PACE Case: Individualizing Medication Recommendations Using Pharmacogenomic Test Results

Challenges
JB is an 81-year-old female PACE participant with a past medical history of allergic rhinitis, anxiety, chronic back pain, chronic kidney disease (CKD) stage 3, coronary artery disease (CAD), dementia with behavioral disturbances, gastroesophageal reflex disease (GERD), hyperlipidemia (HLD), major depressive disorder (MDD), neuropathy, and osteoporosis. She has been admitted to the emergency room multiple times in the past six months due to increased aggressive behaviors with staff and other participants at the PACE center.

Given the participant’s uncontrolled behavioral disturbances, the CareKinesis clinical pharmacist recommended individualizing the participant’s medication regimen by obtaining a pharmacogenomic (PGx) test and performing a medication safety review based upon the results. The participant’s initial MedWise Risk Score^TM was 29/50, which is considered high risk.

The participant’s medication regimen includes:

Genetic polymorphisms and PGx results of key CYP enzymes include:

• CYP1A2 – rapid metabolizer (RM)
• CYP2D6 – poor metabolizer (PM)

Drug-gene interactions identified by the pharmacist include the following:

• As a CYP1A2 RM, the participant’s enzyme activity is increased, potentially reducing the concentration of CYP1A2 substrates (olanzapine), increasing the risk for pharmacotherapy failure.
• As a CYP2D6 PM, the participant’s enzyme activity is significantly decreased, potentially resulting in higher plasma concentrations of CYP2D6 substrates (venlafaxine), increasing the risk of toxicity.

Multi-drug interactions identified by the pharmacist include the following:

• Atorvastatin is a moderate CYP3A4 substrate and mirtazapine is a weak CYP3A4 substrate. Co-administration of atorvastatin and mirtazapine leads to increased mirtazapine concentrations due to competitive inhibition. Although the percentage of mirtazapine metabolized via CYP3A4 is less than 30% and deemed insignificant, the combination of this interaction and the CYP2D6 drug-gene interaction is collectively significant.

Solutions
Based on the pharmacist’s findings and knowing the participant’s genetic makeup, the following recommendations were provided to the PACE prescriber for consideration:

• Olanzapine: Since the participant is a CYP1A2 RM, the concentration of olanzapine may be lower than expected, increasing the risk of pharmacotherapy failure. Given the participant’s uncontrolled aggressive behaviors, an alternative antipsychotic should be considered. Risperidone is the drug of choice for behavioral and psychological symptoms of dementia (BPSD), if an antipsychotic is warranted, risperidone has fewer anticholinergic effects and has a moderate to high level of efficacy in these participants.
  • If olanzapine is changed to risperidone, caution should be exercised when starting therapy, since risperidone is extensively metabolized via the CYP2D6 pathway and the participant is a poor metabolizer of CYP2D6.
• Venlafaxine: The concentration of venlafaxine may be higher than expected due to the participant’s CYP2D6 poor metabolizer status, which can increase the risk of adverse effects from venlafaxine, such as insomnia, weight loss, and dizziness. The participant may experience prescribing cascades due to taking mirtazapine for insomnia and meclizine for dizziness. Per the Dutch Pharmacogenetics Working Group (DPWG) guidelines, venlafaxine should be avoided in participants with poor metabolizer status. Antidepressants that are not metabolized by CYP2D6, or to a lesser extent, like citalopram, should be considered. Please note that citalopram has been studied compared to placebo to manage agitation in dementia patients and provided a clinically apparent reduction in agitation at a 30mg dose. However, doses of citalopram should not exceed 20mg per day in older adults due to the risk of QT prolongation, especially in participants with other risk factors.
• Meclizine: Meclizine is a highly anticholinergic and sedating medication. Evidence has demonstrated that medications with strong anticholinergic and sedative properties are associated with cognitive and physical impairment, including causative or worsened delirium, and falls and fractures. Additionally, the participant’s dizziness may be caused or worsened by the risk of higher than expected concentration of venlafaxine due to the participant’s CYP2D6 PM status. It may be appropriate to consider a gradual dose reduction of meclizine to the lowest effective dose with a goal to discontinue therapy once venlafaxine therapy is changed to an alternative medication.
• Mirtazapine: Since the participant’s insomnia may be a potential risk of high venlafaxine concentration, it may be appropriate to consider re-evaluating the need for mirtazapine, once venlafaxine is switched to an alternative medication. Given the present drug-gene (CYP2D6 PM) and drug-drug interaction (competitive inhibition via CYP3A4 with atorvastatin), the participant is expected to be at an increased risk of adverse drug events associated with mirtazapine. If therapy is continued, it is recommended to separate the time of administration of mirtazapine by at least two to four hours from atorvastatin or consider switching to pravastatin, which is not metabolized via the CYP450 pathway, as appropriate. Additionally, the dose of mirtazapine can be decreased, if the participant experiences any adverse effects, such as drowsiness, xerostomia, and constipation.

Conclusion
PGx test results allowed the PACE clinical pharmacist to offer individualized medication recommendations for this participant based upon her genetic makeup. Possible prescribing cascades were also discovered and addressed. With the acceptance of all recommendations above, the participant’s MedWise Risk Score would decrease to 17/50 (moderate), with the opportunity to further lower the participant’s medication-related risk at future assessments.

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