Patients often wonder why certain medications give them significant side effects. Meanwhile, a clinician may question why a prescribed drug didn't work as well as expected.
Pharmacogenomics — or the science of how genetic variations influence a person’s response to medications — can help explain and anticipate these outcomes, making medication therapy even safer and more effective. But its use may not always be appropriate in every patient case, said speakers at Place Your Bet on Pharmacogenomics (PGx) but Know Your Limits, held Dec. 10 at the 2025 ASHP Midyear Clinical Meeting & Exhibition in Las Vegas.
Genetic variants can affect enzyme metabolism, transporter and receptor pathways, and other processes involved with drugs’ mechanisms of action. For example, standard dosing assumes a patient is a normal metabolizer of that medication. But someone’s genetic phenotype may make them an ultrarapid metabolizer, leading to lower drug concentrations in their systems, or a poor metabolizer who may be more likely to experience the unwanted effects of drug toxicity.
PGx testing can uncover these nuances and, given sufficient evidence, potentially guide pharmacists to adjust the medication dose, recommend alternatives, or at least monitor a patient more closely.
To illustrate how PGx can be applied in a clinical setting, the presenters walked through the hypothetical case study of KC, a 32-year-old woman with depression and chronic pain, among other conditions. Venlafaxine was ineffective at easing her depression symptoms and resulted in persistent nausea. She had previously experienced extreme fatigue when trying escitalopram.
KC is a good candidate for PGx testing, the presenters shared, as it could account for her medication responses and help inform future medication choices. KC’s PGx results, especially pertaining to the CYP2C19 and CYP2D6 genes, indicated the venlafaxine was likely to be working at about 50% efficacy, prompting a switch to fluoxetine.
The presenters also touched on the concept of phenoconversion, when factors such as age, comorbidities, or drug interactions can change a patient’s expressed phenotype, further complicating their medication response. They noted that fluoxetine is a strong inhibitor of CYP2D6, the same gene that activates tramadol, another medication their hypothetical patient takes to manage pain.
Therefore, it would be advisable to choose an antidepressant for KC that won’t interfere with her pain relief. But if this patient had been taking fluoxetine for several months and was doing well, it might be more appropriate to instead select a non-opioid or opioid not impacted by CYP2D6, such as morphine.
In this way, PGx provides a layer of nuance to clinical decision-making without dictating a certain plan of action. “This does not overrule a patient’s actual experience with the medications. We also don’t fix what’s not broken,” said Emily J. Cicali, clinical associate professor at the University of Florida College of Pharmacy. The success of using PGx guidelines relies on having an accurate medication list for that patient, she added.
As a growing area of medicine, PGx has its limitations. Allele names, functions, and phenotype metabolizers are not yet standardized across different resources, making cross-referencing tricky. PGx guidelines are not available for all medications, and testing results do not guarantee a medication will be effective or toxic. Also, PGx results cannot account for past or future allergic reactions. Patients who have had a liver or bone marrow transplant require further consideration, because the DNA in the donated organs won’t match the white blood cell DNA captured by the PGx blood test.
Also, clinicians should not use race, ethnicity, or ancestry as a proxy for PGx recommendations. The human population is too heterogenous for such generalizations to be accurate. “DNA testing is the only way to confirm the presence of a particular genetic variation,” warned Sarah C. Mills, clinical pharmacist practitioner of pharmacogenomics at the Veterans Health Administration.
The presenters pointed to resources for high-quality, evidence-based PGx guidelines that can help clinical pharmacists decide when to order PGx testing and how to interpret the results, including the U.S. Food and Drug Administration and the Clinical Pharmacogenomics Implementation Consortium. Reliable PGx data is available for hundreds of medications, ranging from specialty drugs to some of the most-prescribed treatments — and the number is quickly growing.
More PGx research is needed to identify additional gene-drug interactions, discover unknown variants, and better understand the role of epigenetics in medication response.
“Everyone wants to avoid the undesirable outcomes of a failed therapy treatment, but we also want to maximize the patient’s quality of life,” said Halle Brady, clinical PGx pharmacist with Sanford Health. “Pharmacogenomics can help us in this balancing act of choosing therapy.”
