Summary of Studies Showing Age-Differences in Pharmacokinetics:
Scopolamine
Healthy adult subjects were given
scopolamine hydrobromide 0.5 mg IV if they were under 65 years of age
and 0.3 mg if older than 65 years. These subjects then received a
battery of tests of cognitive function in addition to measurement of
pharmacokinetic variables. Older age was associated with slowed
clearance and increased exposure to scopolamine. Age-related increases
in scopolamine exposure was likely the greatest contributor to the
increased sensitivity to cognitive adverse effects in older adults. The
study authors hypothesized that age-related changes in CYP3A4 activity
or content may have been responsible for the increased scopolamine
exposure in older adults120.
Genetics
In addition to age and sex, it is important that we understand how
genetic variation in CYP activity can influence clinical effect or
toxicity as drugs that are substrates for these enzymes are frequently
used by older adults15.
CYP2D6
Genetic variation in the CYP2D6 gene is well characterized and
gives rise to at least 120 CYP2D6 variants (alleles) that have
altered levels of CYP2D6 enzyme activity. These alleles result from
point mutations, deletions or additions, gene rearrangements and
deletion or duplication/multiplication of the entire gene and have
different distribution among various ethnic groups. Phenotypically,
individuals with two normal CYP2D6 alleles are extensive metabolizers
(EMs), those with one normal and one poor metabolism allele are
intermediate metabolizers (IMs) and those with 2 reduced metabolism
alleles are poor metabolizers (PMs). For CYP2D6, there is a fourth
phenotype, the ultra-rapid metabolizers (UMs) who have at least one
CYP2D6 gene duplication. Of interest, PM variants are common in East
Asian populations and exist across the world. Understanding the effect
of these CYP2D6 variants on pharmacokinetics is important for predicting
drug effect and adverse effect.
The effect of CYP2D6 phenotype on anticholinergic medication exposure
has been investigated in older adults. CYP2D6 phenotypes have been well
characterized with respect to codeine pharmacokinetics and
pharmacodynamics. Limited activation and effect of codeine occurs in
CYP2D6 PMs and increased metabolism and toxicity has been reported in
UMs121. Nortriptyline plasma levels were mostly
correlated to CYP2D6 genotype and sex90. In nursing
home patients exposed to anticholinergic drugs the highest serum
anticholinergic activity was found in groups of CYP2D6
PMs122. Analysis of risperidone metabolism in 70
healthy volunteers (of whom 82.9% were either IM or EM) revealed that
polymorphisms of the CYP2D6 enzyme were much more responsible than sex
for variation in risperidone metabolism. CYP2D6 phenotype explained 52%
of interindividual variability in risperidone pharmacokinetics. The AUC
of the active moiety was found to be 28% higher in CYP2D6 PM compared
with IM, EM and UM. No other genetic markers were found to significantly
affect risperidone concentrations123. This genetic
variation in the metabolism of risperidone is of such magnitude that it
could alter results when conducting bioequivalence
studies124. Differences in dose responses should be
considered as clinically relevant for any person initiated on
risperidone, further supporting using the lowest possible doses at all
times.
The bladder anticholinergic tolterodine is metabolized to a similarly
active 5-hydroxymethyl tolterodine (5-HMT) by CYP2D6. The
bioavailability of tolterodine is strictly related to the genetic
polymorphism of CYP2D6 and it ranges from 10% to
74%125. Byeon et al. investigated the
relationship between CYP2D6 phenotypes and tolterodine pharmacokinetics
in 46 Korean subjects. The single dose and multiple dose
CMax and AUC0-24 of tolterodine was
significantly higher in the PM groups than in the EMs. The ratio of
clearance to bioavailability of tolterodine in the EMs was 5 to 18-fold
higher than PM (variant dependent) in multiple dosing
studies126. A Swedish study also found a difference in
the absorption t1/2 of tolterodine between EM (0.41 h)
and PM (0.53 h) and EM were found to have a slight increase in heart
rate at steady state in comparison to baseline which was thought to be
related to drug exposure127. Interest in understanding
drug induced QT interval prolongation led to study of the effect of
CYP2D6 polymorphism on ECG changes in the use of tolterodine and its
active metabolite 5-HMT. In CYP2D6 PM the systemic exposure to
tolterodine is higher than EM (t1/2 of tolterodine IR 10
h in PM versus 2-3 h in EM) which may contribute to differences in ECG
changes127. However, the total concentration of active
moieties (tolterodine plus 5-HMT) was similar for PM and EM which makes
dose adjustment unhelpful for equalizing drug exposure. Interestingly,
5-HMT and tolterodine may contribute differently to QT interval
prolongation risk and so this was studied as well. QT interval
prolongation in CYP2D6 PM was only slightly greater for PM likely due to
differences in protein binding between the two active
components128. As a further illustration of the impact
of CYP2D6 genetic variation on anticholinergic pharmacokinetics, 4 mg
daily dosing of fesoterodine produced a CMax of 3.45
ng/mL in CYP2D6 PM versus 1.89 ng/mL in CYP2D6 EM. A similar
proportional result was also observed for 8 mg daily dosing of
fesoterodine in PM (CMax of 6.40 ng/mL) versus EM
(CMax 3.98 ng/mL). Fesoterodine equally follows CYP2D6
and CYP3A4 metabolism which should make it less susceptible to CYP2D6
reduced metabolism but this has not been clearly
demonstrated129. The oral antimuscarinic agent
darifenacin is metabolized by CYP3A4 and CYP2D6 with the main metabolite
being inactive130. The oral bioavailability of
darifenacin is significantly altered by the CYP2D6 genotype in a
dose-dependent fashion. In EM the bioavailability of 7.5, 15 and 30 mg
CR oral doses of darifenacin are 15%, 19% and 25%, respectively. In
IM and PM this bioavailability becomes 40 to 90% higher. There is less
impact of the CYP2D6 variants on the systemic elimination of
darifenacin. In UM the t1/2 of darifenacin is 3.12 h,
while in PM it is 3.83 h98.
All told, CYP2D6 is an important contributor to variation in
pharmacokinetics of medications it metabolizes. In a study of patients
with schizophrenia, Jürgens et al. reported that PM and UM did receive
higher doses of medication, including CYP2D6 dependent antipsychotics,
than EM and IM. UM would likely need higher doses to compensate for
their increased metabolism, so it is reassuring to see this in practice.
However higher doses being used by PM may reflect adverse drug events
being misinterpreted as psychotic symptoms leading to inappropriate and
potentially harmful dose increases 131.
CYP2C19 and CYP3A4
Genetic polymorphisms in the CYP2C19 gene
also result in PM, IM and EM phenotypes. To date no studies have
demonstrated a role of CYP2C19 genetic variation in anticholinergic
medication pharmacokinetics. Previous research has failed to identify
individuals with no CYP3A4 activity. Due to the lack of genetic PM of
CYP3A4, other factors such as exposure to drug inducers and inhibitors,
liver function, blood flow, and possibly age and sex are the biggest
considerations for variation in CYP3A4
activity49,54.
Conclusions
Anticholinergic medications pose health risks to older adults. We know
that adverse drug reactions due to anticholinergic medications are most
commonly proportional to plasma drug concentrations or serum
anticholinergic activity12,13,132 which makes sex,
age, and genetic effects on drug disposition relevant for clinical
decision making. Investigating the role of sex, age and CYP polymorphism
on anticholinergic medications confirms that women often experience
increased drug exposure32,101 which likely contributes
to their experience of more adverse drug reactions than
men74,76,94,95,97 and increasing age can also increase
drug exposure. There may be a role for differential dosing of some drugs
based on age and sex. Clinical testing of CYP2D6 polymorphisms and
adoption of peer-reviewed published clinical practice guidelines for
prescribing based on genotype where strong evidence exists may also help
reduce the burden of adverse drug responses in older people.
The take home message is that the greatest increase in drug exposure is
likely experienced by older women. Clinical practice demonstrates that
even a small decrease in dose modestly decreases adverse drug reactions
with negligible effect on efficacy which should encourage clinicians to
minimize anticholinergic drug doses, if anticholinergic medications must
be used at all. While the tenants of Geriatric medicine have been
relatively effective in communicating the importance of lower doses in
older adults, the importance of sex in dosing has been poorly translated
into clinical practice. Monographs frequently provide advice for dosing
in the oldest users but rarely offer advice for dosing in women. With
increased risk of hospitalization, cognitive impairment and mortality as
risks from anticholinergic drug use, improved understanding of sex, age
and genomic testing of CYP isozymes may be indicated to reduce serious
anticholinergic adverse events. Rigorous pharmacokinetic analysis is a
much needed and important next step to allow us to understand how dosing
recommendations can be modified to most safely and effectively treat
older men and women. Studies that have been done in the past often
examined age sex or CYP polymorphisms alone and future work needs to
account for all of these factors so that we may better approach
personalized medicine for optimal outcomes.