinal disease, diabetes or medications that can affect gastric secretion) across three different age groups: young (22 -- 39 years old), middle aged (40 -- 59) and old (60 -- 83). This study found that in the absence of gastric mucosal atrophy (n = 32) there was no relationship between aging and reduced acid secretion [27]. The significant increase in the volume of prescribing of drugs used to reduce acid concentrations in the stomach (i.e., proton pump inhibitors and histamine-2 receptor antagonists) in older adults over the past 20 years will also affect the pH of the stomach and the interpretation of studies addressing this issue [12]. With higher stomach pH, weakly acidic drugs dissolve more rapidly while weakly basic drugs dissolve more slowly, and as such general statements about the effect of gastric acidity on absorption can not be made. Reduced stomach acid concentrations (in the case of people with atrophic gastritis or those taking acid suppressive medications) may cause reduced absorption of weakly basic drugs and, conversely, enhanced absorption of weakly acidic drugs. Examples of basic drugs, which may be affected, include ketoconazole, ampicillin esters and iron compounds [5,26,28,29]. A study of administration of ketoconazole tablets in older adults with an average of two chronic medical conditions found that participants with gastric pH > 5 (n = 6, mean age = 84.5 years) had impaired absorption resulting in significantly lower plasma concentrations than those with pH < 5 (n = 12, mean age = 76 years). The concentrations achieved in the higher pH participants were subtherapeutic and likely to negatively affect the efficacy of ketoconazole in this group [30]. The implications of this study, however, are limited by its small sample size. Similarly, dabigatran etexilate requires a pH < 4 to dissolve. A study in healthy older adults found that coadministration with pantoprazole (a proton pump


2.1.1

4

inhibitor) led to a 20% reduction in dabigatran bioavailability. However, this was not considered clinically significant [31]. Changes in acidity may also affect the extent of absorption of pro-drugs that require an acidic environment for conversion [32]. For example, the conversion of clorazepate into the active desmethyldiazepam is inhibited in subjects with gastric pH artificially increased to > 6, with a corresponding reduction in absorption by almost 50% [33]. This study is limited by its small sample size (n = 4) and was conducted in healthy young adults. Transit time There is some reduction in gastrointestinal motility in old age, including slowed gastric emptying, decreased peristalsis and slowing of colonic transport due to region-specific loss of neurons [34,35]. These changes would generally be expected to impact poorly soluble drugs where increased transit time will allow longer time for dissolution and therefore increased total absorption. Drugs that are highly soluble may have their absorption delayed, resulting in reduced maximum concentration but unchanged total absorption [5,12,32]. Increased transit time may also affect drugs, which are in a slow-release formulation. A study of young healthy male volunteers found that absorption of controlled-release carbamazepine was increased in participants with slower transit times [36]. Studies in older adults are not consistent and the clinical effect is unclear. There is an increase in total absorption of levodopa following administration of Sinemet CR in older versus younger healthy volunteers [37], but no change in total absorption of a slow-release formulation of oxycodone [38]. The high prevalence of comorbid conditions (e.g., diabetes, Parkinson’s disease) and medications (e.g., anticholinergics and opioids) affecting gastrointestinal motility in older adults, and the varying methods utilized in studies (due to the invasiveness of this kind of study) make it difficult to determine if these changes in gastrointestinal function are purely due to age [34,39]. Therefore, fit older adults may not have any change in the rate of gastric emptying compared with younger subjects [40]. 2.1.2

Permeability (passive and active) The permeability of drugs appears unchanged in old age when the medication is absorbed by passive diffusion [5,12,23,41,42]. For example, the absorption of commonly prescribed drugs such as penicillins, diazepam and metronidazole in older adults is unchanged compared with younger adults [29]. While it was previously believed that the majority of drugs are absorbed via passive means, recent research indicates that carrier-mediated, active uptake of drugs may be more common than previously thought [43]. Nutrients requiring active transport for absorption seem to have reduced absorption with aging, that is, glucose, calcium [44] and vitamin B12 [25,45,46]. One transporter that has recently received attention is P-gp, a trans-membrane transporter that is found in the luminal surface of the intestine among other 2.1.3




places in the body including the blood--brain barrier, kidneys and lymphocytes. Its role is a protective one; it actively transports drugs and xenobiotics back into the gut lumen, decreasing absorption [47]. A large number of drugs appear to be P-gp substrates including anticancer drugs, antibiotics, calcium-channel blockers and steroids [22,48,49]. The effect of aging on P-gp activity in humans is still under study, with both increased and decreased activity observed depending on the tissue in question and method of study [22].

First-pass metabolism Oral bioavailability of some medications is reduced due to being metabolized before reaching the systemic circulation (first-pass metabolism). It is generally accepted that most first-pass metabolism occurs in the liver, though there is increasing evidence that drug metabolism, involving both Phase I and Phase II metabolism pathways, can also occur in the intestine [47]. Aging may be associated with a reduction in first-pass metabolism, most likely due to reduced liver blood flow and mass (discussed further below). The clinical effect of reduced first-pass metabolism is likely most significant for drugs that undergo extensive first-pass metabolism [8,49,50]. For example, in those with a high first-pass metabolism, a small reduction in hepatic extraction ratio (e.g., from 95 to 90%) could result in a doubling of serum concentrations [51]. Some examples of increased oral bioavailability in older adults include nifedipine (46% vs 61%, younger vs older adults) [52], labetalol (significant correlation with increased age) [53] and verapamil (though a wide range in bioavailablilty was observed in the older adult group, 9 -- 83%) [54]. Propranolol bioavailability was found to be almost doubled in older adults in one study [55] but unchanged in others [56,57]. By contrast, no significant ageassociated changes in absorption have been reported for other drugs with high first-pass metabolism, including amitriptyline [58], metoprolol [59,60] and morphine [61]. The reasons for these variations in results may be due to the relatively small sample size of the studies, the high inter-participant variability or the small number of drugs with a bioavailability < 25% where the effect will be the most apparent [50]. Additionally, a change in bioavailability of medications with wide therapeutic indexes is unlikely to be clinically relevant. A recent study compared the effect of age on the bioavailability of two dihydropyridine calcium-channel blockers (one with high firstpass metabolism [felodipine] and one with low first-pass metabolism [amlodipine]). Older subjects (with hypertension) had an increase in total drug exposure by ~ 30% for both medications (without any change in apparent elimination half-life) indicating that first-pass metabolism is not significantly affected by age. However, older participants had a greater reduction in blood pressure than younger participants (20 vs 10 mmHg after chronic dosing of both drugs). It is unlikely that such a difference in blood pressure lowering is chiefly accounted for by the relatively small increase in drug 2.1.4

exposure. Pharmacodynamic changes associated with aging appear to be more clinically relevant for these drugs [62]. Changes to first-pass metabolism will also affect medications, which are administered as pro-drugs, potentially reducing concentrations of the activated drug, for example, codeine, enalapril, perindopril and simvastatin [12,63] but the clinical significance of this has not been established. Older adults have been demonstrated to achieve the same, if not higher enalaprilat (the active form of enalapril) plasma concentrations as younger adults although this is confounded by a reduction in renal clearance of both enalapril and enalaprilat in older adults [64,65]. Conversion of oseltamivir to its active metabolite via hydrolysis occurs rapidly in older adults aged > 80, with peak concentrations of the active metabolite actually 22% greater than young healthy participants. Notably, both groups still achieved the required plasma concentration for antiviral activity [66]. These three studies [64-66] had small sample sizes (n = 12, n = 18 and n = 12) and only included healthy subjects and therefore these results cannot be extrapolated to multimorbid older adults. The effect of aging on intestinal metabolism in humans is currently unknown. Several studies in rats show that there is no change in the activity of intestinal CYP enzymes (3A, 1A1, 2B1/2 and 3A1) with aging [67,68], and depending upon the segment of the intestine where metabolism occurred, there are variable changes in Phase II metabolism via glucuronidation in young versus older rats [69]. It is unknown whether these changes observed in animal studies are translatable to humans. Overall, for most medications total absorption is unchanged with aging, and in the instances where it is altered it is unlikely to have a substantial clinical impact. The changes to the different stages of absorption may counterbalance each other, for example reduced gut absorption (secondary to reduced permeability or reduced solubility) may be compensated for by reduced first-pass metabolism. The use of multiple medications by older adults can lead to changes in drug absorption through interactions via metabolism (in the intestines or the liver) and potentially via modification of P-gp activity [5,47]. This, along with concurrent diseases, is likely to have a greater impact on absorption than changes purely due to aging [6]. Oral administration via enteral tubes A number of age-associated acute and chronic medical conditions, for example, Parkinson’s disease, stroke and dementia, might lead to impaired oropharyngeal function, with consequent risk of aspiration of food or other material. When oral intake is inadequate or not recommended (e.g., swallowing difficulties) for a prolonged period of time, patients are often given an enteral feeding tube for administration of nutrition and/or medications [70]. Between 150 and 280 per million inhabitants in the UK receive enteral nutrition at home, with regions with a higher percentage of older adults having the greatest prevalence [71,72]. Incorrect administration 2.2


5


E. Reeve et al.

of drugs via enteral tubes can result in blockage of tubes (necessitating removal and reinsertion), and may alter absorption pharmacokinetics [70]. Enteral feeding tubes have nasal, oral or percutaneous entry sites. Of more relevance to pharmacokinetics, however, will be the location of the distal tip of the feeding tube. Most tubes deliver content to the stomach, mimicking regular oral administration; however, some may end distally in the duodenum or jejunum. This results in medications bypassing the stomach. Medications that act locally in the stomach (e.g., antacids), or require acidity for dissolution (as discussed above), may have reduced efficacy if the enteral tube ends distal to the stomach [70,73]. Medications administered via enteral feeding may also interact with the enteral nutrition formulas (i.e., via chelation to nutrients) or even adsorb to the feeding tube itself [70]. A study of enterally administered phenytoin concurrently with nutritional formula found that phenytoin absorption was reduced by up to 70% [74] due to adhering to enteral tube or interaction with formula (proteins and calcium salts). A systematic review in 2000 found no strong evidence of this interaction in randomized controlled trials of healthy adults; however, it identified numerous reports and studies showing a significant decrease in serum phenytoin concentrations in patients when coadministered with enteral nutrition [75]. A study in 2010 investigating this possible interaction in frail older adults on a geriatric ward did not find a significant difference in plasma concentrations, but concluded that the possibility of an interaction could not be ruled out due to conflicting previous studies [76]. Another study in geriatric inpatients with enteral feeding looked at the effect on clarithromycin pharmacokinetics, again finding no difference in trough or peak concentrations, or time to peak concentration [77]. Other drugs with reports of altered absorption due to nutrient interactions include carbamazepine, warfarin and fluroquinolones though, as with phenytoin and clarithromycin, the studies are inconsistent. Interactions (if existing) may be avoided by spacing medication administration and feeding by 2 h [70,78]. While most tablets can be crushed and mixed with water to allow for enteral administration, there are several significant exceptions to this, for example, tablets that have enteric coatings (to protect the medication from the acidity of the stomach) and those that have a slow/extended/controlled-release formulation. Proton pump inhibitors are acid labile and inactivated by stomach acid, as such proprietary products come with enteric coating. These tablets should not be crushed; however, omeprazole, esomeprazole and lansoprazole come as enteric coated granules within capsules that can be opened and mixed with water for enteral administration while still maintaining the integrity of the formulation. Tablets with controlled-release formulations should not be crushed and administered as this can result in greater peak and lower trough concentrations. Instead, the dose and frequency should be converted to a regular release formulation [70,73]. Lists of 6

medications, which should not be crushed or administered via enteral tubes, have been published and should be consulted before administering older adults regular medications via enteral tubes [79]. Non-oral drug administration While oral ingestion is the most common route for medication administration, several other routes such as the skin and lungs can be used. These may also be affected by the aging process. Atrophy of the dermis and epidermis in older adults may lead to increased absorption of medications applied to the skin (e.g., creams and patches). On the other hand, the skin may also be drier with reduced tissue perfusion, which can impair absorption [42,80]. Roskos et al. [81] found that advanced age reduced the percutaneous absorption of hydrocortisone, benzoic acid, acetylsalicylic acid and caffeine (by ~ 50%). By contrast, there was no change in the absorption of testosterone or oestradiol. This suggests that the absorption of hydrophilic, but not lipophilic, drugs is affected by age. Of the studied drugs, only oestradiol and testosterone are currently administered transdermally for systemic activity and as such the clinical significance of the reduced absorption of the other drugs is not relevant (and may in fact be considered desirable for hydrocortisone, which is used topically for local effects). A study into the transdermal absorption of fentanyl in palliative care patients (age range 40 -- 85 years) found no effect of age on absorption although there was substantial inter-individual variability in fentanyl absorption [82]. A recent review identified significant variability between studies on transdermal absorption in older adults, with some studies finding increased absorption, some reduced absorption and others no change [83]. External factors may be partly responsible for this wide range in variability, with extremes of heat (induced by sauna or exercise) associated with increased transdermal absorption for certain drugs including nicotine and glyceryl trinitrate [84]. Overall, there does not appear to be any clinically relevant change in absorption of drugs transdermally with age, though more research may be required into persons aged > 80. Although there is evidence that some of the barrier-related functions of the skin change progressively with chronological age, there is very little research in this group [80,83,85]. With aging and associated diseases (e.g., chronic obstructive pulmonary disease), older adults have reduced inspiratory capacity and alveolar surface area, which may reduce the effectiveness of locally acting inhaled medications [86-88]. Probably of greater importance, however, is appropriate use of inhalation devices; older adults generally have poorer technique than younger adults [89]. Cognitive function, manual dexterity and hand strength are required for the use of inhalation devices [90] and in older adults there was an association between compliance with metered dose inhalers and mini-mental state exam score [91]. A study of community dwelling older adults found that inaccurate inhaler technique was present with 2.3



between 3 and 28% of those prescribed long-term inhalers [92].


3.

Distribution

Following absorption, the amount of active drug available to exert an effect at the active site(s) is dependent on tissue distribution and the extent of plasma and tissue protein binding, which is broadly quantified as the volume of distribution (the theoretical volume of blood for the concentration yielded after administration of a drug). Changes in body composition (which result in altered tissue binding) and synthesis/ elimination of proteins involved in drug binding in the plasma that occur with aging may therefore affect the distribution of drugs. Body composition There are significant changes in body composition associated with aging, including a relative reduction in total body water, a reduction in muscle mass and a relative increase in body fat. With every year of age over 50, body water decreases by ~ 1% [93]. Muscle mass decreases by about the same amount, though there is a greater loss in men than women [46,94,95]. Body fat increases more in older women than men, with studies indicating an average increase of around 1% per year [46,94,96,97]. When divided into decades of life there is a significant increase in body fat and decrease in fat-free mass up to and including the age group of 70+ years (with participants aged up to 89 years) [98,99]. Although there is some limited evidence that after the age of 80 fat mass actually declines [20,100,101]. The Health, Aging and Body Composition study conducted longitudinal analysis of adults aged 70 -- 79 over a 4-year period. Both total weight gain (21 and 24% of men and women, respectively) and weight loss (31 and 33% of men and women) were observed in this population. Of those who lost weight, there was an approximate loss of 5% lean and 10% fat mass, while in those who gained weight there was only ~ 2% gain of lean mass but an increase of 15% fat mass [102]. The volume of distribution of water-soluble drugs is therefore likely to be reduced and the same administered dose will therefore result in increased peak serum concentrations. For example, the volume of distribution of digoxin reduces with age and it has been suggested that the loading dose should be reduced by 10 -- 20% in older adults. This change may not be clinically important, though therapeutic drug monitoring for specific drugs, including digoxin, might be a useful tool when steady state is achieved [5,12,29]. Lipophilic drugs will, on the other hand, be more likely to have an increase in their volume of distribution and will take longer to be cleared from the body, for example, diazepam, whose halflife may be increased fourfold in an 80 years old compared to a 20 years old [103]. While volume of distribution is relevant for loading doses, changes in volume of distribution are unlikely to affect the overall drug exposure. A decrease in 3.1

volume of distribution (e.g., with digoxin) will result in initially higher peak plasma concentrations; however, this leads to increased clearance as there is greater concentrations of drug available at the elimination organs, resulting in a shorter halflife. The equilibrium between the altered volume of distribution and elimination results in unchanged total exposure to the drug [104]. In fact, the half-life of a drug may have little relevance to clinical efficacy or toxicity in specific circumstances. For example, benzodiazepines with longer half-lives have shown a similar risk of falls as short-acting benzodiazepines [105]. Plasma protein binding The two main drug-binding proteins in plasma are albumin and a1-acid glycoprotein [8]. There has been an observed reduction in plasma albumin concentrations of ~ 10 -- 15% in older adults, which is probably due to increased elimination via the kidneys rather than reduced synthesis [106-109]. While this decrease is statistically significant, the change is relatively small and not considered clinically important [110-113]. Age-related chronic conditions such as arthritis, Crohn’s disease, cancer, acute coronary syndrome and renal and hepatic dysfunction can further decrease albumin concentrations [8,114]. In older adults, a1-acid glycoprotein concentrations can be increased, although this is usually attributed to acute illness or chronic inflammatory disease states including burns, trauma, surgery and cancer, rather than age per se [8,104,114,115]. Severe liver disease can, however, decrease a1-acid glycoprotein concentrations [114]. Individuals with lower plasma albumin concentrations will theoretically have increased free fraction of the drug, and it is this unbound drug that is able to exert therapeutic (and toxic) effects. A study of 22 younger (age 18 -- 33 years) and 22 older (62 -- 87) patients with epilepsy-prescribed phenytoin found a statistically significant increase in unbound fraction in the older group (accompanied by reduced plasma albumin concentrations). However, the reported changes were not considered clinically significant; unbound phenytoin percentage was 12.8% in older adults versus 11.1% in younger [116]. Piroxicam also exhibits increased fraction unbound in older subjects [117,118]. More recently, Chin, Jensen et al. [110] conducted experiments into three benzodiazepines, lorazepam, oxazepam and temazepam, all of which are highly bound to albumin and cleared via the liver. In 60 healthy drug-free subjects aged 19 -- 87, they found a significant reduction in plasma albumin with age of 0.03 g/l per year but there was no relationship between the unbound fraction of any of the drugs and age. Similarly, in a later study in 72 patients prescribed warfarin (aged 18 -- 89), a statistically significant (though small, 45 vs 43 g/l younger vs older adults) reduction in albumin was observed with age but again there was no relationship with protein binding [111]. In practice, however, changes in protein binding (if present) are unlikely to exert clinically significant effects [5,42,104,114]. This is because increased unbound fraction leads to increased availability of the free drug at clearance sites and therefore 3.2


7


E. Reeve et al.

overall drug exposure is virtually unchanged [104]. An increase in unbound fraction of drugs that are renally cleared will lead to an increase in glomerular filtration and may also increase active tubular secretion and decrease passive tubular reabsorption. For orally administered drugs that are hepatically cleared, an increase in unbound fraction will, as with renal clearance, lead to increased clearance. However, changes in protein binding may be clinically relevant for hepatically cleared drugs with high extraction ratios when given intravenously as the fraction unbound will have an effect on total exposure. Examples include diltiazem, propranolol, verapamil, erythromycin and fentanyl [104,114]. Lidocaine protein binding was reported to be increased in older adults with increased a1-acid glycoprotein. Although a longer half-life (not attributable to change in systemic clearance) would increase overall exposure to lidocaine, this study concluded that no dose changes are required in older adults [119].

blood flow). Drugs with a high extraction ratio are limited by hepatic blood flow and a reduction in blood flow will reduce their clearance. By contrast, drugs with a low extraction ratio will not be substantially affected by the reduced blood flow although they are affected by changes in metabolizing capacity (discussed below) [8,12]. A review on the elimination of medications based on their free drug concentration (as opposed to total drug concentration which in older adults can confound findings due to reduced albumin) reported that medications with high extraction ratios consistently have reduced metabolism in older adults with an average of 34 and 54% reduction in clearance following intravenous and oral administration, respectively. Example drugs include amitriptyline (62% lower), fentanyl (6 -- 74%), imipramine (35 -- 45%), levodopa (39%), metoprolol (13%), morphine (16 -- 35%) and verapamil (32 -- 42%) [115]. Transfer of substances into hepatocytes After the drug has reached the liver via the blood stream, it needs to cross the sinusoidal endothelium, travel through the space of Disse and then enter the hepatocytes where it undergoes metabolism. Age-related changes have been observed in the liver sinusoidal endothelial cells (including endothelial thickening, defenestration and collagen deposition, termed pseudocapillarization), which may impede the transfer of substances from the blood to the hepatocytes [129-131]. These changes are similar to those seen in cirrhosis, which has been shown to affect the transfer of oxygen, sucrose and propranolol (highly protein bound) [130]. It has been proposed that the agerelated changes in the liver sinusoidal endothelial cell will affect the transfer of drugs with a large molecular weight (e.g., therapeutic proteins) and those that are extensively protein bound [129]. Studies in aged rats have shown reduced transfer of large molecules such as lipoproteins [132] and liposomal doxorubicin [133]. Similar findings (again in animal studies) were recently reported with acetaminophen, which has low protein binding but is water soluble [134], and diazepam, which is highly protein bound [135]. The clinical relevance of these changes is best examined by looking at the overall change in metabolism of these substances. 4.2

4.

Metabolism

Metabolism results in conversion of an active drug into an inactive drug (or vice versa for pro-drugs). Metabolism by the liver is important for the elimination of active and inactive drugs, which require biotransformation to a more soluble form in order to be excreted by the kidneys. Metabolism occurs via cytochrome P450 (CYP - oxidation, reduction and hydrolysis) and conjugation (glucuronidation, acetylation and sulfation), so called Phase I and Phase II metabolism, respectively [23]. While the liver is the main metabolizing organ, the intestines (discussed above), the lungs, the skin and the kidney all have a metabolizing capacity [120]. Metabolism in the kidney may account for ~ 25% of glucuronidation and sulfate conjugation [121]. Approximately one third of the metabolic clearance of propofol (which is metabolized by uridine diphosphate glucuronosyltransferase [UGT]) is conducted in the kidneys [122]. In addition to metabolism the liver plays important roles including synthesis of albumin, bilirubin, cholesterol and blood clotting factors. In the absence of advanced liver disease, these nonmetabolic functions are generally maintained in older adults [11,23]. Hepatic metabolism depends on the rate of the drug being supplied to the liver (i.e., hepatic blood flow), the transfer of the drug from the blood into the hepatocytes and the ability of the hepatocytes to metabolize the drug (metabolizing capacity) [8]. Hepatic blood flow Both hepatic blood flow and liver size are reduced with age, beginning in approximately the third decade of life [50]. Hepatic blood flow is reduced in adults > 65 years by ~ 20 -- 50% [123-127], and there is a similar reduction in liver size (less blood is required by smaller organs) [23,96,123,128]. This reduction in hepatic blood flow will affect the rate of metabolism of drugs differently depending on their extraction ratio (the ratio of hepatic clearance in relation to hepatic 4.1

8

4.3

Metabolizing capacity Phase I metabolism

4.3.1

Most (but not all) in vitro studies of hepatic content and activity of CYP450 enzymes have found that they are maintained with increasing age (though there are very limited studies looking at ages > 80 years) [5,11,96,136,137]. Yet, most in vivo studies have shown that there is a significant reduction in the clearance of drugs metabolized via Phase I metabolism in older people by ~ 30 -- 50% [11,123]. For example, a study of patients prescribed phenytoin (metabolized by CYP2C9 and CYP2C19) found a decrease in clearance by about one third between the age of 65 and 85 [138]. The effect of aging on different CYP enzymes may vary. For example, a study conducted in 2005 found a decrease in activity of




CYP2C19, yet an increase in CYP2E1 and no change in CYP2D6 [139]. However, the changes found in this and similar studies appear to be small relative to the effect of reduced hepatic blood flow and liver size [96]. Based on in vitro and in vivo results, the observed reduction in metabolism of drugs, which undergo Phase I metabolism, is most likely due to the reduced blood flow and liver size (discussed above), rather than a reduction in the expression or activity of the CYP enzymes [63,127,130,140]. This has, however, been challenged as there is also reduced clearance of drugs that have low extraction ratios (capacity-limited metabolism). A literature review looking into studies of capacity-limited metabolism of drugs with high protein binding found that there was reduced free clearance, even when the total clearance was unchanged. It found reductions in free clearance to the order of 20 -- 60% of many drugs including ibuprofen, temazepam and warfarin. This suggests a reduced metabolizing capacity of Phase I enzymes, which could not be attributed to reduced hepatic blood flow [115]. The reduction in clearance of capacity-limited drugs may be due to the reduced size of the liver (and therefore less areas and enzymes to metabolize), or because of structural changes in the liver discussed above. In addition to the transfer of drugs, the transfer of oxygen into the hepatocytes may be hindered. All enzymatic processes require oxygen as a part of their requirement for energy, and CYP pathways are particularly dependent on oxygen as a co-substrate. Age-related pseudocapillarization may result in reduced oxygen availability within the hepatocytes limiting CYP reactions. This has been proposed as a reason for a reduction in Phase I metabolism of capacity-limited drugs [5,49,130]. This supports the assertion that the metabolizing capacity or production of the enzymes themselves does not reduce with aging, but that Phase I metabolism of both high- and low--extraction ratio drugs can be reduced. As older adults are likely to be exposed to polypharmacy, it has also been investigated (though not extensively) whether inhibition and induction of enzymes are affected by aging. Some early studies had data that indicated a reduced inducing capability with aging [56,141], though the majority indicated that inhibition and induction are not affected, and therefore drug--drug interactions will occur to the same extent as in younger adults [8,142-144]. Phase II metabolism Phase II metabolism does not appear to be altered in older age, and this conclusion is mostly consistent across different studies [123,129,145,146]. For example, several studies have found no difference in the clearance of temazepam (metabolized mostly by glucuronidation) between healthy young and old adults [147-149]. The literature review conducted by Thompson et al. [96] in the development of a physiologically based pharmacokinetic modeling database suggests that there is no age-related difference in Phase II metabolism (via the liver or other sites) in older compared to younger adults, though they note that there is still limited data on this. Similarly, Ginsberg’s 4.3.2

review [20] identified 5 drugs that undergo glucuronidation in which the effect of aging had been studied. While the studies only involved a total of 182 participants across all ages, there was no increase in half-life (when converted to a ratio to young adults) in the pooled data with increasing age. This may be because Phase II reactions only require oxygen indirectly (to produce energy) and not directly as a co-substrate like Phase I reactions. Therefore, they are unlikely to be affected by the structural changes described above that may be responsible for the reduction in capacity-limited Phase I metabolism [49]. It does, however, appear that Phase II metabolism may be reduced in frail older adults. For example, studies of paracetamol [150], metoclopramide [151] and aspirin [152] have shown preserved metabolism in fit older adults, but reduced metabolic clearance in the frail. The clinical consequences of these changes in metabolism in frail older adults may surpass just increased half-lives. A reduction in Phase II conjugation of paracetamol will lead to greater metabolism via the alternative (CYP mediated) pathway, which leads to production of a toxic metabolite. This toxic metabolite is usually neutralized via conjugation with glutathione; however, with frailty (specifically malnutrition), there are less glutathione stores. Therefore, the frail are at greater risk of liver toxicity, even at recommended daily doses due to reduced clearance and greater production and less neutralization of this toxic intermediate [153]. 5.

Elimination

Renal function The main organ responsible for removal of drugs and their metabolites from the body are the kidneys. Traditionally, it was generally accepted that renal function, and therefore the excretion of drugs with renal elimination, reduced with age. A review conduced in 1999 estimated that after the age of 30 there is a reduction in glomerular filtration rate (GFR -- an established marker of renal function) by 8 ml/min every decade. The weight of the kidneys, reduced renal blood flow, number of functioning nephrons and reduced permeability were thought to be the cause [103]. However, this standard reduction of renal function with age may not be completely true, particularly given the previously described increased inter-individual variability in key parameters of organ function. Moreover, many age-related diseases and cardiovascular risk factors (such as hypertension, heart failure, and diabetes), as well as chronic exposure to nephrotoxic drugs (e.g., nonsteroidal anti-inflammatory drugs) can directly affect GFR and may confound the effect of aging on renal function [154,155]. For example, adults with diabetes have a greater decrease in GFR over time than those without diabetes [156] and the concomitant use of nonsteroidal anti-inflammatory drugs with ACE inhibitors/angiotensin receptor antagonists and diuretics significantly increase the risk of renal impairment [157,158]. The Baltimore Longitudinal Study of Ageing found that up to 33% of adults without hypertension did not have any reduction in renal function over a period of 23 years [159]. McLean and 5.1


9


E. Reeve et al.

LeCouteur’s 2004 review concluded that there does appear to be a reduction in renal function with age, but it is less than previously thought in people without any disease or intake of nephrotoxic drugs that can affect kidney function [5]. Recently, several literature reviews have been conducted to build pharmacokinetic modeling databases in an effort to pool all available data on the potential pharmacokinetic implications in different states, such as different age groups and different diseases. Aymanns et al. [160] identified, using their database [161], 127 drugs, which had had their pharmacokinetic parameters analyzed for purely age-related changes. They found that these drugs had an average prolongation in their half-lives of 39% (± 61%). The pharmacokinetic database developed by Ginsberg et al. [20] found a slightly greater increase in the average half-life of drugs in older adults, with those aged 80 -- 84 having an average increase of 60% in their half-life (in comparison to those aged < 60). There are, however, many variables such as the aforementioned disease states and medications that can affect renal function. Interindividual variability is high in older adults and prediction of clearance based on overall datasets is poor [20]. While healthy older adults may have a relatively preserved baseline renal function, there is evidence that renal function reserve (the ability of the kidneys to increase GFR in response to protein load) is reduced even in healthy older adults. An early study with participants up to 80 years found that renal function reserve was preserved with aging [162]. However, a study looking at adults aged > 80 years found that there was a slight reduction in the CrCl of older adults compared to younger adults, though this was still within the normal range (80.4 ± 18.2 ml/min) but renal function reserve (measured by response to appropriate vasodilating stimuli) was significantly reduced [163]. The young adult subjects responded to the vasodilating stimuli with GFR increases of 26 ml/min, while the older adult group showed almost no response, with an increase of only 3 ml/min. This aligns with the knowledge that there is enhanced susceptibility to acute renal failure, impaired recovery of kidney function after acute failure and accelerated renal disease with aging [164]. Recently, the effect of frailty on renal elimination has been studied in a pharmacokinetic modeling analysis of gentamicin. Using gentamicin concentrations and clinical data from two prospective observational inpatient studies (n = 38 older adults), Johnston et al. [165] found that frail patients (defined using the Reported Edmonton Frail Scale score) had ~ 12% lower gentamicin clearance, after accounting for the effect of renal function and weight. As previously described, several comorbidities and cardiovascular risk factors negatively affecting renal function are common in older age. Hypertension is present in more than two thirds of older adults [166], and approximately one quarter have diabetes [167]. In the US, over one third of adults > 70 years old have stage III or IV chronic kidney disease (CKD) [168]. Therefore, regardless of whether reduced renal function is caused purely through the aging process or due to comorbidities, the average 10

population of older adults will have reduced renal function [155,156]. Hence, it is prudent to consider that medications eliminated through renal excretion may have reduced elimination when administered to an older adult, and dosing of these drugs should be guided by the individual patient’s GFR. Longterm medications should be regularly reviewed with recurrent checking of the patient’s GFR as they age and have changes to medications and other risk factors. Where possible, therapeutic drug monitoring should be engaged to guide dosing (in combination with clinical indicators). Estimation of a patient’s GFR is, however, complicated. It is important to emphasize that assessment of renal function of older adults should not rely on measurement of serum creatinine concentrations as the production of creatinine is related to muscle mass, which as discussed earlier is reduced in older adults [9]. Several formulas for calculating estimated GFR (eGFR), which take into account various parameters, exist. By far the most common method is the Cockcroft--Gault formula, which takes into account serum creatinine, age, weight and sex; however, this has been shown to systematically underestimate GFR in older adults and as such its routine use has been questioned [5,12,106,163]. Newer formulas, such as the Modification of Diet in Renal Disease (based on serum creatinine, age, ethnicity, and sex) or the CKD Epidemiology Collaboration (CKD-EPI, based on serum creatinine, age and sex), may be more accurate in older adults [169-171]; however, further validation studies of these measures as a guide for drug dosing are required. While the Cockcroft--Gault formula is known to be flawed, there is more data and experience to support dosing according to these results than the newer calculations [12]. Of note, there is very little data pertaining to older adults aged > 85. In the pharmacokinetic database developed by Ginsberg et al. [20], there was not a statistically significant difference in clearance of medications in those aged > 85 when compared to the reference group. The authors report that this is most likely due to the small number of participants in this age group in the trials, though it is also noted that it may be because the 85+-year olds who enter into pharmacokinetic studies are particularly fit and healthy. It must also be considered that the affect of aging on renal function may not be consistent, and the oldest of older adults may not be consistent with those aged 65 -- 85. While high blood pressure is known to be associated with reduced renal function, a study into the effect of blood pressure in adults older than 85 found that high blood pressure was not associated with reduced renal function, and in fact low blood pressure was associated with accelerated decline in renal function [172].

Other effects of renal disease on drug disposition

5.2

CKD is historically known to alter clearance of drugs that are eliminated via the kidneys, but it can also alter other stages of drug disposition and non-renal clearance of drugs. Studies have indicated increased bioavailability through downregulation of



Pharmacokinetic changes Greatest clinical significance: • Reduced clearance of drugs undergoing Phase I metabolism • Reduced elimination of renally cleared drugs


High inter-individual variability in organ/system function and homeostasis

Pharmacodynamic changes • Both increased and reduced sensitivity to drugs

Other influences on pharmacokinetics • Co-morbidities (including drug-disease interactions) • Co-medications (including drug-drug interactions) • Frailty

All older adults should be treated with a tailored approach according to clinical response (including both benefits and adverse drug reactions) supplemented with knowledge of their renal function, comorbidities and other medications. The dose and appropriateness of medication choice should be reviewed regularly.

Figure 1. Pharmacokinetic and other considerations for medication use in older adults.

enzymes (decreasing first-pass metabolism) and downregulation of efflux transporters (e.g., P-gp), altered distribution due to conformational changes in plasma albumin and decreased hepatic metabolism due to downregulation of enzymes [173,174]. The underlying mechanisms of these changes are not completely clear, but the predominant explanation is that accumulation of uremic toxins (including urea, parathyroid hormone, indoxyl sulfate and cytokines) may cause transcriptional or translational modifications or may directly act on the metabolic pathways (e.g., direct inhibition) [173]. A review conducted in 2008 found both animal and human studies, which demonstrate an effect of CKD on drug metabolism. There is the strongest evidence of suppression (either through reduced expression or direct inhibition) of the CYP enzymes 2C9, 2C19 and 3A4 and acetylation enzymes (e.g., N-acetyl-transferase) and the effect is clinically significant. For example, the non-renal clearance of verapamil (a CYP3A4 substrate) is reduced by over 50% and procainamide (metabolized by N-acetyl-transferase) is reduced by 60% in adults with renal failure [174]. A recently published in vitro study involving administration of four uremic toxins demonstrated > 50% decreases in the activities of CYP1A2, CYP2C9, CYP2E1, CYP3A4 and glucuronidation enzymes UGT1A1, UGT1A9 and UGT2B7 [175]. CKD can also affect renal metabolism. A recent study in rats found that the expression of CYP1A within the kidneys was significantly reduced (by 48%) while CYP3A was unchanged [176]. 6.

Conclusion

There are many physiological and pathophysiological ageassociated changes potentially affecting drug disposition.

The most clinically significant alterations are those affecting the clearance of medications. Absorption of drugs may be affected by reduced gastric acidity, longer transit times, changes to permeability and reduced first-pass metabolism. Non-oral administration of medications and administration via enteral tubes requires special attention in older adults. Changes in body composition and protein binding with aging can affect peak plasma concentrations; however, effect on total exposure is not significant for most medications. Clearance via Phase I metabolism or renal clearance is generally decreased in older adults, with consequently greater total exposure to the drugs. There is, however, large inter-individual variation and so the exact changes that occur with aging and resultant pharmacokinetic parameters of drugs are hard to define. In most cases, multiple factors will affect the benefits and harms of medication use in older adults. For example, methadone used for chronic pain in older adults has resulted in a large number of deaths. Methadone has a long half--life, which makes it susceptible to accumulation and it is also known to have large interindividual variability in pharmacokinetics. Increased risk of toxicity has been associated with age > 65 (most likely due to reduced metabolism via CYP3A4 enzymes), cancer (which can increase a1-acid glycoprotein, which methadone is highly protein bound to, further increasing its half-life) and concomitant use of certain medications (which can inhibit CYP3A4) [177-179]. Additionally, aging can also result in pharmacodynamic changes, which can result in increased adverse drug reactions and decreased efficacy independent of pharmacokinetic alterations (Figure 1). Therefore, all older adults should be treated with a tailored approach according to clinical response (including both


11

E. Reeve et al.

benefits and adverse drug reactions) supplemented with knowledge of their GFR, comorbidities and other medications with the dose and appropriateness of medication choice reviewed regularly.


7.

Expert opinion

A substantial amount of work has been conducted over the last 30 -- 40 years to address whether advancing age significantly affects drug disposition in humans. Despite significant advances in the field, particularly regarding drug metabolism and elimination, a number of issues remain unsolved. This prevents prescribers from optimally managing medical conditions in the ever-growing older population. First, the conduct of pharmacokinetic studies as part of drug development programs in the pharmaceutical industry remains largely confined to subjects aged 18 -- 65 years. The often stringent inclusion and exclusion criteria in such studies means that virtually all recruited older patients belong to the ‘healthier’ range, that is, very few, if any, comorbidities, preserved renal function and limited number of concomitantly prescribed drugs. In essence, data obtained from these studies are potentially quite different from what it might be expected if the same studies were conducted in the majority of patients managed in clinical practice, a cohort of frail older subjects with significant inter-individual organ function variability and polypharmacy. Second, published studies on drug disposition and pharmacokinetics specifically conducted in older subjects, albeit scientifically sound, have primarily focused on a number of relatively old drugs, that is, propranolol, lidocaine, digoxin, procainamide and cimetidine. While some of these drugs might still have a place in current clinical practice it is concerning that little knowledge is available regarding relatively new drugs and drug classes extensively prescribed for the management of either acute or chronic conditions in this population. These include the biologics, new oral anticoagulant and antidiabetic drugs, antivirals and anticancer drugs. Third, virtually, no information on age-associated changes in drug disposition and pharmacokinetics is available in subjects > 80 years, the fastest growing subgroup within the older population. This lack of information parallels to a certain extent the paucity of data on changes, if any, in the

12

structure and function of key metabolizing and clearance organs, for example, liver and kidney, in the same age group. What can be done to overcome these hurdles? At a time when global financial constraints limit the design and conduct of large Phase II and Phase III studies including a sufficient number of older participants, several alternative strategies might improve our knowledge in this area. A number of professional societies in Europe advocate an increased participation of older patients in clinical research. The running of pharmacokinetic studies in a more naturalistic setting, for example, patients with different degrees of frailty, organ function and reserve and number of concomitant drugs, might still yield important information provided that the individual impact of these confounding factors is rigorously accounted for by means of statistical modeling. A number of computational approaches might complement the proposed clinical studies. For example, coupling in vitro--in vivo extrapolation with physiology-based pharmacokinetic modeling and simulation has been recently shown to predict relevant pharmacokinetic parameters in older adults [180]. Similarly, the use of semi-physiological approaches that allow extrapolation of pharmacokinetic data from a healthy state to different degrees of renal and liver impairment might prove useful in this context [181]. It is, however, important to emphasize that the success and clinical use of these approaches largely depend on a thorough understanding of the main physiological and biochemical changes occurring with advancing age. As previously described, this knowledge remains limited in people > 80 years. In the opinion of the authors, a close collaboration between pharmaceutical industry, academia and research organizations, patient groups and professional societies will be instrumental in further advancing our knowledge on drug disposition and pharmacokinetics in old age over the next 10 -- 20 years.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.



Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.


1.

United Nations Department of Economic and Social Affairs Population Division. World population ageing 2013. United Nations publication, New York: 2013

2.

Fedarko NS. The biology of aging and frailty. Clin Geriatr Med 2011;27:27-37

3.

Richter C. Oxidative damage to mitochondrial DNA and its relationship to ageing. Int J Biochem Cell Biol 1995;27:647-53

4.

5.

6.

Higami Y, Shimokawa I. Apoptosis in the aging process. Cell Tissue Res 2000;301:125-32 McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev 2004;56:163-84 Sera LC, McPherson ML. Pharmacokinetics and pharmacodynamic changes associated with aging and implications for drug therapy. Clin Geriatr Med 2012;28:273-86

7.

Kirkwood TBL, Austad SN. Why do we age? Nature 2000;408:233-8

8.

Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol 2004;57:6-14

9.

Amella EJ. Presentation of illness in older adults. If you think you know what you’re looking for, think again. AORN J 2006;83:372-89

10.

Schmader KE, Baron R, Haanpaa ML, et al. Treatment considerations for elderly and frail patients with neuropathic pain. Mayo Clin Proc 2010;85:S26-32

11.

12.

13.

14.

different?: a review of the specific changes. Drugs Aging 2011;28:617-33 15.

16.

17.

18.

19.

20.

.

21.

22.

Schmucker D. Liver function and phase I drug metabolism in the elderly. Drugs Aging 2001;18:837-51

..

Hilmer SN. ADME-tox issues for the elderly. Expert Opin Drug Metab Toxicol 2008;4:1321-31

23.

Nelson EA, Dannefer D. Aged heterogeneity: fact or fiction? The fate of diversity in gerontological research. Gerontologist 1992;32:17-23 Deneer VHM, Van Hemel NM. Is antiarrhythmic treatment in the elderly

26.

Hurwitz A, Brady DA, Schaal S, et al. Gastric acidity in older adults. JAMA 1997;278:659-62

27.

Lehnert T, Heider D, Leicht H, et al. Review: health care utilization and costs of elderly persons with multiple chronic conditions. Med Care Res Rev 2011;68:387-420

Nakamura K, Ogoshi K, Makuuchi H. Influence of aging, gastric mucosal atrophy and dietary habits on gastric secretion. Hepatogastroenterology 2006;53:624-8

28.

Australian Institute of Health and Welfare. Older Australia at a glance. AIHW; Canberra: 2007

Geller AM, Zenick H. Aging and the environment: a research framework. Environ Health Perspect 2005;113:1257-62

29.

Schmucker D. Aging and drug disposition: an update. Pharmacol Rev 1985;37:133-48

30.

Hurwitz A, Ruhl CE, Kimler BF, et al. Gastric function in the elderly: effects on absorption of ketoconazole. J Clin Pharmacol 2003;43:996-1002

31.

Stangier J, Stahle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008;47:47-59

32.

Gidal BE. Drug absorption in the elderly: biopharmaceutical considerations for the antiepileptic drugs. Epilepsy Res 2006;68(Suppl 1):S65-9

33.

Abruzzo CW, Macasieb T, Weinfeld R, et al. Changes in the oral absorption characteristics in man of dipotassium clorazepate at normal and elevated gastric pH. J Pharmacokinet Biopharm 1977;5:377-90

34.

O’Mahony D, O’Leary P, Quigley EM. Aging and intestinal motility. Drugs Aging 2002;19:515-27

35.

Drozdowski L, Thomson AB. Aging and the intestine. World J Gastroenterol 2006;12:7578-84

36.

Wilding I, Davis S, Hardy J, et al. Relationship between systemic drug absorption and gastrointestinal transit after the simultaneous oral administration of carbamazepine as a controlled-release system and as a suspension of 15Nlabelled drug to healthy volunteers. Br J Clin Pharmacol 1991;32:573-9

37.

Yeh K, August T, Bush D, et al. Pharmacokinetics and bioavailability of Sinemet CR: a summary of human studies. Neurology 1989;39:25-38

38.

Kaiko RF, Benzinger DP, Fitzmartin RD, et al. Pharmacoltinetic-pharmacodynamic

Shi S, Morike K, Klotz U. The clinical implications of ageing for rational drug therapy. Eur J Clin Pharmacol 2008;64:183-99

Prescriptions dispensed in the community. Statistics for 1996 to 2006. The Information Centre (Health Care), England: 2007 Mangoni AA. Predicting and detecting adverse drug reactions in old age: challenges and opportunities. Expert Opin Drug Metab Toxicol 2012;8:527-30 Ginsberg G, Hattis D, Russ A, Sonawane B. Pharmacokinetic and pharmacodynamic factors that can affect sensitivity to neurotoxic sequelae in elderly individuals. Environ Health Perspect 2005;113:1243-9 An analysis of the changes in half-lives of drugs based on the method of elimination from a therapeutic drug pharmacokinetic data set. Hochhaus G, Barrett JS, Derendorf H. Evolution of pharmacokinetics and pharmacokinetic/dynamic correlations during the 20th century. J Clin Pharmacol 2000;40:908-17 Mangoni AA. The impact of advancing age on P-glycoprotein expression and activity: current knowledge and future directions. Expert Opin Drug Metab Toxicol 2007;3:315-20 A comprehensive review of the effect of age on P-glycoprotein expression and activity. Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 2009;41:67-76

24.

Feldman M. The mature stomach: still pumping out acid? JAMA 1997;278:681-2

25.

Blechman MB, Gelb AM. Aging and gastrointestinal physiology. Clin Geriatr Med 1999;15:429-38


13

E. Reeve et al.

relationships of controlled-release oxycodone. Clin Pharmacol Ther 1996;59:52-61 39.


40.

41.

Orr WC, Chen CL. Aging and neural control of the GI tract: IV. Clinical and physiological aspects of gastrointestinal motility and aging. Am J Physiol Gastrointest Liver Physiol 2002;283:G1226-31 Gainsborough N, Maskrey VL, Nelson ML, et al. The association of age with gastric emptying. Age Ageing 1993;22:37-40 Valentini L, Ramminger S, Haas V, et al. Small intestinal permeability in older adults. Physiol Rep 2014;2:e00281

42.

Turnheim K. Drug therapy in the elderly. Exp Gerontol 2004;39:1731-8

43.

Dobson PD, Kell DB. Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? Nat Rev Drug Discov 2008;7:205-20

44.

Armbrecht HJ, Boltz MA, Kumar VB. Intestinal plasma membrane calcium pump protein and its induction by 1,25 (OH)(2)D(3) decrease with age. Am J Physiol 1999;277:G41-7

pharmacodynamics of nifedipine. Br J Clin Pharmacol 1988;25:297-305 53.

Kelly J, McGarry K, O’Malley K, O’Brien E. Bioavailability of labetalol increases with age. Br J Clin Pharmacol 1982;14:304-5

54.

Storstein L, Larsen A, Midtbø K, Saevareid L. Pharmacokinetics of calcium blockers in patients with renal insufficiency and in geriatric patients. Acta Med Scand Suppl 1983;681:25-30

55.

Castleden C, George C. The effect of ageing on the hepatic clearance of propranolol. Br J Clin Pharmacol 1979;7:49-54

56.

Vestal R, Wood A, Branch R, et al. Effects of age and cigarette smoking on propranolol disposition. Clin Pharmacol Ther 1979;26:8

57.

Colangelo PM, Blouin RA, Steinmetz JE, et al. Age and propranolol stereoselective disposition in humans. Clin Pharmacol Ther 1992;51:489-94

58.

Toyoshima M, Inada M, Kameyama M. Effects of aging on intracellular transport of vitamin B12 (B12) in rat enterocytes. J Nutr Sci Vitaminol(Tokyo) 1983;29:1-10

59.

46.

Russell RM. Changes in gastrointestinal function attributed to aging. Am J Clin Nutr 1992;55:1203S-7S

60.

47.

Doherty M, Charman W. The mucosa of the small intestine. Clin Pharmacokinet 2002;41:235-53

48.

Gupta S. P-glycoprotein expression and regulation. Age-related changes and potential effects on drug therapy. Drugs Aging 1995;7:19-29

61.

49.

ElDesoky ES. Pharmacokinetic-pharmacodynamic crisis in the elderly. Am J Ther 2007;14:488-98

62.

50.

Wilkinson GR. The effects of diet, aging and disease-states on presystemic elimination and oral drug bioavailability in humans. Adv Drug Deliv Rev 1997;27:129-59

45.

51.

Wynne H. Drug metabolism and ageing. J Br Menopause Soc 2005;11:51-6

52.

Robertson DR, Waller DG, Renwick AG, George CF. Age-related changes in the pharmacokinetics and

14

63.

64.

Schulz P, Turner-Tamiyasu K, Smith G, et al. Amitriptyline disposition in young and elderly normal men. Clin Pharmacol Ther 1983;33:360-6 Nation R, Vine J, Triggs E, Learoyd B. Plasma level of chlormethiazole and two metabolites after oral administration to young and aged human subjects. Eur J Clin Pharmacol 1977;12:137-45

65.

Macdonald N, Sioufi A, Howie C, et al. The effects of age on the pharmacokinetics and pharmacodynamics of single oral doses of benazepril and enalapril. Br J Clin Pharmacol 1993;36:205-9

66.

Abe M, Smith J, Urae A, et al. Pharmacokinetics of oseltamivir in young and very elderly subjects. Ann Pharmacother 2006;40:1724-30

67.

Warrington JS, Greenblatt DJ, von Moltke LL. Age-related differences in CYP3A expression and activity in the rat liver, intestine, and kidney. J Pharmacol Exp Ther 2004;309:720-9

68.

Palasz A, Wiaderkiewicz A, Wiaderkiewicz R, et al. Age-related changes in the mRNA levels of CYP1A1, CYP2B1/2 and CYP3A1 isoforms in rat small intestine. Genes Nutr 2012;7:197-207

69.

Bolling BW, Blumberg JB, Chen C-YO. Microsomal quercetin glucuronidation in rat small intestine depends on age and segment. Drug Metab Dispos 2011;39:1406-14

70.

Williams NT. Medication administration through enteral feeding tubes. Am J Health Syst Pharm 2008;65:2347-57 A review of medication administration via enteral tubes.

.

71.

Elia M, Stratton R, Holden C, et al. Home artificial nutritional support: the value of the British Artificial Nutrition Survey. Clin Nutr 2001;20:61-6

72.

Baillie S, Bateman D, Coates P, Woodhouse K. Age and the pharmacokinetics of morphine. Age Ageing 1989;18:258-62

Pironi L, Candusso M, Biondo A, et al. Prevalence of home artificial nutrition in Italy in 2005: a survey by the Italian Society for Parenteral and Enteral Nutrition (SINPE). Clin Nutr 2007;26:123-32

73.

Leenen FH, Coletta E. Pharmacokinetic and antihypertensive profile of amlodipine and felodipine-ER in younger versus older patients with hypertension. J Cardiovasc Pharmacol 2010;56:669-75

Magnuson BL, Clifford TM, Hoskins LA, Bernard AC. Enteral nutrition and drug administration, interactions, and complications. Nutr Clin Pract 2005;20:618-24

74.

Hilmer SN, McLachlan AJ, Le Couteur DG. Clinical pharmacology in the geriatric patient. Fundam Clin Pharmacol 2007;21:217-30

Bauer LA. Interference of oral phenytoin absorption by continuous nasogastric feedings. Neurology 1982;32:570-0

75.

Lees KR, Reid JL. Age and the pharmacokinetics and pharmacodynamics of chronic enalapril treatment. Clin Pharmacol Ther 1987;41:597-602

Yeung SCA, Ensom MH. Phenytoin and enteral feedings: does evidence support an interaction? Ann Pharmacother 2000;34:896-905

76.

Lubart E, Berkovitch M, Leibovitz A, et al. Phenytoin blood concentrations in hospitalized geriatric patients: oral versus

Taguchi M, Nozawa T, Mizumaki K, et al. Nonlinear mixed effects model analysis of the pharmacokinetics of metoprolol in routinely treated Japanese patients. Biol Pharm Bull 2004;27:1642-8



people: recommendations for prescribing. Drugs Aging 2008;25:415-43


nasogastric feeding tube administration. Ther Drug Monit 2010;32:185-8 77.

Lubart E, Berkovitch M, Leibovitz A, et al. Pharmacokinetics of ciprofloxacin in hospitalized geriatric patients: comparison between nasogastric tube and oral administration. Ther Drug Monit 2013;35:653-6

78.

Fish DN, Abraham E. Pharmacokinetics of a clarithromycin suspension administered via nasogastric tube to seriously ill patients. Antimicrob Agents Chemother 1999;43:1277-80

79.

80.

81.

82.

83.

99.

90.

Barrons R, Pegram A, Borries A. Inhaler device selection: special considerations in elderly patients with chronic obstructive pulmonary disease. Am J Health Syst Pharm 2011;68:1221-32

100. Ravaglia G, Morini P, Forti P, et al. Anthropometric characteristics of healthy Italian nonagenarians and centenarians. Br J Nutr 1997;77:9-17

91.

Allen SC, Jain M, Ragab S, Malik N. Acquisition and short-term retention of inhaler techniques require intact executive function in elderly subjects. Age Ageing 2003;32:299-302

92.

Ho SF, O’Mahony MS, Steward JA, et al. Inhaler technique in older people in the community. Age Ageing 2004;33:185-8

93.

Fulop T Jr, Worum I, Csongor J, et al. Body composition in elderly people. I. Determination of body composition by multiisotope method and the elimination kinetics of these isotopes in healthy elderly subjects. Gerontology 1985;31:6-14

Roskos KV, Maibach HI, Guy RH. The effect of aging on percutaneous absorption in man. J Pharmacokinet Biopharm 1989;17:617-30

84.

Vanakoski J, Seppa¨la¨ T. Heat exposure and drugs. Clin Pharmacokinet 1998;34:311-22

85.

Luebberding S, Krueger N, Kerscher M. Age-related changes in skin barrier function - quantitative evaluation of 150 female subjects. Int J Cosmet Sci 2013;35:183-90

86.

Pride N. Ageing and changes in lung mechanics. Eur Respir J 2005;26:563-5

87.

Fain SB, Altes TA, Panth SR, et al. Detection of age-dependent changes in healthy adult lungs with diffusionweighted 3He MRI. Acad Radiol 2005;12:1385-93

88.

Crompton GK, Barnes PJ, Broeders M, et al. The need to improve inhalation technique in Europe: a report from the aerosol drug management improvement team. Respir Med 2006;100:1479-94

Kaestli LZ, Wasilewski-Rasca AF, Bonnabry P, Vogt-Ferrier N. Use of transdermal drug formulations in the elderly. Drugs Aging 2008;25:269-80

Konda S, Meier-Davis SR, Cayme B, et al. Age-related percutaneous penetration part 2: effect of age on dermatopharmacokinetics and overview of transdermal products. Skin Therapy Lett 2012;17:5-7

Gupta P, O’Mahony MS. Potential adverse effects of bronchodilators in the treatment of airways obstruction in older

Sillanpa¨a¨ E, Cheng S, Ha¨kkinen K, et al. Body composition in 18-to 88-year-old adults -- comparison of multifrequency bioimpedance and dual-energy X-ray absorptiometry. Obesity 2014;22:101-9

89.

Mitchell J. Oral dosage forms that should not be crushed. Last update: January 2014 Available from: www.ismp. org/tools/donotcrush.pdf

Van Nimmen NF, Poels KL, Menten JJ, et al. Fentanyl transdermal absorption linked to pharmacokinetic characteristics in patients undergoing palliative care. J Clin Pharmacol 2010;50:667-78

a cross-sectional study. Eur J Nutr 2014;53:167-76

94.

95.

96.

..

97.

98.

Kyle UG, Genton L, Hans D, et al. Total body mass, fat mass, fat-free mass, and skeletal muscle in older people: cross-sectional differences in 60-year-old persons. J Am Geriatr Soc 2001;49:1633-40 Hughes VA, Frontera WR, Wood M, et al. Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health. J Gerontol A Biol Sci Med Sci 2001;56:B209-17 Thompson CM, Johns DO, Sonawane B, et al. Database for physiologically based pharmacokinetic (PBPK) modeling: physiological data for healthy and health-impaired elderly. J Toxicol Environ Health B Crit Rev 2009;12:1-24 Comprehensive review and development of a physiologically based pharmacokinetic database. Hughes VA, Roubenoff R, Wood M, et al. Anthropometric assessment of 10-y changes in body composition in the elderly. Am J Clin Nutr 2004;80:475-82 Ga´ba A, Prˇidalova´ M. Age-related changes in body composition in a sample of Czech women aged 18--89 years:


101. Kuczmarski MF, Kuczmarski RJ, Najjar M. Descriptive anthropometric reference data for older Americans. J Am Diet Assoc 2000;100:59-66 102. Newman AB, Lee JS, Visser M, et al. Weight change and the conservation of lean mass in old age: the health, aging and body composition study. Am J Clin Nutr 2005;82:872-8 103. Mu¨hlberg W, Platt D. Age-dependent changes of the kidneys: pharmacological implications. Gerontology 1999;45:243-53 104. Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002;71:115-21 .. Description of a systematic approach of exposure and equilibration time concepts to determine the effect of changes in protein binding. 105. de Vries OJ, Peeters G, Elders P, et al. The elimination half-life of benzodiazepines and fall risk: two prospective observational studies. Age Ageing 2013;42:764-70 106. Fehrman-Ekholm I, Skeppholm L. Renal function in the elderly (>70 years old) measured by means of iohexol clearance, serum creatinine, serum urea and estimated clearance. Scand J Urol Nephrol 2004;38:73-7 107. Schmucker DL. Liver function and phase I drug metabolism in the elderly: a paradox. Drugs Aging 2001;18:837-51 108. Greenblatt D. Reduced serum albumin concentration in the elderly: a report from the Boston collaborative drug surveillance program. J Am Geriatr Soc 1979;27:20-2 109. Campion EW, Delabry LO, Glynn RJ. The effect of age on serum albumin in healthy males: report from the normative aging study. J Gerontol 1988;43:M18-20 110. Chin PKL, Jensen BP, Larsen HS, Begg EJ. Adult age and ex vivo protein

15

E. Reeve et al.


binding of lorazepam, oxazepam and temazepam in healthy subjects. Br J Clin Pharmacol 2011;72:985-9

123. Le Couteur DG, McLean AJ. The aging liver. Clin Pharmacokinet 1998;34:359-73

111. Jensen BP, Chin PKL, Roberts RL, Begg EJ. Influence of adult age on the total and free clearance and protein binding of (R)- and (S)-warfarin. Br J Clin Pharmacol 2012;74:797-805

124. Cotreau MM, von Moltke LL, Greenblatt DJ. The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet 2005;44:33-60

112. Fu A, Nair KS. Age effect on fibrinogen and albumin synthesis in humans. Am J Physiol 1998;275:E1023-30

125. Wynne HA, Cope LH, Mutch E, et al. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology 1989;9:297-301

113. Gunasekera J, Lee D, Jones L, et al. Does albumin fall with increasing age in the absence of disease. Age Ageing 1996;25:P29 114. Grandison MK, Boudinot FD. Age-related changes in protein binding of drugs: implications for therapy. Clin Pharmacokinet 2000;38:271-90 115. Butler J, Begg E. Free drug metabolic clearance in elderly people. Clin Pharmacokinet 2008;47:297-321 . A comprehensive review and re-analysis of the elimination of medications based on their free drug concentration. 116. Patterson M, Heazelwood R, Smithurst B, Eadie M. Plasma protein binding of phenytoin in the aged: in vivo studies. Br J Clin Pharmacol 1982;13:423-5 117. Boudinot SG, Funderburg ED, Boudinot FD. Effects of age on the pharmacokinetics of piroxicam in rats. J Pharm Sci 1993;82:254-7 118. Karim A, Noveck R, McMahon FG, et al. Oxaprozin and piroxicam, nonsteroidal antiinflammatory drugs with long half-lives: effect of protein-binding differences on steady-state pharmacokinetics. J Clin Pharmacol 1997;37:267-78 119. Cusack B, O’Malley K, Lavan J, et al. Protein binding and disposition of lignocaine in the elderly. Eur J Clin Pharmacol 1985;29:323-9 120. Krishna DR, Klotz U. Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet 1994;26:144-60 121. Anders M. Metabolism of drugs by the kidney. Kidney Int 1980;18:636-47 122. Hiraoka H, Yamamoto K, Miyoshi S, et al. Kidneys contribute to the extrahepatic clearance of propofol in humans, but not lungs and brain. Br J Clin Pharmacol 2005;60:176-82

16

126. Zoli M, Magalotti D, Bianchi G, et al. Total and functional hepatic blood flow decrease in parallel with ageing. Age Ageing 1999;28:29-33 127. Zeeh J, Platt D. The aging liver: structural and functional changes and their consequences for drug treatment in old age. Gerontology 2002;48:121-7 128. Woodhouse K, Wynne H. Age-related changes in liver size and hepatic blood flow. Clin Pharmacokinet 1988;15:287-94 129. McLachlan AJ, Pont LG. Drug metabolism in older people -- a key consideration in achieving optimal outcomes with medicines. J Gerontol A Biol Sci Med Sci 2012;67:175-80 130. Le Couteur DG, Fraser R, Kilmer S, et al. The hepatic sinusoid in aging and cirrhosis. Clin Pharmacokinet 2005;44:187-200 131. Le Couteur DG, Warren A, Cogger VC, et al. Old age and the hepatic sinusoid. Anat Rec 2008;291:672-83 .. A comprehensive review of the structural changes in the liver with ageing. 132. Hilmer SN, Cogger VC, Fraser R, et al. Age-related changes in the hepatic sinusoidal endothelium impede lipoprotein transfer in the rat. Hepatology 2005;42:1349-54

135. Mitchell SJ, Huizer-Pajkos A, Cogger VC, et al. The influence of old age and poloxamer-407 on the hepatic disposition of diazepam in the isolated perfused rat liver. Pharmacology 2012;90:233-41 136. Parkinson A, Mudra DR, Johnson C, et al. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol Appl Pharmacol 2004;199:193-209 137. Sotaniemi EA, Arranto AJ, Pelkonen O, Pasanen M. Age and cytochrome P450linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions[ast]. Clin Pharmacol Ther 1997;61:331-9 138. Battino D, Croci D, Mamoli D, et al. Influence of aging on serum phenytoin concentrations: a pharmacokinetic analysis based on therapeutic drug monitoring data. Epilepsy Res 2004;59:155-65 139. Bebia Z, Buch SC, Wilson JW, et al. Bioequivalence revisited: influence of age and sex on CYP enzymes. Clin Pharmacol Ther 2004;76:618-27 140. Schmucker DL. Age-related changes in liver structure and function: implications for disease? Exp Gerontol 2005;40:650-9 141. Twum-Barima Y, Finnigan T, Habash AI, et al. Impaired enzyme induction by rifampicin in the elderly. Br J Clin Pharmacol 1984;17:595-7 142. Kinirons M, O’Mahony M. Drug metabolism and ageing. Br J Clin Pharmacol 2004;57:540-4 143. Hines LE, Murphy JE. Potentially harmful drug-drug interactions in the elderly: a review. Am J Geriatr Pharmacother 2011;9:364-77

133. Hilmer SN, Cogger VC, Muller M, Le Couteur DG. The hepatic pharmacokinetics of doxorubicin and liposomal doxorubicin. Drug Metab Dispos 2004;32:794-9

144. Fromm MF, Dilger K, Busse D, et al. Gut wall metabolism of verapamil in older people: effects of rifampicinmediated enzyme induction. Br J Clin Pharmacol 1998;45:247-55

134. Mitchell SJ, Huizer-Pajkos A, Cogger VC, et al. Age-related pseudocapillarization of the liver sinusoidal endothelium impairs the hepatic clearance of acetaminophen in rats. J Gerontol A Biol Sci Med Sci 2011;66A:400-8

145. Herd B, Wynne H, Wright P, et al. The effect of age on glucuronidation and sulphation of paracetamol by human liver fractions. Br J Clin Pharmacol 1991;32:768-70


146. Court MH. Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme


angiotensin receptor blockers with nonsteroidal anti-inflammatory drugs and risk of acute kidney injury: nested casecontrol study. BMJ 2013;346:e8525


inducers, and genetic polymorphism using the human liver bank as a model system. Drug Metab Rev 2010;42:209-24 147.

Divoll M, Greenblatt DJ, Harmatz JS, Shader RI. Effect of age and gender on disposition of temazepam. J Pharm Sci 1981;70:1104-7

159.

Lindeman R, Tobin J, Shock N. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985;33:278-85

148.

Ghabrial H, Desmond P, Watson K, et al. The effects of age and chronic liver disease on the elimination of temazepam. Eur J Clin Pharmacol 1986;30:93-7

160.

Aymanns C, Keller F, Maus S, et al. Review on pharmacokinetics and pharmacodynamics and the aging kidney. Clin J Am Soc Nephrol 2010;5:314-27 Analysis of results from a pharmacokinetic database of changes in the half-lives of medications in older adults.

149.

Smith R, Divoll M, Gillespie W, Greenblatt D. Effect of subject age and gender on the pharmacokinetics of oral triazolam and temazepam. J Clin Psychopharmacol 1983;3:172-5

150.

Wynne HA, Cope LH, Herd B, et al. The association of age and frailty with paracetamol conjugation in man. Age Ageing 1990;19:419-24

151.

Wynne H, Yelland C, Cope L, et al. The association of age and frailty with the pharmacokinetics and pharmacodynamics of metoclopramide. Age Ageing 1993;22:354-9

152.

Williams F, Wynne H, Woodhouse K, Rawlins M. Plasma aspirin esterase: the influence of old age and frailty. Age Ageing 1989;18:39-42

153.

Mitchell SJ, Kane AE, Hilmer SN. Age-related changes in the hepatic pharmacology and toxicology of paracetamol. Curr Gerontol Geriatr Res 2011;2011:624156

154.

Fliser D, Franek E, Ritz E. Renal function in the elderly–is the dogma of an inexorable decline of renal function correct? Nephrol Dial Transplant 1997;12:1553-5

155.

Sesso R, Prado F, Vicioso B, Ramos LR. Prospective study of progression of kidney dysfunction in communitydwelling older adults. Nephrology 2008;13:99-103

156.

157.

158.

Tsaih S-W, Korrick S, Schwartz J, et al. Lead, diabetes, hypertension, and renal function: the normative aging study. Environ Health Perspect 2004;112(11):1178-82 Loboz KK, Shenfield GM. Drug combinations and impaired renal function--the ‘triple whammy’. Br J Clin Pharmacol 2005;59:239-43 Lapi F, Azoulay L, Yin H, et al. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and

..

161.

Keller F, Frankewitsch T, Zellner D, et al. Standardized structure and modular design of a pharmacokinetic database. Comput Methods Programs Biomed 1998;55:107-15

162.

Fliser D, Zeier M, Nowack R, Ritz E. Renal functional reserve in healthy elderly subjects. J Am Soc Nephrol 1993;3:1371-7

163.

Esposito C, Plati A, Mazzullo T, et al. Renal function and functional reserve in healthy elderly individuals. J Nephrol 2007;20:617-25

164.

Schmitt R, Coca S, Kanbay M, et al. Recovery of kidney function after acute kidney injury in the elderly: a systematic review and meta-analysis. Am J Kidney Dis 2008;52:262-71

165.

Johnston C, Hilmer S, McLachlan A, et al. The impact of frailty on pharmacokinetics in older people: using gentamicin population pharmacokinetic modeling to investigate changes in renal drug clearance by glomerular filtration. Eur J Clin Pharmacol 2014;70:549-55

estimating equations. Curr Opin Nephrol Hypertens 2010;19:298 171. Stevens LA, Schmid CH, Greene T, et al. Comparative performance of the CKD epidemiology collaboration (CKDEPI) and the modification of diet in renal disease (MDRD) study equations for estimating GFR levels Above 60 mL/ min/1.73m2. Am J Kidney Dis 2010;56:486-95 172. van Bemmel T, Woittiez K, Blauw GJ, et al. Prospective study of the effect of blood pressure on renal function in old age: the Leiden 85-plus study. J Am Soc Nephrol 2006;17:2561-6 173. Nolin T, Naud J, Leblond F, Pichette V. Emerging evidence of the impact of kidney disease on drug metabolism and transport. Clin Pharmacol Ther 2008;83:898-903 174. Dreisbach AW, Lertora JJ. The effect of chronic renal failure on drug metabolism and transport. Expert Opin Drug Metab Toxicol 2008;4:1065-74 175. Barnes KJ, Rowland A, Polasek TM, Miners JO. Inhibition of human drugmetabolising cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in vitro by uremic toxins. Eur J Clin Pharmacol 2014;70:1097-106 176. Naud J, Michaud J, Beauchemin S, et al. Effects of chronic renal failure on kidney drug transporters and cytochrome P450 in rats. Drug Metab Dispos 2011;39:1363-9 177. Delgado-Guay MO, Bruera E. Management of pain in the older person with cancer. Oncology (Williston Park) 2008;22:56-61 178. Plummer JL, Gourlay GK, Cherry DA, Cousins MJ. Estimation of methadone clearance: application in the management of cancer pain. Pain 1988;33:313-22

166.

Lionakis N, Mendrinos D, Sanidas E, et al. Hypertension in the elderly. World J Cardiol 2012;4:135

167.

Kirkman MS, Briscoe VJ, Clark N, et al. Diabetes in older adults. Diabetes Care 2012;35:2650-64

179. Modesto-Lowe V, Brooks D, Petry N. Methadone deaths: risk factors in pain and addicted populations. J Gen Intern Med 2010;25:305-9

168.

Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA 2007;298:2038-47

180. Polasek TM, Patel F, Jensen BP, et al. Predicted metabolic drug clearance with increasing adult age. Br J Clin Pharmacol 2013;75:1019-28

169.

Lassiter J, Bennett WM, Olyaei AJ. Drug Dosing in Elderly Patients with Chronic Kidney Disease. Clin Geriatr Med 2013;29:657-705

170.

Stevens LA, Padala S, Levey AS. Advances in glomerular filtration rate

181. Strougo A, Yassen A, Krauwinkel W, et al. A semiphysiological population model for prediction of the pharmacokinetics of drugs under liver and renal disease conditions. Drug Metab Dispos 2011;39:1278-87


17

E. Reeve et al.


Affiliation

Emily Reeve†1 BPharm (Hons) PhD, Michael D Wiese2 BPharm PhD & Arduino A Mangoni3 PhD FRCP FRACP † Author for correspondence 1 Postdoctoral Research Associate, University of Sydney, Kolling Institute for Medical Research, School of Medicine, Cognitive Decline Partnership Centre, Ageing and Pharmacology, Level 12 Kolling building, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia Tel: +02 99264 924; Fax: +02 99264 926; E-mail: [email protected] 2 Senior Lecturer in Pharmacotherapeutics, University of South Australia, School of Pharmacy and Medical Sciences, Adelaide, SA, Australia 3 Professor of Clinical Pharmacology, Flinders University and Flinders Medical Centre, School of Medicine, Department of Clinical Pharmacology, Adelaide, Australia

18


Drug-induced liver injury in older adults.

Drug therapies in older adults (part 2).

Drug disposition alterations in liver disease: extrahepatic effects in cholestasis and nonalcoholic steatohepatitis.

Current drug treatment of hyperlipidemia in older adults.

Appropriate prescribing and important drug interactions in older adults.

Drug Burden Index in older adults: theoretical and practical issues.

Drug cessation in complex older adults: time for action.

Understanding adverse drug reactions in older adults through drug-drug interactions.

Drug-drug interactions and adverse drug reactions in polypharmacy among older adults: an integrative review.

Impact of Drug-Drug and Drug-Disease Interactions on Gait Speed in Community-Dwelling Older Adults.

[Moderate potentially drug-induced hyponatremia in older adults: benefit in drug reduction].

Multimodal neuroimaging evidence of alterations in cortical structure and function in HIV-infected older adults.

Alterations in platelet function during aging: clinical correlations with thromboinflammatory disease in older adults.

Drug disposition and liver disease.

Severe potential drug-drug interactions in older adults with dementia and associated factors.

Polypharmacy, drug-drug interactions, and potentially inappropriate medications in older adults with human immunodeficiency virus infection.

Thrombocytopenia in older adults.

Asthma in older adults.

Readability of prescription drug labels by older and younger adults.

Drug disposition and drug-drug interaction data in 2013 FDA new drug applications: a systematic review.

Implications of Recent Drug Approvals for Older Adults.

The importance of stereochemistry in drug action and disposition.

A linear recirculation model for drug disposition.

Altered hepatic blood flow and drug disposition.