PACE Case: Optimizing Medications through Pharmacogenomic Testing

A 68-year-old female PACE participant presents with a past medical history of type 2 diabetes, diabetic neuropathy, anxiety, gastroesophageal reflux disease (GERD), and osteoporosis. She tells the PACE prescriber about her uncontrolled symptoms of depression and increased GERD symptoms during the evening. The participant’s MedWise Risk ScoreTM is 30 out of 50 (high).

The participant’s medication regimen includes:

  • Acetaminophen 650 mg, 1 tablet PO every eight hours as needed for pain
  • Aspirin 81 mg, 1 tablet PO daily for circulation
  • Metformin ER 500 mg, 1 tablet PO daily with breakfast for blood sugar control
  • Insulin glargine (Lantus® Solostar pen) 100 units/ml, 12 units SQ once daily for blood sugar control
  • Pregabalin 150 mg, 1 capsule PO twice daily for nerve pain
  • Venlafaxine 150 mg + 37.5 mg, 1 capsule (187.5 mg) PO daily for mood
  • Ibandronate 150 mg, 1 tablet PO once a month
  • Lisinopril 40 mg, 1 tablet PO daily for blood pressure
  • Atorvastatin 40 mg, 1 tablet PO daily at breakfast for cholesterol
  • Omeprazole DR 20 mg, 1 tablet PO daily for heart burn
  • Ranitidine 150 mg, 1 tablet PO twice daily for stomach acid
  • Buprenorphine 15 mcg/hour, 1 patch topically once weekly for pain
  • Ondansetron 4 mg, 1 tablet PO daily as needed for nausea

During a polypharmacy call with a CareKinesis clinical pharmacist, the PACE prescriber stated that the participant did not experience any symptom relief despite the venlafaxine dose increase. The pharmacist recommended ordering a pharmacogenomics (PGx) test to determine if genetic variants in metabolizing enzymes were influencing the efficacy and safety of the participant’s drug regimen. The prescriber ordered the PGx test and the results revealed that the participant had the following variants:

  • CYP2C19: Ultra-rapid metabolizer (UM)
  • CYP2D6: Poor metabolizer (PM)

The presence of the two variants has the potential to affect the participant’s medication regimen significantly. The participant currently takes omeprazole and venlafaxine at the same time of the day, both of which are metabolized through CYP2C19. However, omeprazole has a stronger affinity for CYP2C19 compared to venlafaxine. Due to this multi-drug interaction, the participant may be phenoconverted from a CYP2C19 UM to a normal metabolizer (NM) for venlafaxine. Venlafaxine is also metabolized through CYP2D6, for which this individual is a PM. Due to the multi-drug-gene interaction, the participant is likely to have a higher concentration of venlafaxine. Of note, venlafaxine is an active drug, which is further metabolized to both inactive and active metabolites (e.g., desvenlafaxine) via CYP2C19 and CYP2D6. The participant is a CYP2D6 PM, therefore higher concentrations of venlafaxine are expected, increasing the risk for side effects. Additionally, the effectiveness of venlafaxine has been associated with its ratio between the active metabolite, desvenlafaxine. Therefore, this individual is at an increased risk for both side effects and potential pharmacotherapy failure.

The participant currently takes omeprazole for GERD. Because the participant is a CYP2C19 UM, which is a major pathway involved in the metabolism of omeprazole, she may be experiencing pharmacotherapy failure at normally prescribed doses due to the presence of this variant.

Clinical Pharmacist Recommendation(s):

  1. Consider tapering the participant off venlafaxine and initiating duloxetine utilizing a cross-taper technique. Per the Dutch Pharmacogenomics Working Group (DPWG) guidelines, venlafaxine can be substituted for duloxetine, which is not metabolized by CYP2C19. Although duloxetine is metabolized through CYP2D6, current guidelines state that the clinical effects of CYP2D6 polymorphisms are not significant for duloxetine.
  2. Consider increasing the dose of omeprazole to manage the participant’s GERD symptoms. Based on guidelines for the CYP2C19 UM phenotype, if PPIs are required, a dose increase of up to three-fold should be considered for omeprazole. Continue to assess GERD symptoms (e.g., dysphagia, heartburn, regurgitation of food or stomach contents) after the dose change and reassess periodically to determine if PPI therapy should be continued.
  3. In addition to the CNS depressant effects, older adults may be particularly susceptible to the constipating effects of opioids. Nausea, a GERD symptom, is often the result of opioid-induced constipation. The prophylactic use of a chronic stimulant laxative is recommended with opioid use. If buprenorphine is continued for pain management, consider initiating scheduled constipation prophylaxis with senna 8.6 mg to 17.2 mg QD to BID.

All of the recommendations were accepted by the PACE prescriber. The prescriber reports the participant’s mood is stable, as is the fibromyalgia pain since the switch to duloxetine and with the continued pregabalin. The prescriber also reported the participant is controlled on both the omeprazole and ranitidine combination, however, she will continue to monitor. Utilizing PGx results, in conjunction with the use of the MedWise™ Matrix, the CareKinesis clinical pharmacist was able to identify possible reasons for the participant’s lack of response to both venlafaxine and omeprazole, and optimize her pharmacologic therapy by individualization.

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