Precision Medicine in Action: The Role of Pharmacogenomics in Guiding Prescribing

Modern medicine has traditionally relied on a reactive, one-size-fits-all prescribing approach. Under this approach, patients are prescribed a standard first-line drug at a predetermined dose based on their diagnosed condition. Unfortunately, this overlooks the biological complexity of individual patients, often resulting in treatment failures or severe adverse drug reactions.

The medical community is transitioning away from this unpredictable trial-and-error cycle and pivoting toward precision medicine. Precision medicine is a broad concept that integrates multiple clinical and molecular variables to customize health care delivery to a patient’s genetic footprint.¹ Genomic medicine has become an important aspect of precision medicine and encompasses many areas, including proteomics, transcriptomics, metabolomics, and metagenomics, each providing biomarkers that can be useful as therapeutic guides.²

Pharmacogenomics recognizes that small variations in DNA can alter drug absorption, distribution, metabolism, and excretion. By identifying patient-specific genetic profiles prior to prescribing, pharmacogenomics can bridge the gap between raw genetic data and clinical decision-making, optimizing therapeutic selection and dosing while minimizing medication risks.¹

Understanding Pharmacogenomics

Individual genetics affect how the body responds to medications, primarily by altering the structure or activity of metabolic enzymes, drug transporters, and cellular receptors. These genetic variations may change how a drug moves through the body (pharmacokinetics) or what the drug does to the body (pharmacodynamics). Pharmacogenomics can explain why a medication may be very effective for one patient, ineffective for another, and toxic for yet another patient.

Pharmacokinetics: Altering Drug Processing

Mutations in DNA most commonly affect metabolism, which primarily occurs in the liver via the cytochrome P450 (CYP) enzyme system. Patients are grouped into 4 metabolic categories based on genetic changes. Poor metabolizers lack the functional enzymes required to break the drug down; intermediate metabolizers process drugs at a slightly reduced rate; extensive metabolizers process the drug at the standard, expected rate; and ultrarapid metabolizers metabolize the drug before it can work.³

The clinical effect of a specific metabolic category depends on how the drug is formulated. A standard active drug will not be cleared by poor metabolizers, leading to toxic buildup, whereas ultrarapid metabolizers clear it too quickly, rendering it useless. Prodrugs, which are inactive until metabolized, are not activated by poor metabolizers, and ultrarapid metabolizers create an active drug too quickly, risking toxicity.^4,5

Pharmacodynamics: Altering Drug Targets

Genetics also changes the shape or activity of the target the medication is trying to bind to, such as cellular receptors or proteins. If a gene mutation changes the receptor’s shape, the drug may be unable to bind to it, making it less effective. Certain genes can cause the immune system to mistakenly treat a medication as a foreign invader, creating an immune response.⁶

Clinical Applications

Pharmacogenomics helps guide physician prescribing to optimize therapeutic outcomes and minimize adverse effects.

Psychiatric and Mental Health

Selecting appropriate mental health medications often requires a trial-and-error approach that can be prolonged and increase patient suffering and suicide risks. Variations in the liver enzymes CYP2D6 and CYP2C19 strongly dictate the blood levels of common selective serotonin reuptake inhibitors and tricyclic antidepressants. Poor metabolizers are prone to drug toxicities, whereas ultrarapid metabolizers fail to experience the effect of the drug due to fast clearance.⁷

Cardiovascular

Some antiplatelet therapies, such as clopidogrel (Plavix; Sanofi, Bristol Myers Squibb), are inactive prodrugs that require enzyme activation through CYP2C19 to exert protective effects against stent thrombosis. Patients with genetically insufficient CYP2C19 enzymatic activity cannot activate the drug, leaving them unprotected.⁸

Variations in the CYP2C9 and VKORC1 genes affect how quickly patients break down warfarin (Coumadin; Bristol Myers Squibb), a commonly used blood thinner, as well as how sensitive their blood-clotting systems are to the drug. As warfarin has a narrow therapeutic index, clinicians use genetic testing to calculate the safest starting dose of warfarin, thereby preventing dangerous bleeding.⁹

Oncology

Pharmacogenomics in oncology uses the patient’s genetic profile and the tumor’s DNA to determine both how the patient processes drugs and how the tumor behaves, helping match patients with targeted therapies.¹⁰

When using thiopurines, genetic variations in the TPMT and NUDT15 enzymes can cause severe bone marrow suppression. Patients with dihydropyrimidine dehydrogenase deficiency cannot break down fluorouracil and capecitabine, which can lead to fatal toxicities if standard doses are given. Variants in UGT1A1 reduce the clearance of irinotecan (Camptosar; Pfizer), increasing the risk of severe diarrhea and neutropenia.¹¹ These are just a few examples of many in the field of oncology.

Infectious Disease and Immunology

Serious, immunologically driven hypersensitivities can be prevented through pharmacogenomic-guided prescribing. Testing for the HLA-B*57:01 allele is mandatory when treating patients with HIV with abacavir (Ziagen; ViiV Healthcare) to avoid fatal allergic reactions.¹² Similar testing may prevent severe cutaneous reactions, such as Stevens-Johnson syndrome, when initiating some epilepsy or pain medications.¹³

Benefits of Pharmacogenomic-Guided Prescribing

Pharmacogenomic-guided prescribing is a precise strategy in which treatments are tailored to a patient’s unique genetic makeup. By analyzing variations in the genes that encode drug-metabolizing enzymes and drug targets, pharmacogenomic-guided prescribing provides significant safety, efficacy, and economic benefits.¹⁴

Enhanced Safety

The prevention of severe, perhaps even life-threatening, adverse drug reactions remains the primary benefit of pharmacogenomic testing. This testing preemptively identifies genetic mutations that may interfere with pharmacokinetics or pharmacodynamics.¹⁵

Improved Efficacy

Pharmacogenomics helps clinicians find effective medications at the correct doses without wasting time on trial and error. By weeding out poor and ultrarapid metabolizers, clinicians can precisely identify the medication and dose that will most benefit the patient.

Economic Impact

Although there is an up-front investment in genomic testing, it provides long-term economic savings. Because individual DNA never changes, a single multigene panel test can serve as a permanent reference that safely guides prescribing across multiple medical specialties for a lifetime.

About the Author

Kathleen Kenny, PharmD, RPh, earned her doctoral degree from the University of Colorado Health Sciences Center in Aurora. She has more than 30 years of experience as a community pharmacist and works as a clinical medical writer based in Albuquerque, New Mexico.

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