Potential utility of precision medicine for older adults with polypharmacy: a case series study

Figures & data

Figure 1 Genetic variants tested in the study.

Table 1 Clinical summary of case series

Case #1	Case #2	Case #3
Demographics
74-Year-old/female/Hispanic/White	78-Year-old/male/Hispanic/White	83-Year-old/male/non-Hispanic/White
Comorbidities
Asthma, COPD, CHF, hypertension, type 2 diabetes, hyperlipidemia	CHF, atrial fibrillation, CKD, COPD, hyperlipidemia, gout, BPH, GERD, Patent Foramen Ovale, gastritis	COPD, atrial flutter, hypertension, herpes zoster, polyneuropathy
Medications
Albuterol sulfate	Albuterol sulfate	Albuterol sulfate
Aspirin	Allopurinol	Amiodarone HCl
Atorvastatin calcium	Atorvastatin calcium	Aspirin
Clonidine HCl	Calcitriol	Dabigatran etexilate mesylate
Diclofenac potassium	Carvedilol	Digoxin
Esomeprazole magnesium	Diltiazem HCl	Diltiazem HCl
Fluticasone propionate	Esomeprazole magnesium	Dimethyl sulfoxide
Fluticasone/salmeterol	Ferrous sulfate	Esomeprazole magnesium
Furosemide	Fluocinonide	Fluticasone/vilanterol
Lidocaine/prilocaine	Fluticasone/vilanterol	Furosemide
Losartan/hydrochlorothiazide	Furosemide	Gabapentin
Meclizine HCl	Losartan potassium	Lidocaine
Memantine HCl	Montelukast sodium	Losartan potassium
Metoclopramide HCl	Naproxen	Montelukast
Metolazone	Olopatadine hydrochloride	Polyethylene glycol 3350
Metoprolol succinate	Tamsulosin HCl	Pregabalin
Montelukast sodium	Warfarin sodium	Tamsulosin HCl
Nitrofurantoin monohyd/M-cryst		Tiotropium bromide
Nortriptyline HCl
Olopatadine HCl
Oxybutynin chloride
Prednisone
Primidone
Roflumilast
Sitagliptin phos/metformin HCl
Tiotropium bromide
Hospitalization history
Six hospitalizations in the past 5 years	23 hospitalizations in the past 5 years	Two hospitalizations in the past 5 years

Abbreviations: CHF, congestive heart failure; CKD, chronic kidney disease; BPH, benign prostatic hyperplasia; GERD, gastroesophageal reflux disease; COPD, Chronic Obstructive Pulmonary Disease.

Table 2 Genotype/phenotype results

Gene panel	Case #1	Case #2	Case #3
CYP2C19	*1/*1	*1/*1	*1/*1
	Normal metabolizer	Normal metabolizer	Normal metabolizer
CYP2C9/VKORC1	*1/*1/*A/*A	*1/*1/*G/*A	*1/*1/*G/*G
	Normal metabolizer/high sensitivity	Normal metabolizer/intermediate sensitivity	Normal metabolizer/low sensitivity
CYP2D6	*2/*4	*1/*2(XN)	*1/*4
	Normal metabolizer	Rapid metabolizer	Normal metabolizer
CYP3A4/CYP3A5	*1/*1B/*3/*6	*1/*1/*3/*3	*1/*1/*3/*3
	Poor metabolizer	Normal metabolizer	Normal metabolizer

Note: Bold entries indicate significant cytochrome polymorphism.

Figure 2 Potential drug–gene and drug–drug interactions in the Case #1.

Notes: S: substrate; +: inducer; −: inhibitor; yellow background: mutant allele.
Abbreviation: Hctz, hydrochlorothiazide.

Figure 3 Potential drug–gene and drug–drug interactions in the Case #2.

Notes: S: substrate; +: inducer; −: inhibitor; yellow background: mutant allele.

Figure 4 Potential drug–gene and drug–drug interactions in the Case #3.

Notes: S: substrate; +: inducer; −: inhibitor.

Table 3 Barriers for implementing PGx testing in older adults with polypharmacy in routine clinical care

Barrier	How to address
Limited number of certified PGx facilities	Create a comprehensive public resource of certified facilities that is maintained and curated by designated academic centers and industry
Lack of provider knowledge	Develop online CME courses and training tools
Complexity of PGx testing results	Introduce evidence-based clinical pathways
Uncertainty in interpretation of PGx results	Create and maintain evidence-based consensus guidelines
Lack of clinical evidence on using PGx results	Conduct clinical trials demonstrating clinical efficacy
EMR does not support PGx result storage and review	Develop informatics solutions for storage, representation, and secure exchange of PGx data
Lack of computerized decision support	Introduce intelligent decision support allowing to account simultaneously for multiple drug–gene and drug–drug interactions and assist in medication regimen optimization
Lack of patient education	Develop interactive apps to support patient engagement in medication management and facilitate patient–provider communication on PGx testing

Abbreviations: PGx, pharmacogenomic; CME, continuing medical education; EMR, electronic medical record.

Table S1 Summary of potential drug–gene and drug–drug interactions in Case #1

	Impact	Action	Mechanism
Drug–gene interactions
Atorvastatin calcium and CYP3A4/CYP3A5	Major	Consider dose reduction	CYP3A4/3A5 poor metabolizer status may lead to decreased metabolism of atorvastatin
Fluticasone/salmeterol and CYP3A4/CYP3A5	Major	Monitor therapy	CYP3A4/3A5 poor metabolizer status may result in decreased metabolism of fluticasone/salmeterol
Lidocaine/prilocaine and CYP3A4/CYP3A5	Major	Monitor therapy	Poor metabolizer status may result in decreased metabolism of CYP3A4/CYP3A5 substrates (lidocaine)
Losartan/hydrochlorothiazide and CYP3A4/CYP3A5	Moderate	Monitor therapy	Poor metabolizer status may result in decreased metabolism of CYP3A4/CYP3A5 substrates (losartan)
Montelukast sodium and CYP3A4/CYP3A5	Major	Monitor therapy	CYP3A4/3A5 poor metabolizer may cause decreased metabolism of montelukast
Prednisone and CYP3A4/CYP3A5	Moderate	Monitor therapy	Due to CYP3A4/3A5 poor metabolizer status, less prednisone (inactive) may be converted to prednisolone (active form)
Roflumilast and CYP3A4/CYP3A5	Moderate	Monitor therapy	CYP3A4/3A5 poor metabolizer status may result in increased exposure to roflumilast
Drug–drug interactions based on CYP450 metabolism
Primidone and roflumilast	Major	Avoid combination	CYP3A4 inducers (primidone) may decrease the serum concentration of roflumilast
Atorvastatin calcium and primidone	Major	Consider modification	CYP3A4 inducers (primidone) may increase the metabolism of CYP3A4 substrates
Losartan/hydrochlorothiazide and primidone	Major	Consider modification	CYP3A4 inducers (primidone) may increase the metabolism of CYP3A4 substrates
Diclofenac potassium and primidone	Moderate	Monitor therapy	CYP2C9 inducers (primidone) may decrease the serum concentration of diclofenac
Prednisone and primidone	Moderate	Monitor therapy	CYP3A4 inducers (primidone) may decrease the serum concentration of prednisone
Non-CYP450 drug–drug interactions
Meclizine HCl and tiotropium bromide	Major	Avoid combination	Anticholinergic agents may enhance the anticholinergic effect of tiotropium
Nortriptyline HCl and tiotropium bromide	Major	Avoid combination	Anticholinergic agents may enhance the anticholinergic effect of tiotropium
Oxybutynin chloride and tiotropium bromide	Major	Avoid combination	Anticholinergic agents may enhance the anticholinergic effect of tiotropium
Aspirin and diclofenac potassium	Major	Consider modification	An increased risk of bleeding may be associated with use of this combination
Clonidine HCl and metoprolol succinate	Major	Consider modification	Alpha2-agonists may enhance the atrioventricular-blocking effect of beta-blockers. Beta-blockers may enhance the rebound hypertensive effect of alpha2-agonists
Clonidine HCl and nortriptyline HCl	Moderate	Consider modification	Tricyclic antidepressants may diminish the antihypertensive effect of alpha2-agonists
Diclofenac potassium and furosemide	Moderate	Consider modification	Nonsteroidal anti-inflammatory agents may diminish the diuretic effect of loop diuretics
Metoclopramide HCl and nortriptyline HCl	Major	Consider modification	Metoclopramide may enhance the adverse/toxic effect of tricyclic antidepressants
Prednisone and roflumilast	Major	Consider modification	Roflumilast may enhance the immunosuppressive effect of prednisone
Meclizine HCl and oxybutynin chloride	Moderate	Monitor therapy	Anticholinergic agents may enhance the adverse/toxic effect of other anticholinergic agents
Nortriptyline HCl and oxybutynin chloride	Moderate	Monitor therapy	Anticholinergic agents may enhance the adverse/toxic effect of other anticholinergic agents

Table S2 Drug–drug interactions in Case #2

	Impact	Action	Mechanism
Drug–gene interactions
Carvedilol and CYP2D6	Major	Monitor therapy	CYPD6 rapid metabolizer status may increase metabolism of carvedilol
Warfarin and CYP2C9/VKORC1	Minor	Monitor therapy	Lower starting warfarin doses may be required due to reduced VKORC1 functionality
Drug–drug interactions based on CYP450 metabolism
Carvedilol and losartan potassium	Moderate	Monitor therapy	CYP2C9 inhibitors (losartan) may increase the serum concentration of carvedilol
Diltiazem HCl and fluticasone and vilanterol	Moderate	Monitor therapy	CYP3A4 inhibitors (diltiazem) may decrease the metabolism of CYP3A4 substrates
Losartan potassium and warfarin sodium	Moderate	Monitor therapy	CYP2C9 inhibitors (losartan) may decrease the metabolism of CYP2C9 substrates
Non-CYP450 drug–drug interactions
Albuterol sulfate and carvedilol	Major	Avoid combination	Beta-blockers may diminish the bronchodilatory effect of beta2-agonists
Carvedilol and fluticasone and vilanterol	Major	Avoid combination	Beta-blockers may diminish the bronchodilatory effect of beta2-agonists
Allopurinol and warfarin sodium	Moderate	Consider modification	Allopurinol may enhance the anticoagulant effect of vitamin K antagonists
Atorvastatin calcium and diltiazem HCl	Major	Consider modification	Diltiazem HCl may increase the serum concentration of atorvastatin calcium. Atorvastatin calcium may increase the serum concentration of diltiazem HCl
Carvedilol and tamsulosin HCl	Moderate	Consider modification	Beta-blockers may enhance the orthostatic hypotensive effect of alpha1-blockers
Furosemide and naproxen	Moderate	Consider modification	Nonsteroidal anti-inflammatory agents may diminish the diuretic effect of loop diuretics
Naproxen and warfarin sodium	Moderate	Consider modification	Nonsteroidal anti-inflammatory drug (nonselective) may enhance the anticoagulant effect of vitamin K antagonists

Table S3 Drug–drug interactions in Case #3

	Impact	Action	Mechanism
Drug–gene interactions
None	N/A	N/A	N/A
Drug–drug interactions based on CYP450 metabolism
Amiodarone HCl and losartan potassium	Moderate	Monitor therapy	CYP2C8 inhibitors (moderate) may decrease the metabolism of CYP2C8 substrates (amiodarone)
Diltiazem HCl and fluticasone/vilanterol	Moderate	Monitor therapy	CYP3A4 inhibitors (diltiazem) may decrease the metabolism of CYP3A4 substrates (fluticazone)
Diltiazem HCl and lidocaine	Moderate	Monitor therapy	CYP3A4 inhibitors (diltiazem) may decrease the metabolism of CYP3A4 substrates
Non-CYP450 drug–drug interactions
Albuterol sulfate and amiodarone HCl	Major	Consider modification	QTc-prolonging agents may enhance the QTc-prolonging effect of highest risk QTc-prolonging agents
Amiodarone HCl and dabigatran etexilate mesylate	Major	Consider modification	Amiodarone may increase the serum concentration of dabigatran etexilate
Amiodarone HCl and digoxin	Major	Consider modification	Amiodarone may increase the serum concentration of cardiac glycosides
Amiodarone HCl and diltiazem HCl	Major	Consider modification	Calcium channel blockers may enhance the bradycardic effect of amiodarone. Sinus arrest has been reported
Amiodarone HCl and fluticasone/vilanterol	Major	Consider modification	QTc-prolonging agents may enhance the QTc-prolonging effect of highest risk QTc-prolonging agents

Abbreviations: N/A, not available; QTc, corrected QT.