The successful sequencing of the human genome brought with it innumerable advances in biotechnology, science, and medicine, not the least of which is the ability to tailor medications to a patient’s genetic makeup. Pharmacogenomics is the study of how genes influence an individual’s response to medications. Although the term often is used interchangeably with pharmacogenetics, the latter usually refers to how polymorphisms in a single gene influence response to a single medication.
Pharmacogenomic information is available in the product labeling of more than 150 FDA-approved drugs and describes the risk for adverse drug events, genotype-specific dosing, and/or variations in pharmacokinetic and pharmacodynamic parameters.1 Since the 1950s, pharmacogenomic research has sought to uncover the relationship between treatment response and inherited genetic differences, but the application of these findings in clinical practice in a sustainable and scalable model is a more recent initiative with immense potential to further enhance patient care.
Common Therapeutic Uses
The Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines were created to help clinicians interpret and apply genetic results to the care of patients.2 To date, there are published CPIC guidelines applying to 16 drug classes (see TABLE 1); all guidelines are regularly updated to incorporate emerging evidence, and evidence is reviewed periodically to develop guidelines for additional drug-gene pairs.
Preventing adverse drug events (ADEs) is a national patient safety priority, as ADEs account for more than 700,000 emergency department visits and 120,000 hospitalizations annually and add up to approximately $3.5 billion in extra medical costs.3,4 For several medications, pharmacogenomics can help clinicians predict whether a patient may experience a particular adverse drug reaction given a typical dose of the drug. A classic example is the thiopurine methyltransferase (TPMT) gene, which encodes the TPMT enzyme involved in inactivating thiopurines, such as azathioprine and mercaptopurine, often prescribed for patients with acute lymphoblastic leukemia or inflammatory bowel disease.5 A person who inherits two inactive TPMT alleles has deficient TPMT activity, which can lead to accumulation of high concentrations of the active thioguanine nucleotide metabolite and, subsequently, severe myelosuppression. Obtaining a TPMT genotype before a thiopurine is prescribed can determine proactively whether prescribing a thiopurine is a safe therapeutic option and if a dose reduction is warranted to minimize the risk of myelosuppression.
For certain medications, routine therapeutic drug monitoring is the standard of care, as attaining and maintaining drug levels within a narrow therapeutic range can be challenging. Organ transplant recipients, for example, who require long-term immunosuppressive therapy, are among the most complex to manage. Individualizing immunosuppressants in the critical days after transplantation is key to preventing organ rejection and prolonging graft function and survival. Although therapeutic drug monitoring is helpful for adjusting doses based on trough concentrations, it is not helpful for determining the initial dose. Consider, for example, the fact that tacrolimus is metabolized by CYP3A5. In addition to other clinical factors, knowing a patient’s CYP3A5 genotype can help tailor the initial dose and increase the likelihood of quickly achieving target concentrations of the immunosuppressant.6
Pharmacogenomics can be utilized to select the medication that is likely to work best for a patient when there are several options in a particular drug class to choose from, such as antiplatelet therapy prescribed for patients undergoing a percutaneous coronary intervention after a myocardial infarction. Clopidogrel is broken down to its active metabolite via a two-step enzymatic process involving CYP2C19. Patients prescribed clopidogrel with a CYP2C19 genotype reflective of poor CYP2C19 function are at increased risk for adverse cardiovascular events due to reduced platelet inhibition and increased residual platelet aggregation.7 In the absence of contraindications, prasugrel and ticagrelor are preferable to clopidogrel.
While many of the pharmacogenomic examples provided thus far concern germline variations, tumor molecular profiling can be performed to guide chemotherapy and other targeted therapies. For example, in patients with unresectable or metastatic melanoma who harbor BRAF V600E or V600K mutations, a signaling pathway (MAPK/ERK pathway) is hyperactivated leading to tumor cell growth and proliferation.8 This hyperactivated signaling pathway can be targeted and suppressed with trametinib, an MEK inhibitor.
Integrating Pharmacogenomics Into Patient Care
Health care centers implementing pharmacogenomics are currently taking one of two approaches. Pharmacogenomic testing can be performed and integrated into patient care activities either preemptively (before a drug is prescribed) or at the time a drug is prescribed. With preemptive pharmacogenomic testing, a panel of genes is tested on a patient and stored in the electronic health record (EHR) so that results are available for clinical decision-making at the time a medication is prescribed. The main advantage to preemptive pharmacogenomic testing is that a single blood test or buccal swab supplies results that are applicable over a patient’s lifetime, informing not only present, but future, treatments with pharmacogenomic information.
Another approach to implementing pharmacogenomics is to introduce a single gene at a time into the health system, providing immediate benefits from testing and increasing the likelihood that results are utilized to guide treatment. The downside is that waiting until a clinician determines a patient needs a medication impacted by pharmacogenomics can cause treatment delays, particularly if the lab has a long turnaround time for results.
Pharmacogenomics can be an invaluable tool for preventing ADEs, tailoring initial doses of certain drugs and quickly achieving target concentrations of others, guiding chemotherapy and other targeted therapies, and narrowing drug choices within a class.
The second part of this two-part series will discuss how to implement a pharmacy-managed pharmacogenomics clinic.
Teresa T. Vo, PharmD, BCPS, is an assistant professor at the University of South Florida (USF) College of Pharmacy and College of Medicine, where she is leading initiatives to implement pharmacogenomics. Prior to joining USF Health, she completed a pharmacy practice residency at Memorial Health University Medical Center and a clinical pharmacogenomics residency at the University of Florida Health Personalized Medicine Program.
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