PACE Case Study: Clinical Application of Pharmacogenomics Testing to Reduce Adverse Effects

A 59-year-old male PACE participant has a past medical history of left pontine cerebrovascular accident (CVA), generalized anxiety disorder (GAD), major depressive disorder with psychotic features, sinus tachycardia, hypertension, chronic pain syndrome, degenerative joint disease, urinary retention, insomnia, tremor, schizoaffective disorder bipolar type, and chronic kidney disease stage 3 (CrCl 62 mL/min). His MedWise Risk Score™ at the time of review was 27 out of 50 (high).

The participant’s initial medication regimen included:

• Acetaminophen 500mg, 2 tablets PO TID for degenerative joint disease of hips, knee, and ankles
• Aspirin 81mg, 1 tablet PO daily for clot prevention
• Benztropine 0.5mg, 1 tablet PO daily for tremors
• Buspirone 15mg, 1 tablet PO TID for anxiety
• Doxepin 25mg, 1 tablet PO daily for insomnia
• Duloxetine 60mg, 1 capsule PO daily for schizoaffective disorder bipolar type
• Fentanyl 12mcg/hr patch, apply 1 patch topically every 72 hours for pain
• Hydroxyzine 25 mg, 1 capsule PO daily as needed
• Iloperidone 6mg, 1 tablet PO BID for schizoaffective disorder bipolar type
• Menthol/camphor 0.2%-3.5% gel, apply topically to the affected areas TID
• Metoprolol succinate ER 25mg, 1 tablet PO daily for hypertension and sinus tachycardia
• Midodrine 5mg, 1 tablet PO TID for orthostatic hypotension
• Midodrine 2.5mg, 1 tablet (+5mg) PO TID for orthostatic hypotension
• Pregabalin 150mg, 1 capsule PO BID for chronic pain

The PACE prescriber requested the CareKinesis clinical pharmacist to review the participant’s medication regimen with the goal of stabilizing his psychiatric symptoms and alleviating the current adverse effects such as orthostatic hypotension and tremor. To provide improved individualization of the participant’s medication regimen and mitigation of potential adverse effects, the prescriber also ordered a pharmacogenomic (PGx) test.

Genetic polymorphisms and PGx results of key CYP enzymes include:
• CYP2C9 – Poor metabolizer (PM)
• CYP2D6 – Intermediate metabolizer (IM)
• CYP2C19 – Normal metabolizer (NM)
• CYP3A5– Poor metabolizer (PM)

The CareKinesis clinical pharmacist reviewed the participant’s medication regimen for multi-drug interactions along with drug-gene interactions, which are drug interactions caused by presence of genetic variation. Drug-gene interactions identified include:

• As a CYP2D6 intermediate metabolizer, the participant’s enzyme activity is decreased, potentially increasing the concentrations of doxepin, duloxetine, iloperidone, and metoprolol.
• Although the participant is a CYP2C9 poor metabolizer, no medications in his initial regimen would be affected by this status.

Based upon the clinical pharmacist’s findings and the participant’s genetic results, the following recommendations were provided to the PACE prescriber for consideration:

    1. Duloxetine and metoprolol have stronger affinity for the CYP2D6 enzyme and buspirone has a stronger affinity for the CYP3A4 enzyme. These medications are expected to competitively inhibit the metabolism of iloperidone and may result in a process known as phenoconversion, whereby the individual’s phenotype is converted from a CYP2D6 intermediate metabolizer status to a poor metabolizer status. As a result, this participant is at an increased risk for adverse effects from iloperidone. To mitigate the CYP2D6 interaction with iloperidone, consider changing the time of administration for metoprolol and duloxetine from morning to noon. Additionally, to mitigate the CYP3A4 interaction, consider re-evaluating buspirone as recommended below.
    2. Doxepin has a high sedative and anticholinergic burden, which may increase the risk of falls and other adverse drug events (ADEs) in older adults. Additionally, the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend using a 25% reduction of the starting dose of doxepin in CYP2D6 intermediate metabolizers, then adjusting dose based on medication monitoring. Consider re-evaluating the benefit of continuing doxepin in this participant. If therapy is no longer deemed necessary, consider a gradual dose reduction of doxepin, with initiation of an alternative medication for insomnia, such as melatonin 1mg PO at bedtime. Counsel to take one hour prior to bedtime.
    3. The Dutch Pharmacogenetics Working Group (DPWG) guideline recommends that if a gradual reduction in heart rate is desired, or in the event of symptomatic bradycardia, consider increasing the metoprolol dose in smaller doses and/or prescribe no more than 50% of the standard dose. However, for other indications, the guideline does not recommend any changes; use clinical monitoring to guide dose adjustments. Closely monitor for ADEs of metoprolol such as hypotension, bradycardia, and dizziness. If the participant is experiencing signs and symptoms of toxicity, consider alternative antihypertensive therapy for metoprolol that is not primarily affected by CYP2D6 metabolism, such as atenolol, which also mitigates interactions since nonCYP metabolized.
    4. Buspirone has a stronger affinity for the CYP3A4 enzyme, as compared with fentanyl, iloperidone, and hydroxyzine, which are all weak substrates of the enzyme. As a result, buspirone is expected to competitively inhibit the metabolism of these medications when taken at or around the same time of day, resulting in increased concentrations and risk for adverse effects.
      • In an effort to mitigate this interaction, when participant becomes more stable, attempt a gradual dose reduction to discontinue buspirone, since duloxetine has anxiolytic effects. Buspirone has been known to have limited effectiveness for the treatment of anxiety in clinical practice. Due to its quicker onset of action, buspirone may initially be prescribed until therapeutic effects are seen with antidepressant therapy, which often takes at least four weeks. Akathisia, agitation and restlessness, has been reported in a small number of patients which may be a result of buspirone’s central dopamine receptor antagonism. Signs of dopamine-related movement disorders include dystonia, akathisia, pseudo-parkinsonism and tardive dyskinesia, all of which may be contributing to the tremor and increase fall risk.
      • Given the pharmacokinetic profile, potential for anticholinergic side effects and duplicate therapy, consider re-evaluating the use of as needed hydroxyzine.
  1. Duloxetine is a moderate substrate of the CYP2D6 enzyme. Since the participant’s genetic results indicate that he is an intermediate metabolizer of the enzyme, concentrations of duloxetine may be higher than expected. However, the participant is expected to respond well to therapy with duloxetine and clinical evidence does not support any dose reductions at this time. In consideration of experiencing orthostatic hypotension, requiring midodrine, consider reducing the duloxetine dose from 60mg to 30mg daily, and as tolerates, to 20mg daily. Continue to closely monitor for ADEs such as orthostatic hypotension that may increase fall risk, insomnia and/or drowsiness while the participant continues therapy with duloxetine.

Outcomes:
Hydroxyzine and doxepin were discontinued. Metoprolol was changed to atenolol 12.5mg daily in the morning, duloxetine dose was decreased to 30mg and administration time was changed to noon, and the iloperidone dose was decreased to 4mg BID. With the aforementioned medication changes made based on the clinical pharmacist recommendations, a significant improvement has been made in the participant’s medication safety. The participant’s MedWise Risk Score™ was reduced from 27 out of 50 (high risk) to 17 out of 50, which is considered moderate risk. The participant’s mood and tremor will continue to be monitored. A gradual dose reduction to potentially discontinue buspirone is being considered.

In an effort to mitigate this interaction, when participant becomes more stable, attempt a gradual dose reduction to discontinue buspirone, since duloxetine has anxiolytic effects. Buspirone has been known to have limited effectiveness for the treatment of anxiety in clinical practice. Due to its quicker onset of action, buspirone may initially be prescribed until therapeutic effects are seen with antidepressant therapy, which often takes at least four weeks. Akathisia, agitation and restlessness, has been reported in a small number of patients which may be a result of buspirone’s central dopamine receptor antagonism. Signs of dopamine-related movement disorders include dystonia, akathisia, pseudo-parkinsonism and tardive dyskinesia, all of which may be contributing to the tremor and increase fall risk.Given the pharmacokinetic profile, potential for anticholinergic side effects and duplicate therapy, consider re-evaluating the use of as needed hydroxyzine.Duloxetine is a moderate substrate of the CYP2D6 enzyme. Since the participant’s genetic results indicate that he is an intermediate metabolizer of the enzyme, concentrations of duloxetine may be higher than expected. However, the participant is expected to respond well to therapy with duloxetine and clinical evidence does not support any dose reductions at this time. In consideration of experiencing orthostatic hypotension, requiring midodrine, consider reducing the duloxetine dose from 60mg to 30mg daily, and as tolerates, to 20mg daily. Continue to closely monitor for ADEs such as orthostatic hypotension that may increase fall risk, insomnia and/or drowsiness while the participant continues therapy with duloxetine.