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.