Review

Alterations in drug disposition

in older adults
Emily Reeve†, Michael D Wiese & Arduino A Mangoni
†
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

Introduction physiological and pathophysiological changes can affect drug disposition.
Absorption This is particularly important in view of the extensive medication prescribing
Distribution and exposure in older adults.
Areas covered: Using a framework of the four primary pharmacokinetic pro-
Metabolism
cesses (Absorption, Distribution, Metabolism and Elimination), this review
Elimination
dis- cusses the current evidence of the pharmacokinetic changes that occur
Conclusion with aging, particularly ‘healthy aging,’ focusing on developments in this field
Expert opinion 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 metabo- lism and elimination, a number of issues remain unsolved.
In particular, lack of inclusion of older adults with multimorbidity and
those aged > 80 and mini- mal 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 cardiovascu- lar
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 peo-
ple 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 1

All rights reserved: reproduction in whole or in part not permitted
E. Reeve et
al.

prescriptions doubled over the decade of 1996 -- 2006 from

Article highlights. 21.2 to 40.8 items per person [18]. Older adults are more
● While advancing age is associated with suscep- tible to adverse drug reactions and other medication-
physiological changes to the gastrointestinal tract, the related errors, a common cause of mortality and morbidity in
effect on absorption is unlikely to be clinically this pop- ulation [19]. Given that the older adult population is
significant with the possible exception of drugs with heteroge- nous and often characterized by multimorbidity,
high first-pass metabolism. In older adults with determining what changes are purely due to aging is difficult
atrophic gastritis, or those taking acid-suppressive to establish. For example, diseases of the liver and kidney, the
medications, basic compounds may have impaired organs primarily responsible for drug metabolism and
dissolution resulting in reduced bioavailability. elimination, are more common in older adults than younger
● Changes in pharmacokinetics must be ones. Another major determinant of the pharmacokinetics of a
considered for medications with non-oral medication is the other medications that the individual is
administration as well as for medications taking, so-called drug--drug interactions [20]. The increased
administered via enteral feeding tubes. prevalence of poly- pharmacy and therefore increased
● Changes in body composition and specific potential for drug--drug interactions also make it difficult to
plasma proteins can affect the volume of distribution determine whether the altered pharmacokinetics are purely
of medications; however, this does not appear to have due to aging.
major clinical implications for the vast majority of The potential effect of age on pharmacokinetics was first
drugs. discussed at the end of the 1970s [21] and there has been
● The most clinically significant age-associated much attention paid to the topic since then. However, despite
alterations in pharmacokinetics are those affecting increased knowledge and advances in technology and techni-
drug clearance. Clearance via Phase I metabolism or ques that are used to investigate the aging process in experi-
renal clearance is generally decreased in older mental models as well as in humans, much is still unknown.
adults, with possible increased total drug exposure. For example, the knowledge of the role of P-glycoprotein (P-
● Reduced hepatic blood flow is mostly gp) in different body tissues and its interactions with med-
responsible for reduced Phase I metabolism. ications is increasing, though whether these interactions are
However, changes in the structure of the liver
affected by aging is still mostly unknown [22].
parenchyma, reducing transfer of oxygen into
hepatocytes, may be responsible for reduced
Using a framework of the four primary pharmacokinetic
metabolism of capacity-limited drugs.
processes (Absorption, Distribution, Metabolism and Elimi-
● Not all older adults will experience significant
nation), this review discusses the current evidence of the phar-
renal impairment with aging, but due to the high macokinetic changes that occur with aging, focusing mainly
prevalence of comorbidities and medications affecting on developments in this field over the last 10 years (Table 1).
renal function, renally cleared drugs should be A literature search was conducted in Medline and Embase
reviewed regularly. Chronic kidney disease can affect using the terms ‘pharmacokinetics,’ ‘medication’ and ‘age’
all stages of drug disposition due to accumulation of and variations on these, with the results restricted to January
uremic toxins including increased bioavailability 2004--May 2014. Review articles identified had their refer-
through downregulation of enzymes (decreasing first- ence lists searched for relevant articles. This search was
pass metabolism) and downregulation of efflux supple- mented with searches using the terms
transporters (e.g., P-glycoprotein), altered distribution absorption, distribution, metabolism and elimination
due to conformational changes in plasma albumin and where insufficient literature had been identified from the
decreased hepatic metabolism due to downregulation first search strategy. Where appropriate, original research
of enzymes. articles were obtained, however, due to the breadth of this
research topic, key review
This box summarizes key points contained in the article.
articles are also discussed.

2. Absorption
one organ may be maintained (e.g., the liver) while another
(e.g., the lungs) is compromised [10]. Importantly, inter- 2.1 Absorption after oral administration
individual variability increases with advancing age, and as
such older adults (those aged > 65) cannot be considered a After a medication is administered orally, it may undergo
homogeneous group [11-13]. some or all of dissolution, absorption (which may be passive
or active) and metabolism in the gastrointestinal tract and/or
Age-related changes in physiology can influence the
liver (so-called first-pass metabolism) before it reaches the
pharma- cokinetics of medications, and the overall effect is sys- temic circulation. The fraction of an orally administered
dependent on the individual drug characteristics (e.g., dose that reaches the systemic circulation (i.e., the oral
lipophilicity, degree of protein binding), mechanism of bioavailabil- ity) may therefore be influenced by several
elimination, intercurrent disease states and concomitantly factors including gastric pH, gastrointestinal motility,
taken drugs [14]. These will influence the effective dose, intestinal permeability and integrity of the mucosa, drug
frequency of administration, treat- ment duration and in transporter function and
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 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.

Change in older adults Clinical significance Example drugs

Absorption
Gastric acidity Hypochlorhydria due to gastric Potential reduced absorption Ketoconazole has impaired
mucosal atrophy more common of weakly basic drugs, absorption in older adults with
in older adults enhanced absorption of pH > 5
Reduced gastric acidity may also weakly acid drugs where
be caused by medication use, for increased pH is present
example, proton pump inhibitors
and histamine-2 receptor
antagonists, in this group
Transit time May be unchanged -- reduced --
due to certain comorbidities (e.g., Unlikely to have a clinical
diabetes, Parkinson’s Disease) significance
and certain medications (e.g.,
anticholinergics and opioids)
Permeability
Passive Unchanged -- --
Carrier mediated May be reduced Reduced absorption of Glucose, calcium, Vitamin B12
certain
nutrients
P-glycoprotein activity Both increased and decreased Unclear --
activities have been reported
First-pass metabolism Reduced first-pass metabolism due May or may not be clinically Nifedipine, labetalol and
to reduced liver blood flow and significant depending on verapamil have all increased
mass extent of first-pass metabolism bioavailability in older adults
and therapeutic indices (clinical significance uncertain)
Overall Reported changes due to aging alone are unlikely to be clinically significant
Distribution
Body composition Relative reduction in total Uncertain --
body water
Reduction in muscle mass
Relative increase in body fat
Plasma protein binding Small reduction in plasma Unlikely --
albumin
(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)
Overall Reported changes due to aging alone are unlikely to be clinically
significant
Metabolism Amitriptyline, fentanyl,
Hepatic blood flow Reduced by 20 -- 50% Drugs with high extraction morphine, verapamil
ratios will have reduced
clearance
Transfer of Pseudocapillarization may impede Unclear Most likely to affect large
substances into the transfer of substances into molecules and those
hepatocytes hepatocytes highly protein bound

Metabolizing capacity
Phase I Reduced (mostly due to Reduction in metabolism Ibuprofen, warfarin, temazepam
reduced hepatic blood flow and of drugs that undergo
mass and reduced oxygen Phase I metabolism can be
availability) clinically significant
Phase II No change -- --
Overall Reduced Phase I metabolism and potentially higher plasma drug concentrations
Elimination
Renal function Reduced renal function is Depending on the renal Digoxin
common function of the individual, the
in older adults effect may be clinically
significant
Overall Renally cleared drugs will have reduced elimination with consequential increase in half-life and
plasma concentration
expression and gastrointestinal blood flow and metabolism. inhibitor) led to a 20% reduction in dabigatran bioavailabil-
Reductions in gastric emptying, gastrointestinal motility, gas- ity. However, this was not considered clinically significant [31].
tric acid secretions (increased gastric pH), gastrointestinal Changes in acidity may also affect the extent of absorption
blood flow and intestinal surface area have all been observed of pro-drugs that require an acidic environment for conver-
with aging [23], but the overall effect of these changes does sion [32]. For example, the conversion of clorazepate into the
not appear to significantly change the total absorption for active desmethyldiazepam is inhibited in subjects with gastric
most medications. The potential impact of these changes is pH artificially increased to > 6, with a corresponding reduc-
discussed below. tion in absorption by almost 50% [33]. This study is limited
by its small sample size (n = 4) and was conducted in healthy
2.1.1 Gastric acidity
young adults.
It was originally proposed that a decline in gastric acid secre-
tion was a normal part of the aging process. However, more
2.1.2 Transit time
recent studies have challenged this, noting that in healthy
older adults, levels of fasting and stimulated gastric acid There is some reduction in gastrointestinal motility in old age,
secre- tion were not significantly reduced compared to including slowed gastric emptying, decreased peristalsis and
younger counterparts [24,25]. The earlier findings of reduced slowing of colonic transport due to region-specific loss of
acid secre- tion may be due to the relatively high prevalence neu- rons [34,35]. These changes would generally be expected to
of hypochlo- rhydria secondary to gastric mucosal atrophy in impact poorly soluble drugs where increased transit time
older adults (5 -- 10%) compared to < 1% in younger will allow longer time for dissolution and therefore increased
subjects [24-26]. A recent study looking into the effect of age on total absorption. Drugs that are highly soluble may have their
acid secretion enrolled 47 relatively healthy participants absorption delayed, resulting in reduced maximum concen-
(adults scheduled for surgery, without upper gastrointestinal tration but unchanged total absorption [5,12,32]. Increased
disease, diabetes or medications that can affect gastric transit time may also affect drugs, which are in a slow-release
secretion) across three different age groups: young (22 -- 39 formulation. A study of young healthy male volunteers found
years old), middle aged (40 -- 59) and old (60 -- 83). This that absorption of controlled-release carbamazepine was
study found that in the absence of gastric mucosal atrophy (n increased in participants with slower transit times [36]. Studies
= 32) there was no rela- tionship between aging and reduced in older adults are not consistent and the clinical effect is
acid secretion [27]. The significant increase in the volume of unclear. There is an increase in total absorption of levodopa
prescribing of drugs used to reduce acid concentrations in the following administration of Sinemet CR in older versus youn-
stomach (i.e., pro- ton pump inhibitors and histamine-2 ger healthy volunteers [37], but no change in total absorption
receptor antagonists) in older adults over the past 20 years of a slow-release formulation of oxycodone [38]. The high
will also affect the pH of the stomach and the interpretation prevalence of comorbid conditions (e.g., diabetes, Parkinson’s
of studies addressing this issue [12]. disease) and medications (e.g., anticholinergics and opioids)
With higher stomach pH, weakly acidic drugs dissolve affecting gastrointestinal motility in older adults, and the
more rapidly while weakly basic drugs dissolve more slowly, varying methods utilized in studies (due to the invasiveness
and as such general statements about the effect of gastric acid- of this kind of study) make it difficult to determine if these
ity on absorption can not be made. Reduced stomach acid changes in gastrointestinal function are purely due to
concentrations (in the case of people with atrophic gastritis age [34,39]. Therefore, fit older adults may not have any change
or those taking acid suppressive medications) may cause in the rate of gastric emptying compared with younger
reduced absorption of weakly basic drugs and, conversely, subjects [40].
enhanced absorption of weakly acidic drugs. Examples of
basic drugs, which may be affected, include ketoconazole, 2.1.3 Permeability (passive and active)
ampicillin esters and iron compounds [5,26,28,29]. A study of The permeability of drugs appears unchanged in old age when
administration of ketoconazole tablets in older adults with the medication is absorbed by passive diffusion [5,12,23,41,42].
an average of two chronic medical conditions found that par- For example, the absorption of commonly prescribed drugs
ticipants with gastric pH > 5 (n = 6, mean age = 84.5 years) such as penicillins, diazepam and metronidazole in older
had impaired absorption resulting in significantly lower adults is unchanged compared with younger adults [29].
plasma concentrations than those with pH < 5 (n = 12, While it was previously believed that the majority of drugs
mean age = 76 years). The concentrations achieved in the are absorbed via passive means, recent research indicates that
higher pH participants were subtherapeutic and likely to neg- carrier-mediated, active uptake of drugs may be more com-
atively affect the efficacy of ketoconazole in this group [30]. mon than previously thought [43]. Nutrients requiring active
The implications of this study, however, are limited by its transport for absorption seem to have reduced absorption
small sample size. Similarly, dabigatran etexilate requires a with aging, that is, glucose, calcium [44] and vitamin
pH < 4 to dissolve. A study in healthy older adults found B12 [25,45,46]. One transporter that has recently received
that coadministration with pantoprazole (a proton pump attention is P-gp, a trans-membrane transporter that is
found in the luminal surface of the intestine among other
places in the body including the blood--brain barrier, kidneys exposure. Pharmacodynamic changes associated with aging
and lymphocytes. Its role is a protective one; it actively trans- appear to be more clinically relevant for these drugs [62].
ports drugs and xenobiotics back into the gut lumen, Changes to first-pass metabolism will also affect medica-
decreasing absorption [47]. A large number of drugs appear tions, which are administered as pro-drugs, potentially reduc-
to be P-gp substrates including anticancer drugs, antibiotics, ing concentrations of the activated drug, for example,
calcium-channel blockers and steroids [22,48,49]. The effect of codeine, enalapril, perindopril and simvastatin [12,63] but the
aging on P-gp activity in humans is still under study, with clinical significance of this has not been established. Older
both increased and decreased activity observed depending adults have been demonstrated to achieve the same, if not
on the tissue in question and method of study [22]. higher enalaprilat (the active form of enalapril) plasma con-
centrations as younger adults although this is confounded by
a reduction in renal clearance of both enalapril and enalaprilat
2.1.4 First-pass metabolism in older adults [64,65]. Conversion of oseltamivir to its active
Oral bioavailability of some medications is reduced due to metabolite via hydrolysis occurs rapidly in older adults
being metabolized before reaching the systemic circulation aged > 80, with peak concentrations of the active metabolite
(first-pass metabolism). It is generally accepted that most first- actually 22% greater than young healthy participants. Nota-
pass metabolism occurs in the liver, though there is increasing bly, both groups still achieved the required plasma concentra-
evidence that drug metabolism, involving both Phase I and tion for antiviral activity [66]. These three studies [64-66] had
Phase II metabolism pathways, can also occur in the intestine small sample sizes (n = 12, n = 18 and n = 12) and only
[47]. Aging may be associated with a reduction in first-pass
included healthy subjects and therefore these results cannot
metabolism, most likely due to reduced liver blood flow and be extrapolated to multimorbid older adults.
mass (discussed further below). The clinical effect of reduced The effect of aging on intestinal metabolism in humans
first-pass metabolism is likely most signifi- cant for drugs that is currently unknown. Several studies in rats show that
undergo extensive first-pass metabo- lism [8,49,50]. For there is no change in the activity of intestinal CYP
example, in those with a high first-pass metabolism, a small enzymes (3A, 1A1, 2B1/2 and 3A1) with aging [67,68], and
reduction in hepatic extraction ratio (e.g., from 95 to 90%) depending upon the segment of the intestine where
could result in a doubling of serum concentrations [51]. Some metabolism occurred, there are variable changes in Phase II
examples of increased oral bioavail- ability in older adults metabolism via glucuronidation in young versus older rats
include nifedipine (46% vs 61%, youn- ger vs older adults) [69]. It is unknown whether these changes observed in

[52], labetalol (significant correlation with increased age) [53] animal studies are translatable to humans.
and verapamil (though a wide range in bio- availablilty was Overall, for most medications total absorption is
observed in the older adult group, 9 -- 83%) [54]. unchanged with aging, and in the instances where it is altered
Propranolol bioavailability was found to be almost doubled in it is unlikely to have a substantial clinical impact. The changes
older adults in one study [55] but unchanged in others [56,57]. to the different stages of absorption may counterbalance each
By contrast, no significant age- associated changes in other, for example reduced gut absorption (secondary to
absorption have been reported for other drugs with high first- reduced permeability or reduced solubility) may be compen-
pass metabolism, including amitripty- line [58], metoprolol sated for by reduced first-pass metabolism. The use of multi-
[59,60] and morphine [61]. The reasons for these variations in ple medications by older adults can lead to changes in drug
results may be due to the relatively small sample size of the absorption through interactions via metabolism (in the intes-
studies, the high inter-participant variability or the small tines or the liver) and potentially via modification of P-gp
number of drugs with a bioavailability < 25% where the effect activity [5,47]. This, along with concurrent diseases, is likely
will be the most apparent [50]. Additionally, a change in to have a greater impact on absorption than changes purely
bioavailability of medications with wide therapeu- tic indexes due to aging [6].
is unlikely to be clinically relevant. A recent study compared
the effect of age on the bioavailability of two dihy- 2.2 Oral administration via enteral tubes
dropyridine calcium-channel blockers (one with high first- A number of age-associated acute and chronic medical condi-
pass metabolism [felodipine] and one with low first-pass tions, for example, Parkinson’s disease, stroke and dementia,
metabolism [amlodipine]). Older subjects (with hyperten- might lead to impaired oropharyngeal function, with conse-
sion) had an increase in total drug exposure by ~ 30% for quent risk of aspiration of food or other material. When
both medications (without any change in apparent elimina- oral intake is inadequate or not recommended (e.g., swallow-
tion half-life) indicating that first-pass metabolism is not sig- ing difficulties) for a prolonged period of time, patients are
nificantly affected by age. However, older participants had a often given an enteral feeding tube for administration of
greater reduction in blood pressure than younger participants nutrition and/or medications [70]. Between 150 and 280 per
(20 vs 10 mmHg after chronic dosing of both drugs). It is million inhabitants in the UK receive enteral nutrition at
unlikely that such a difference in blood pressure lowering is home, with regions with a higher percentage of older adults
chiefly accounted for by the relatively small increase in drug having the greatest prevalence [71,72]. Incorrect administration
of drugs via enteral tubes can result in blockage of tubes medications, which should not be crushed or administered
(necessitating removal and reinsertion), and may alter absorp- via enteral tubes, have been published and should be con-
tion pharmacokinetics [70]. sulted before administering older adults regular medications
Enteral feeding tubes have nasal, oral or percutaneous entry via enteral tubes [79].
sites. Of more relevance to pharmacokinetics, however, will
be the location of the distal tip of the feeding tube. Most tubes 2.3 Non-oral drug administration
deliver content to the stomach, mimicking regular oral While oral ingestion is the most common route for medica-
administration; however, some may end distally in the duode- tion administration, several other routes such as the skin
num or jejunum. This results in medications bypassing the and lungs can be used. These may also be affected by the
stomach. Medications that act locally in the stomach (e.g., aging process.
antacids), or require acidity for dissolution (as discussed Atrophy of the dermis and epidermis in older adults may
above), may have reduced efficacy if the enteral tube ends lead to increased absorption of medications applied to the
distal to the stomach [70,73]. skin (e.g., creams and patches). On the other hand, the skin
Medications administered via enteral feeding may also may also be drier with reduced tissue perfusion, which can
interact with the enteral nutrition formulas (i.e., via chelation impair absorption [42,80]. Roskos et al. [81] found that
to nutrients) or even adsorb to the feeding tube itself [70]. advanced age reduced the percutaneous absorption of hydro-
A study of enterally administered phenytoin concurrently cortisone, benzoic acid, acetylsalicylic acid and caffeine
with nutritional formula found that phenytoin absorption (by ~ 50%). By contrast, there was no change in the absorp-
was reduced by up to 70% [74] due to adhering to enteral tion of testosterone or oestradiol. This suggests that the
tube or interaction with formula (proteins and calcium salts). absorption of hydrophilic, but not lipophilic, drugs is affected
A systematic review in 2000 found no strong evidence of this by age. Of the studied drugs, only oestradiol and testosterone
interaction in randomized controlled trials of healthy adults; are currently administered transdermally for systemic activity
however, it identified numerous reports and studies showing and as such the clinical significance of the reduced absorption
a significant decrease in serum phenytoin concentrations in of the other drugs is not relevant (and may in fact be consid-
patients when coadministered with enteral nutrition [75]. ered desirable for hydrocortisone, which is used topically for
A study in 2010 investigating this possible interaction in frail local effects). A study into the transdermal absorption of fen-
older adults on a geriatric ward did not find a significant dif- tanyl in palliative care patients (age range 40 -- 85 years)
ference in plasma concentrations, but concluded that the pos- found no effect of age on absorption although there was
sibility of an interaction could not be ruled out due to substantial inter-individual variability in fentanyl
conflicting previous studies [76]. Another study in geriatric absorption [82]. A recent review identified significant
inpatients with enteral feeding looked at the effect on clari- variability between stud- ies on transdermal absorption in
thromycin pharmacokinetics, again finding no difference in older adults, with some stud- ies finding increased absorption,
trough or peak concentrations, or time to peak concentra- some reduced absorption and others no change [83]. External
tion [77]. Other drugs with reports of altered absorption due factors may be partly responsible for this wide range in
to nutrient interactions include carbamazepine, warfarin and variability, with extremes of heat (induced by sauna or
fluroquinolones though, as with phenytoin and clarithromy- exercise) associated with increased transdermal absorption for
cin, the studies are inconsistent. Interactions (if existing) certain drugs including nicotine and glyceryl trinitrate [84].
may be avoided by spacing medication administration and Overall, there does not appear to be any clinically relevant
feeding by 2 h [70,78]. change in absorption of drugs transdermally with age, though
While most tablets can be crushed and mixed with water to more research may be required into persons aged > 80.
allow for enteral administration, there are several significant Although there is evidence that some of the barrier-related
exceptions to this, for example, tablets that have enteric coat- functions of the skin change progressively with chronological
ings (to protect the medication from the acidity of the stom- age, there is very little research in this group [80,83,85].
ach) and those that have a slow/extended/controlled-release With aging and associated diseases (e.g., chronic obstruc-
formulation. Proton pump inhibitors are acid labile and inac- tive pulmonary disease), older adults have reduced inspiratory
tivated by stomach acid, as such proprietary products come capacity and alveolar surface area, which may reduce the
with enteric coating. These tablets should not be crushed; effec- tiveness of locally acting inhaled medications [86-88].
however, omeprazole, esomeprazole and lansoprazole come Probably of greater importance, however, is appropriate use of
as enteric coated granules within capsules that can be opened inhala- tion devices; older adults generally have poorer
and mixed with water for enteral administration while still technique than younger adults [89]. Cognitive function, manual
maintaining the integrity of the formulation. Tablets with dexterity and hand strength are required for the use of
controlled-release formulations should not be crushed and inhalation devi- ces [90] and in older adults there was an
administered as this can result in greater peak and lower association between compliance with metered dose inhalers
trough concentrations. Instead, the dose and frequency should and mini-mental state exam score [91]. A study of community
be converted to a regular release formulation [70,73]. Lists of dwelling older adults found that inaccurate inhaler technique
was present with
between 3 and 28% of those prescribed long-term volume of distribution (e.g., with digoxin) will result in
inhalers [92]. initially higher peak plasma concentrations; however, this
leads to increased clearance as there is greater concentrations
3. Distribution of drug available at the elimination organs, resulting in a
shorter half- life. The equilibrium between the altered volume
Following absorption, the amount of active drug available of distribution and elimination results in unchanged total
to exert an effect at the active site(s) is dependent on tissue exposure to the drug [104]. In fact, the half-life of a drug may
distri- bution and the extent of plasma and tissue protein have little relevance to clinical efficacy or toxicity in specific
binding, which is broadly quantified as the volume of circumstances. For example, benzodiazepines with longer
distribution (the theoretical volume of blood for the half-lives have shown a similar risk of falls as short-acting
concentration yielded after administration of a drug). benzodiazepines [105].
Changes in body composition (which result in altered
tissue binding) and synthesis/ elimination of proteins 3.2 Plasma protein binding
involved in drug binding in the plasma that occur with The two main drug-binding proteins in plasma are albumin
aging may therefore affect the distribution of drugs. and a1-acid glycoprotein [8]. There has been an observed
reduction in plasma albumin concentrations of ~ 10 -- 15%
3.1 Body composition in older adults, which is probably due to increased elimina-
There are significant changes in body composition associated tion via the kidneys rather than reduced synthesis [106-109].
with aging, including a relative reduction in total body water, While this decrease is statistically significant, the change is
a reduction in muscle mass and a relative increase in body fat. rel- atively small and not considered clinically important [110-
With every year of age over 50, body water decreases by ~ 113]. Age-related chronic conditions such as arthritis, Crohn’s

1% [93]. Muscle mass decreases by about the same amount, dis- ease, cancer, acute coronary syndrome and renal and
though there is a greater loss in men than women [46,94,95]. Body hepatic dysfunction can further decrease albumin
fat increases more in older women than men, with studies concentra- tions [8,114]. In older adults, a1-acid glycoprotein
indi- cating an average increase of around 1% per year concentra- tions can be increased, although this is usually
[46,94,96,97] . When divided into decades of life there is a
attributed to acute illness or chronic inflammatory disease
significant increase in body fat and decrease in fat-free mass states including burns, trauma, surgery and cancer, rather than
up to and including the age group of 70+ years (with age per se [8,104,114,115]. Severe liver disease can, however,
participants aged up to 89 years) [98,99]. Although there is some decrease a1-acid glycoprotein concentrations [114].
limited evidence that after the age of 80 fat mass actually Individuals with lower plasma albumin concentrations will
declines [20,100,101]. The Health, Aging and Body Composition theoretically have increased free fraction of the drug, and it is
study conducted longitudinal analysis of adults aged 70 -- 79 this unbound drug that is able to exert therapeutic (and toxic)
over a 4-year period. Both total weight gain (21 and 24% of effects. A study of 22 younger (age 18 -- 33 years) and 22
men and women, respectively) and weight loss (31 and 33% older (62 -- 87) patients with epilepsy-prescribed phenytoin
of men and women) were observed in this population. Of found a statistically significant increase in unbound fraction in
those who lost weight, there was an approximate loss of 5% the older group (accompanied by reduced plasma albumin
lean and 10% fat mass, while in those who gained weight con- centrations). However, the reported changes were not
there was only ~ 2% gain of lean mass but an increase of consid- ered clinically significant; unbound phenytoin
15% fat mass [102]. percentage was 12.8% in older adults versus 11.1% in younger
The volume of distribution of water-soluble drugs is there- [116]. Piroxi- cam also exhibits increased fraction unbound in
fore likely to be reduced and the same administered dose will older sub- jects [117,118]. More recently, Chin, Jensen et al.
therefore result in increased peak serum concentrations. For [110] conducted experiments into three benzodiazepines, loraze-
example, the volume of distribution of digoxin reduces with pam, oxazepam and temazepam, all of which are highly
age and it has been suggested that the loading dose should bound to albumin and cleared via the liver. In 60 healthy
be reduced by 10 -- 20% in older adults. This change may drug-free subjects aged 19 -- 87, they found a significant
not be clinically important, though therapeutic drug monitor- reduction in plasma albumin with age of 0.03 g/l per year
ing for specific drugs, including digoxin, might be a useful but there was no relationship between the unbound fraction
tool when steady state is achieved [5,12,29]. Lipophilic drugs of any of the drugs and age. Similarly, in a later study in
will, on the other hand, be more likely to have an increase 72 patients prescribed warfarin (aged 18 -- 89), a statistically
in their volume of distribution and will take longer to be significant (though small, 45 vs 43 g/l younger vs older
cleared from the body, for example, diazepam, whose half- adults) reduction in albumin was observed with age but again
life may be increased fourfold in an 80 years old compared there was no relationship with protein binding [111].
to a 20 years old [103]. While volume of distribution is relevant In practice, however, changes in protein binding (if present)
for loading doses, changes in volume of distribution are are unlikely to exert clinically significant effects [5,42,104,114].
unlikely to affect the overall drug exposure. A decrease in This is because increased unbound fraction leads to increased
availability of the free drug at clearance sites and therefore
overall drug exposure is virtually unchanged [104]. An increase blood flow). Drugs with a high extraction ratio are limited
in unbound fraction of drugs that are renally cleared will lead by hepatic blood flow and a reduction in blood flow will
to an increase in glomerular filtration and may also increase reduce their clearance. By contrast, drugs with a low
active tubular secretion and decrease passive tubular reabsorp- extrac- tion ratio will not be substantially affected by the
tion. For orally administered drugs that are hepatically reduced blood flow although they are affected by changes
cleared, an increase in unbound fraction will, as with renal in metabo- lizing capacity (discussed below) [8,12]. A review
clearance, lead to increased clearance. However, changes in on the elimi- nation of medications based on their free drug
protein bind- ing may be clinically relevant for hepatically concentration (as opposed to total drug concentration
cleared drugs with high extraction ratios when given which in older adults can confound findings due to reduced
intravenously as the fraction unbound will have an effect on albumin) reported that medications with high extraction
total exposure. Examples include diltiazem, propranolol, ratios consistently have reduced metabolism in older adults
verapamil, erythromycin and fentanyl [104,114]. Lidocaine with an average of 34 and 54% reduction in clearance
protein binding was reported to be increased in older adults following intravenous and oral administration, respectively.
with increased a1-acid glycopro- tein. Although a longer half- Example drugs include amitriptyline (62% lower), fentanyl
life (not attributable to change in systemic clearance) would (6 -- 74%), imipramine
increase overall exposure to lido- caine, this study concluded (35 -- 45%), levodopa (39%), metoprolol (13%), morphine
that no dose changes are required in older adults [119]. (16 -- 35%) and verapamil (32 -- 42%) [115].

4. Metabolism 4.2 Transfer of substances into hepatocytes

After the drug has reached the liver via the blood stream, it
Metabolism results in conversion of an active drug into an needs to cross the sinusoidal endothelium, travel through the
inactive drug (or vice versa for pro-drugs). Metabolism by space of Disse and then enter the hepatocytes where it under-
the liver is important for the elimination of active and inactive goes metabolism. Age-related changes have been observed in
drugs, which require biotransformation to a more soluble the liver sinusoidal endothelial cells (including endothelial
form in order to be excreted by the kidneys. Metabolism thickening, defenestration and collagen deposition, termed
occurs via cytochrome P450 (CYP - oxidation, reduction pseudocapillarization), which may impede the transfer of sub-
and hydrolysis) and conjugation (glucuronidation, acetylation stances from the blood to the hepatocytes [129-131]. These
and sulfation), so called Phase I and Phase II metabolism, changes are similar to those seen in cirrhosis, which has been
respectively [23]. While the liver is the main metabolizing shown to affect the transfer of oxygen, sucrose and
organ, the intestines (discussed above), the lungs, the skin propranolol (highly protein bound) [130]. It has been proposed
and the kidney all have a metabolizing capacity [120]. Metabo- that the age- related changes in the liver sinusoidal endothelial
lism in the kidney may account for ~ 25% of glucuronidation cell will affect the transfer of drugs with a large molecular
and sulfate conjugation [121]. Approximately one third of the weight (e.g., thera- peutic proteins) and those that are
metabolic clearance of propofol (which is metabolized by uri- extensively protein bound [129]. Studies in aged rats have
dine diphosphate glucuronosyltransferase [UGT]) is con- shown reduced transfer of large molecules such as
ducted in the kidneys [122]. lipoproteins [132] and liposomal doxorubicin [133]. Similar
In addition to metabolism the liver plays important roles findings (again in animal studies) were recently reported with
including synthesis of albumin, bilirubin, cholesterol and acetaminophen, which has low protein binding but is water
blood clotting factors. In the absence of advanced liver dis- soluble [134], and diazepam, which is highly protein bound [135].
ease, these nonmetabolic functions are generally maintained The clinical relevance of these changes is best examined by
in older adults [11,23]. Hepatic metabolism depends on the looking at the overall change in metabolism of these
rate of the drug being supplied to the liver (i.e., hepatic blood substances.
flow), the transfer of the drug from the blood into the hepato-
cytes and the ability of the hepatocytes to metabolize the drug 4.3 Metabolizing capacity
(metabolizing capacity) [8]. 4.3.1 Phase I metabolism
Most (but not all) in vitro studies of hepatic content and activ-
4.1 Hepatic blood flow ity of CYP450 enzymes have found that they are maintained
Both hepatic blood flow and liver size are reduced with age, with increasing age (though there are very limited studies
beginning in approximately the third decade of life [50]. looking at ages > 80 years) [5,11,96,136,137]. Yet, most in vivo
Hepatic blood flow is reduced in adults > 65 years by ~ 20 -- studies have shown that there is a significant reduction in
50% [123-127], and there is a similar reduction in liver size (less the clearance of drugs metabolized via Phase I metabolism
blood is required by smaller organs) [23,96,123,128]. in older people by ~ 30 -- 50% [11,123]. For example, a study
This reduction in hepatic blood flow will affect the rate of of patients prescribed phenytoin (metabolized by
metabolism of drugs differently depending on their extraction CYP2C9 and CYP2C19) found a decrease in clearance by
ratio (the ratio of hepatic clearance in relation to hepatic 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 review [20] identified 5 drugs that undergo glucuronidation in
CYP2D6 [139]. However, the changes found in this and simi- which the effect of aging had been studied. While the studies
lar studies appear to be small relative to the effect of reduced only involved a total of 182 participants across all ages, there
hepatic blood flow and liver size [96]. was no increase in half-life (when converted to a ratio to
Based on in vitro and in vivo results, the observed young adults) in the pooled data with increasing age. This
reduction in metabolism of drugs, which undergo Phase I may be because Phase II reactions only require oxygen
metabolism, is most likely due to the reduced blood flow and indirectly (to produce energy) and not directly as a co-
liver size (dis- cussed above), rather than a reduction in the substrate like Phase I reactions. Therefore, they are unlikely to
expression or activity of the CYP enzymes [63,127,130,140]. This be affected by the structural changes described above that may
has, however, been challenged as there is also reduced be responsible for the reduction in capacity-limited Phase I
clearance of drugs that have low extraction ratios (capacity- metabolism [49]. It does, however, appear that Phase II
limited metabolism). A literature review looking into studies metabolism may be reduced in frail older adults. For example,
of capacity-limited metabolism of drugs with high protein studies of paracetamol [150], metoclopramide [151] and aspirin
binding found that there was reduced free clearance, even [152] have shown preserved metabolism in fit older adults, but
when the total clearance was unchanged. It found reductions reduced metabolic clearance in the frail. The clinical
in free clearance to the order of 20 -- 60% of many drugs consequences of these changes in metabolism in frail older
including ibuprofen, tema- zepam and warfarin. This suggests adults may surpass just increased half-lives. A reduction in
a reduced metabolizing capacity of Phase I enzymes, which Phase II conjugation of paracetamol will lead to greater
could not be attributed to reduced hepatic blood flow [115]. metabolism via the alternative (CYP medi- ated) pathway,
The reduction in clear- ance of capacity-limited drugs may be which leads to production of a toxic metabolite. This toxic
due to the reduced size of the liver (and therefore less areas metabolite is usually neutralized via conjugation with
and enzymes to metabolize), or because of structural changes glutathione; however, with frailty (specifically malnutrition),
in the liver dis- cussed above. In addition to the transfer of there are less glutathione stores. Therefore, the frail are at
drugs, the transfer of oxygen into the hepatocytes may be greater risk of liver toxicity, even at recommended daily doses
hindered. All enzy- matic processes require oxygen as a part due to reduced clearance and greater production and less
of their requirement for energy, and CYP pathways are neutraliza- tion of this toxic intermediate [153].
particularly dependent on oxygen as a co-substrate. Age-
related pseudocapillarization may result in reduced oxygen 5. Elimination
availability within the hepato- cytes limiting CYP reactions.
This has been proposed as a rea- son for a reduction in Phase I
5.1 Renal function
metabolism of capacity-limited drugs [5,49,130]. This supports the
assertion that the metaboliz- ing capacity or production of the The main organ responsible for removal of drugs and their
enzymes themselves does not reduce with aging, but that metabolites from the body are the kidneys. Traditionally, it
Phase I metabolism of both high- and low--extraction ratio was generally accepted that renal function, and therefore the
drugs can be reduced. excretion of drugs with renal elimination, reduced with age.
A review conduced in 1999 estimated that after the age
As older adults are likely to be exposed to polypharmacy, it of 30 there is a reduction in glomerular filtration rate
has also been investigated (though not extensively) whether (GFR -- an established marker of renal function) by 8 ml/min
inhibition and induction of enzymes are affected by aging.
every decade. The weight of the kidneys, reduced renal blood
Some early studies had data that indicated a reduced inducing
flow, number of functioning nephrons and reduced permeabil-
capability with aging [56,141], though the majority indicated
ity were thought to be the cause [103]. However, this standard
that inhibition and induction are not affected, and therefore
reduction of renal function with age may not be completely
drug--drug interactions will occur to the same extent as in
true, particularly given the previously described increased
younger adults [8,142-144]. inter-individual variability in key parameters of organ func-
tion. Moreover, many age-related diseases and cardiovascular
4.3.2 Phase II metabolism risk factors (such as hypertension, heart failure, and diabetes),
Phase II metabolism does not appear to be altered in older as well as chronic exposure to nephrotoxic drugs (e.g., nonste-
age, and this conclusion is mostly consistent across different roidal anti-inflammatory drugs) can directly affect GFR and
stud- ies [123,129,145,146]. For example, several studies have found may confound the effect of aging on renal function [154,155].
no difference in the clearance of temazepam (metabolized For example, adults with diabetes have a greater decrease in
mostly by glucuronidation) between healthy young and GFR over time than those without diabetes [156] and the
old adults [147-149]. The literature review conducted by concomitant use of nonsteroidal anti-inflammatory drugs
Thompson et al. [96] in the development of a physiologically with ACE inhibitors/angiotensin receptor antagonists and diu-
based pharmacokinetic modeling database suggests that there retics significantly increase the risk of renal impairment [157,158].
is no age-related difference in Phase II metabolism (via the The Baltimore Longitudinal Study of Ageing found that up to
liver or other sites) in older compared to younger adults, 33% of adults without hypertension did not have any
though they note that there is still limited data on this. reduction in renal function over a period of 23 years [159].
Similarly, Ginsberg’s McLean and
LeCouteur’s 2004 review concluded that there does appear to population of older adults will have reduced renal func-
be a reduction in renal function with age, but it is less than tion [155,156]. Hence, it is prudent to consider that medications
pre- viously thought in people without any disease or eliminated through renal excretion may have reduced elimina-
intake of nephrotoxic drugs that can affect kidney function tion when administered to an older adult, and dosing of these
[5]. drugs should be guided by the individual patient’s GFR.
Recently, several literature reviews have been conducted to Long- term medications should be regularly reviewed with
build pharmacokinetic modeling databases in an effort to pool recurrent checking of the patient’s GFR as they age and have
all available data on the potential pharmacokinetic implica- changes to medications and other risk factors. Where possible,
tions in different states, such as different age groups and dif- therapeutic drug monitoring should be engaged to guide
ferent diseases. Aymanns et al. [160] identified, using their dosing (in combi- nation with clinical indicators).
database [161], 127 drugs, which had had their pharmacoki- Estimation of a patient’s GFR is, however, complicated. It
netic parameters analyzed for purely age-related changes. is important to emphasize that assessment of renal function of
They found that these drugs had an average prolongation in older adults should not rely on measurement of serum
their half-lives of 39% (± 61%). The pharmacokinetic data- creatinine concentrations as the production of creatinine is
base developed by Ginsberg et al. [20] found a slightly greater related to mus- cle mass, which as discussed earlier is reduced
increase in the average half-life of drugs in older adults, with in older adults [9]. Several formulas for calculating estimated
those aged 80 -- 84 having an average increase of 60% in their GFR (eGFR), which take into account various parameters,
half-life (in comparison to those aged < 60). There are, how- exist. By far the most common method is the Cockcroft--Gault
ever, many variables such as the aforementioned disease states formula, which takes into account serum creatinine, age,
and medications that can affect renal function. Inter- weight and sex; however, this has been shown to
individual variability is high in older adults and prediction systematically underestimate GFR in older adults and as such
of clearance based on overall datasets is poor [20]. its routine use has been ques- tioned [5,12,106,163]. Newer
While healthy older adults may have a relatively preserved formulas, such as the Modification of Diet in Renal Disease
baseline renal function, there is evidence that renal function (based on serum creatinine, age, ethnicity, and sex) or the
reserve (the ability of the kidneys to increase GFR in response CKD Epidemiology Collaboration (CKD-EPI, based on serum
to protein load) is reduced even in healthy older adults. An creatinine, age and sex), may be more accurate in older adults
early study with participants up to 80 years found that renal [169-171]; however, further valida- tion studies of these measures
function reserve was preserved with aging [162]. However, a as a guide for drug dosing are required. While the Cockcroft--
study looking at adults aged > 80 years found that there was Gault formula is known to be flawed, there is more data and
a slight reduction in the CrCl of older adults compared to experience to support dosing according to these results than
younger adults, though this was still within the normal range the newer calculations [12].
(80.4 ± 18.2 ml/min) but renal function reserve (measured by Of note, there is very little data pertaining to older adults
response to appropriate vasodilating stimuli) was significantly aged > 85. In the pharmacokinetic database developed by
reduced [163]. The young adult subjects responded to the vaso- Ginsberg et al. [20], there was not a statistically significant dif-
dilating stimuli with GFR increases of 26 ml/min, while the ference in clearance of medications in those aged > 85 when
older adult group showed almost no response, with an compared to the reference group. The authors report that
increase of only 3 ml/min. This aligns with the knowledge this is most likely due to the small number of participants in
that there is enhanced susceptibility to acute renal failure, this age group in the trials, though it is also noted that it
impaired recovery of kidney function after acute failure and may be because the 85+-year olds who enter into pharmacoki-
accelerated renal disease with aging [164]. netic studies are particularly fit and healthy. It must also be
Recently, the effect of frailty on renal elimination has been considered that the affect of aging on renal function may
studied in a pharmacokinetic modeling analysis of gentami- not be consistent, and the oldest of older adults may not be
cin. Using gentamicin concentrations and clinical data from consistent with those aged 65 -- 85. While high blood pressure
two prospective observational inpatient studies (n = 38 older is known to be associated with reduced renal function, a study
adults), Johnston et al. [165] found that frail patients (defined into the effect of blood pressure in adults older than 85 found
using the Reported Edmonton Frail Scale score) had ~ 12% that high blood pressure was not associated with reduced renal
lower gentamicin clearance, after accounting for the effect of function, and in fact low blood pressure was associated with
renal function and weight. accelerated decline in renal function [172].
As previously described, several comorbidities and
cardiovas- cular risk factors negatively affecting renal
function are common in older age. Hypertension is present in 5.2 Other effects of renal disease
more than two thirds of older adults [166], and approximately on drug disposition
one quarter have diabe- tes [167]. In the US, over one third of CKD is historically known to alter clearance of drugs that are
adults > 70 years old have stage III or IV chronic kidney eliminated via the kidneys, but it can also alter other stages of
disease (CKD) [168]. Therefore, regardless of whether reduced drug disposition and non-renal clearance of drugs. Studies
renal function is caused purely through the aging process or have indicated increased bioavailability through
due to comorbidities, the average downregulation of
 Pharmacokinetic changes Pharmacodynamic changes
Greatest clinical significance: Both increased and reduced sensitivity
Reduced clearance of drugs undergoing to drugs
Phase I metabolism
Reduced elimination of renally cleared
drugs
Other influences on
pharmacokinetics
Co-morbidities (including drug-disease
interactions)
High inter-individual variability in Co-medications (including drug-drug
organ/system function and interactions)
homeostasis 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 The most clinically significant alterations are those affecting
downregulation of efflux transporters (e.g., P-gp), altered the clearance of medications. Absorption of drugs may be
distribution due to con- formational changes in plasma affected by reduced gastric acidity, longer transit times,
albumin and decreased hepatic metabolism due to changes to permeability and reduced first-pass metabolism.
downregulation of enzymes [173,174]. The underlying Non-oral administration of medications and administration
mechanisms of these changes are not completely clear, but the via enteral tubes requires special attention in older adults.
predominant explanation is that accumulation of uremic toxins Changes in body composition and protein binding with aging
(including urea, parathyroid hormone, indoxyl sulfate and can affect peak plasma concentrations; however, effect on
cytokines) may cause transcriptional or translational total exposure is not significant for most medications.
modifications or may directly act on the metabolic pathways Clearance via Phase I metabolism or renal clearance is
(e.g., direct inhibition) [173]. A review conducted in 2008 found generally decreased in older adults, with consequently greater
both animal and human studies, which demonstrate an effect total exposure to the drugs. There is, however, large inter-
of CKD on drug metabolism. There is the strongest evidence individual variation and so the exact changes that occur with
of suppression (either through reduced expression or direct aging and resultant phar- macokinetic parameters of drugs are
inhibi- tion) of the CYP enzymes 2C9, 2C19 and 3A4 and hard to define. In most cases, multiple factors will affect the
acetylation enzymes (e.g., N-acetyl-transferase) and the effect benefits and harms of med- ication use in older adults. For
is clinically significant. For example, the non-renal clearance example, methadone used for chronic pain in older adults has
of verapamil (a CYP3A4 substrate) is reduced by over 50% resulted in a large number of deaths. Methadone has a long
and procainamide (metabolized by N-acetyl-transferase) is half--life, which makes it suscep- tible to accumulation and it
reduced by 60% in adults with renal failure [174]. A recently is also known to have large inter- individual variability in
published in vitro study involving administration of four pharmacokinetics. Increased risk of toxicity has been
uremic toxins demonstrated > 50% decreases in the activities associated with age > 65 (most likely due to reduced
of CYP1A2, CYP2C9, CYP2E1, CYP3A4 and metabolism via CYP3A4 enzymes), cancer (which can
glucuronidation enzymes UGT1A1, UGT1A9 and UGT2B7 increase a1-acid glycoprotein, which methadone is highly
[175]. CKD can also affect renal metabolism. A recent study in
protein bound to, further increasing its half-life) and concom-
rats found that the expres- sion of CYP1A within the kidneys itant use of certain medications (which can inhibit
was significantly reduced (by 48%) while CYP3A was CYP3A4) [177-179]. Additionally, aging can also result in phar-
unchanged [176]. macodynamic changes, which can result in increased adverse
drug reactions and decreased efficacy independent of pharma-
6. Conclusion cokinetic alterations (Figure 1).
Therefore, all older adults should be treated with a tailored
There are many physiological and pathophysiological age- approach according to clinical response (including both
associated changes potentially affecting drug disposition.
benefits and adverse drug reactions) supplemented with structure and function of key metabolizing and clearance
knowledge of their GFR, comorbidities and other medica- organs, for example, liver and kidney, in the same age group.
tions with the dose and appropriateness of medication choice What can be done to overcome these hurdles? At a time
reviewed regularly. when global financial constraints limit the design and conduct
of large Phase II and Phase III studies including a sufficient
7. Expert opinion number of older participants, several alternative strategies
might improve our knowledge in this area. A number of pro-
A substantial amount of work has been conducted over the fessional societies in Europe advocate an increased participa-
last 30 -- 40 years to address whether advancing age signifi- tion of older patients in clinical research. The running of
cantly affects drug disposition in humans. Despite significant pharmacokinetic studies in a more naturalistic setting, for
advances in the field, particularly regarding drug metabolism example, patients with different degrees of frailty, organ func-
and elimination, a number of issues remain unsolved. This tion and reserve and number of concomitant drugs, might still
prevents prescribers from optimally managing medical condi- yield important information provided that the individual
tions in the ever-growing older population. First, the conduct impact of these confounding factors is rigorously accounted
of pharmacokinetic studies as part of drug development pro- for by means of statistical modeling. A number of computa-
grams in the pharmaceutical industry remains largely con- tional approaches might complement the proposed clinical
fined to subjects aged 18 -- 65 years. The often stringent studies. For example, coupling in vitro--in vivo extrapolation
inclusion and exclusion criteria in such studies means that vir- with physiology-based pharmacokinetic modeling and simu-
tually all recruited older patients belong to the ‘healthier’ lation has been recently shown to predict relevant pharmaco-
range, that is, very few, if any, comorbidities, preserved renal kinetic parameters in older adults [180]. Similarly, the use of
function and limited number of concomitantly prescribed semi-physiological approaches that allow extrapolation of
drugs. In essence, data obtained from these studies are poten- pharmacokinetic data from a healthy state to different degrees
tially quite different from what it might be expected if the of renal and liver impairment might prove useful in this con-
same studies were conducted in the majority of patients man- text [181]. It is, however, important to emphasize that the
aged in clinical practice, a cohort of frail older subjects with success and clinical use of these approaches largely depend on
significant inter-individual organ function variability and pol- a thor- ough understanding of the main physiological and
ypharmacy. Second, published studies on drug disposition biochemical changes occurring with advancing age. As
and pharmacokinetics specifically conducted in older subjects, previously described, this knowledge remains limited in
albeit scientifically sound, have primarily focused on a num- people > 80 years. In the opinion of the authors, a close
ber of relatively old drugs, that is, propranolol, lidocaine, collaboration between pharma- ceutical industry, academia
digoxin, procainamide and cimetidine. While some of these and research organizations, patient groups and professional
drugs might still have a place in current clinical practice it is societies will be instrumental in further advancing our
concerning that little knowledge is available regarding rela- knowledge on drug disposition and pharmaco-
tively new drugs and drug classes extensively prescribed for kinetics in old age over the next 10 -- 20 years.
the management of either acute or chronic conditions in
this population. These include the biologics, new oral antico- Declaration of interest
agulant and antidiabetic drugs, antivirals and anticancer
drugs. Third, virtually, no information on age-associated The authors have no relevant affiliations or financial involve-
changes in drug disposition and pharmacokinetics is available ment with any organization or entity with a financial interest
in subjects > 80 years, the fastest growing subgroup within the in or financial conflict with the subject matter or materials
older population. This lack of information parallels to a cer- discussed in the manuscript. This includes employment, con-
tain extent the paucity of data on changes, if any, in the sultancies, honoraria, stock ownership or options, expert testi-
mony, grants or patents received or pending, or royalties.
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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: emily.reeve@sydney.edu.au
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