The PACE philosophy centers on the belief that frail individuals and their families should be served in the community whenever possible.1 Under a value-based model, PACE programs assume full financial risk to provide comprehensive services—coordinated by their interdisciplinary team (IDT) of health professionals—to help participants maintain independent living and avoid nursing home placement for as long as medically feasible.2 Thus, PACE programs are financially incentivized to avoid unnecessary healthcare utilizations and medical expenditures, such as emergency department (ED) visits and hospitalizations,2 and to promote favorable outcomes for participants.
This review synthesizes published evidence on the clinical, economic, and humanistic outcomes of incorporating pharmacogenomics (PGx) into the PACE model of care. Notably, several of these peer-reviewed studies were co-authored by current members of the ChorusRx team who are long-time researchers at the intersection of PGx and PACE.
Older adults are particularly susceptible to medication-related problems (MRPs) and vulnerable to adverse drug events (ADEs). MRPs are suboptimal situations in which medication regimens cause or contribute to negative outcomes;7,11 ADEs are injuries resulting from medical interventions related to drugs.3 Contributing factors include:
MRPs and ADEs impose a significant burden on the U.S. healthcare system. In outpatient settings alone, they account for approximately 3.5 million physician office visits, 1 million ED visits, and 125,000 hospital admissions annually.3,4 The annual cost of medication-related morbidity and mortality exceeds $500 billion, which is roughly 20% of total U.S. healthcare expenditures.5 Further, it costs about $2,500 to treat an individual who experiences a treatment failure or a new medical problem after initial medication use.5 This level of polypharmacy substantially raises the risk of MRPs and ADEs.
PACE participants represent a clinically complex cohort of older adults. On average, they are 75 years old, have several functional limitations, and are diagnosed with six chronic conditions.6 According to the National PACE Association, a typical PACE participant has approximately six prescriptions filled per month.6 However, this figure underestimates total medication burden. Data from pharmacies servicing PACE programs indicate that participants take closer to 13 to 16 medications per day.7-10 This level of polypharmacy substantially raises the risk of MRPs and ADEs.3,7,11
PACE participants are particularly susceptible to medication-related problems and adverse drug events.
An observational study found an average of two clinically actionable MRPs per PACE participant.7 Most often, these problems involved three or more drugs interacting simultaneously, as well as drug classes frequently implicated in safety concerns for older adults, including anticoagulants, antiplatelets, antidepressants, antipsychotics, and opioids. More than half of the drug interactions involved pharmacokinetic-based interactions, and most of these interactions involved the cytochrome P450 (CYP450) enzyme system.
PACE providers regularly encounter complex prescribing scenarios that require specialized medication expertise—such as that provided by geriatric pharmacists—to optimize care for their participants. Another study found that, over a 10-month period, PACE providers directed 414 drug information inquiries to board-certified geriatric pharmacists during routine interdisciplinary care.8 More than half of these inquiries concerned medication safety issues.8
When responding to drug information inquiries, pharmacists most recommended starting alternative therapies (18.0%), initiating new medications (16.7%), and changing drug dosages (12.1%).8 Prescribers implemented at least 79.3% of recommendations made by pharmacists,8 showing high trust in pharmacist expertise and strong interdisciplinary collaboration.
Prescribers typically accept nearly 80% of pharmacists’ recommendations to mitigate MRPs and ADEs for PACE participants.7,8
These studies underscore the real-world medication safety challenges confronting PACE providers. They also provide compelling evidence for integrating pharmacists into the IDT as a high-value strategy for safeguarding PACE participants. However, because PACE programs bear 100% of the financial risk for medication-related morbidity, additional proactive strategies are needed to minimize harm and optimize outcomes for participants.
Genetic variant information also allows a clinician to identify phenoconversion, a process whereby drug interactions can modify a genotype-predicted phenotypic expression.10,13-16 For example, an individual with a CYP2D6 *1|*1 genotype is predicted to be a normal CYP2D6 metabolizer. However, when taking paroxetine—a potent CYP2D6 inhibitor—they would be converted to a poor metabolizer phenotype.16,17 In this state, the metabolism of CYP2D6 substrates such as risperidone would be impaired, potentially increasing the risk of risperidone-related toxicity.16
Incorporating genetic factors into a precision medicine strategy could help PACE organizations identify participants at the highest risk for medication-related morbidity and ultimately help curb the clinical and economic consequences of MRPs and ADEs.
PGx is a core element of precision medicine that examines how genetic factors contribute to variability in medication response. Clinicians can apply PGx information to guide medication selection and dosing—maximizing benefits while minimize risks to the individual.10,18
Historically, a major barrier to implementing PGx into routine clinical care was the lack of guidance on applying test results to medication regimens. To overcome this barrier, several government and professional organizations have translated research findings into evidence-based clinical actions for drug-gene interactions. PGx information is now included in the labeling of more than 400 FDA-approved drugs19 and the Clinical Pharmacogenetics Implementation Consortium (CPIC) has published evidence-based guidelines for over 150 drugs with actionable recommendations based on PGx information.20
PGx involves using information about a participant’s genetic variants to optimize their medication regimen.
When PGx testing is integrated into PACE, pharmacists are empowered to detect MRPs—particularly drug-gene interactions—that may otherwise go undetected but are clinically significant for optimizing medication use in older adults.10,21
The PHARM-GENOME-PACE project evaluated the feasibility of implementing pharmacist-led PGx services in PACE.10 During the project period, 296 participants had their PGx test results interpreted by PGx-trained, board-certified geriatric pharmacists.10 Nearly every participant (99.7%) had at least one genetic variant, and more than one-third (35.8%) had four or more.10 During consultations, pharmacists discovered that participants frequently used drugs posing drug-gene interactions risks. Most participants had at least one drug-gene interaction; 29.1% had one interaction, 24.3% had two interactions, 10.5% had three interactions, and 9.8% had four or more interactions.10 The most frequently implicated drug classes for drug-gene interactions were anticoagulants, antiplatelets, antidepressants, and opioids.10 These drug classes are frequently implicated in safety concerns for older adults,7 most notably drug-induced falls, ED visits, and hospitalizations.3,12,22-24 Among the 446 drug-gene interactions, pharmacists determined that more than half were severe enough to warrant a drug dosage adjustment or a medication regimen change.10 The overwhelming majority (89.0%) of pharmacists' recommendations to mitigate PGx-associated risks were accepted by referring prescribers.10
This innovative project demonstrated that PACE programs can feasibly implement pharmacist-led PGx services.10 Moreover, the project highlighted the leadership role of pharmacists in moving PGx from research to practice within the PACE model of care. Pharmacists and prescribers can collaborate to integrate PGx information into participants’ care and PACE workflows.10
Nearly 3 out of 4 PACE participants have at least one drug-gene interaction that may warrant a medication regimen change.10
Based on a convenience sample of 100 participants from the PHARM-GENOME-PACE project, researchers found a high prevalence of genetic variants and interactions in this population:25
CYP2D6 was the most frequently implicated gene, accounting for 36.1% of drug-gene interactions and 39.2% of drug-drug-gene interactions.25 Furthermore, the majority (62.9%) of the phenoconversions pharmacists affected the CYP3A4 isoenzyme.25
These findings have clinical and financial implications for PACE participants. First, without PGx testing, potentially harmful drug interactions may go undetected in participants. Second, genetic variants affecting the most clinically relevant CYP450 isoenzymes—such as CYP2D6 and CYP3A4—may influence responses to a substantial proportion of medications taken by participants, many of which are metabolized by or inhibit these enzymes.14,15,26-28
As an example, certain opioids prescribed for pain management, such as codeine, hydrocodone, oxycodone, and tramadol, undergo biotransformation via CYP2D6 to produce the active metabolites responsible for their analgesic effects. This includes codeine to morphine, hydrocodone to hydromorphone, oxycodone to oxymorphone, and tramadol to O-desmethyl-tramadol.29 The clinical and financial implications of CYP2D6 variants that impair this pathway are well-documented.18,29-32 In one analysis, average healthcare expenditures were more than $2,000 higher for opioid users with CYP2D6-mediated drug-drug interactions, compared to those without interactions.31
Many medications prescribed for PACE participants could be affected by genetic variants and interactions with CYP450 isoenzymes.25
Landmark studies have demonstrated that applying PGx information to optimize medication regimens can reduce MRPs and enhance therapeutic effectiveness while reducing costs, compared to traditional prescribing methods or standards of care.33-37 A systematic review found that PGx-guided treatments (based on CPIC guidelines) were cost-effective or cost-saving in 71% of studies.35 In a study of older adults taking psychoactive medications, PGx-guided prescribing yielded cost savings of $3,000 per member per year, compared to traditional prescribing.37 Finally, an extension of the PHARM-GENOME-PACE project found that pharmacist recommendations, guided by PGx testing, could avoid $1,000 to $2,000 per actionable drug-gene interaction.38
These studies demonstrate that that adding pharmacist-led PGx services to traditional medication management could avoid substantial costs for PACE programs.38 Actual savings in 2026 are likely even higher due to declining PGx testing costs, inflation adjustments, and the lifelong utility of test results across the care continuum.
PGx testing in PACE populations can enhance medication safety and effectiveness while reducing unnecessary medical costs.
| ← REACTIVE |
⇄ HYBRID |
→ PROACTIVE |
| Participant not responding to drug(s) as intended (e.g., ineffectiveness) despite therapy adjustments | Participant expected to be prescribed new drug(s) for which actionable PGx-based recommendations exist | Participant due for assessment of reenrollment, requiring comprehensive medication review |
A supplemental strategy is to engage PGx-trained pharmacists to help identify participants at greatest risk for MRPs, including genetic interactions, and determine who could benefit most from PGx testing.10 This strategy can optimize the clinical utility of PGx testing and avert unnecessary spending within PACE’s capitated payment model.
An individual’s genetic profile remains constant throughout their life, regardless of age or chronic health conditions.39 This has an important clinical implication: PGx results are portable and can inform every future medication decision.10,40 Once enrolled, PACE participants can remain in the program through the end of their lives, provided they maintain functional and financial eligibility.41 Participants are typically enrolled in PACE for a period of three to five years.41,42 Consequently, PGx testing offers lifelong clinical utility for PACE participants due to the immutable and portable nature of genetic data.39 Because PGx data continuously guides future prescribing decisions, PACE organizations may realize an escalating financial return on investment with PGx testing.
PACE programs can realize a compounding return-on-investment with PGx testing, since genetic information continuously informs prescribing decisions.
PACE participants face elevated risk for MRPs and ADEs due to older age, polypharmacy, and multimorbidity. While aging and chronic disease do not alter a participant’s genetic profile, polypharmacy can significantly impact phenotypic expression through drug-gene and drug-drug-gene interactions. PGx testing enables clinicians to identify these interactions, uncovering otherwise hidden sources of medication risk before they lead to ADEs and poor outcomes.
Evidence-based PGx guidelines, including those published by CPIC, have grown immensely over the past decade, strengthening the integration of PGx into clinical practice settings such as PACE. Concurrently, studies have increasingly demonstrated that PGx testing maximizes the benefits and minimizes the risks of high-risk drugs in older adults, including anticoagulants, antiplatelets, antidepressants, and opioids, reaping improved economic outcomes for healthcare organizations.
The PACE model of care presents an excellent opportunity for utilizing PGx testing in clinically complex older adults. As medication experts, pharmacists are well-equipped to collaborate with PACE IDTs on applying PGx information to optimize medication regimens and deliver on what matters most: enabling participants to live independently and safely.
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