Characterization of hepatic enzyme activity in older adults with dementia: potential impact on personalizing pharmacotherapy

Abstract

Objective

To determine the frequency of pharmacogenomic variants and concurrent medications that may alter the efficacy and tolerability of acetylcholinesterase inhibitors (AChEIs).

Materials and methods

A multisite cross-sectional study was carried out across four memory care practices in the greater Indianapolis area. Participants were adults aged 65 years and older with a diagnosis of probable or possible Alzheimer’s disease (AD) (n=105). Blood samples and self-reported medication data were collected. Since two of the three AChEIs are metabolized by cytochrome P450 (CYP)-2D6, we determined the frequency of functional genetic variants in the CYP2D6 gene and calculated their predicted CYP2D6-activity scores. Concurrent medication data were collected from self-reported medication surveys, and their predicted effect on the pharmacokinetics of AChEIs was determined based on their known effects on CYP2D6 and CYP3A4/5 enzyme activities.

Results

Among the 105 subjects enrolled, 72% were female and 36% were African American. Subjects had a mean age of 79.6 years. The population used a mean of eight medications per day (prescription and nonprescription). The CYP2D6 activity score frequencies were 0 (3.8%), 0.5 (4.8%), 1.0 (36.2%), 1.5–2.0 (51.4%), and >2.0 (3.8%). Nineteen subjects (18.1%) used a medication considered a strong or moderate inhibitor of CYP2D6, and eight subjects (7.6%) used a medication considered a strong or moderate inhibitor of CYP3A4/5. In total, 28.6% of the study population was predicted to have reduced activity of the CYP2D6 or CYP3A4/5 enzymes due to either genetic variants or concomitant medications.

Conclusion

Both pharmacogenetic variants and concurrent drug therapies that are predicted to alter the pharmacokinetics of AChEIs should be evaluated in older adults with AD. Pharmacogenetic and drug-interaction data may help personalize AD therapy and increase adherence by improving tolerability.

Keywords:

• dementia
• acetylcholinesterase inhibitor
• pharmacogenomics

Acknowledgments

This work was supported by grant R01HS019818-01 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors, and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. The sponsor had no role in the study design, evaluation, or manuscript development.

Disclosure

The authors report no conflicts of interest in this work.

Supplementary materials

Table S1 Cytochrome P450-2D6 genotype frequencies and Hardy–Weinberg (HW) test

Table S2 Medications with influence on hepatic enzymes used by study subjects