Pharmacogenomic testing can increase effectiveness of needed therapies, avoid cost and patient frustration by eliminating ineffective therapies, and prevent or minimize adverse drug reactions.
In a study of over 140,000 people living in Olmsted County in the course of a single year, 70% of the population received at least one prescription, 50% received two or more prescriptions, and 20% received five or more prescriptions. With so many people takingso many drugs, providers need information that will increase effectiveness of needed therapies, avoid cost and patientfrustration by eliminating ineffective therapy, and preventor minimize adverse drug reactions.
The Mayo Clinic RIGHT Study looked at five different genes affecting drug metabolism in a group of more than 1,000 people and found that 99% ofthe participants had at least one genetic finding that could affect how they metabolize, or react to, drugs.
Would you like toknow more about understanding your patient's personal drug responseto help guide prescribing? In the next ten minutes, we'll explore three key messages regarding pharmacogenomics, commonly abbreviated as PGx. When you're finished watching,you should be able to discussimportant pharmacogenomic concepts, understand how pharmacogenomics impacts your practice, and identify resources foradditional information to support pharmacogenomics in your practice.
Before we get any further, it's important to understand some ofthe vocabulary commonly used,including pharmacogenomics, pharmacokinetics and pharmacodynamics. By definition,pharmacogenomics is the study ofhow genes affect a person's response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes andtheir functions) to develop effective, safe medications and doses that will be tailored to a person's genetic makeup.
A person's genes can affect pharmacokinetics, or how the body absorbs, metabolizes, distributes, and excretes drugs, and the concentration of thedrug in your body over time. A person's genes can also affect pharmacodynamics, or the effect the drug has on the body. A person's genetic makeup may result in a lack of desired effect or even adverse drug reactionsat normal concentrations.
To illustrate how pharmacogenomics can be important, let's review the following case study:
Dan went to see a doctor because of his history of major depressive disorder. He told his doctor that in the past his antidepressant medications did not work. His doctor prescribed 75 milligrams of venlafaxine daily. After two weeks, Dan still had unresolved symptoms, so his physician increased the dose to 150 milligrams daily. Even with the increased dose, he continued to struggle with the symptoms, and it was affecting his job.
His physician decided to order pharmacogenomic testing. Dan's pharmacogenomictest result showed that hewas a CYP2D6 poor metabolizer, indicating that he couldn't metabolize the prodrug venlafaxine into its active form. So, his physician changed the prescription to an antidepressant not metabolized by the CYP2D6 pathway and Dan's symptoms improved.
"Poor metabolizer." "Prodrug." "CYP2D6." Let's explore what these terms mean and what this all means for Dan. Cytochrome P450, often referred to as CYP or "sip," is a family of enzymes responsible for the metabolism of many drugs. In fact, the P450 enzyme CYP2D6 is involved in the metabolism of approximately 25% of all the drugs used clinically. Venlafaxine is a prodrug, which means it must be metabolized, or activated, before it will have the desired effect. Dan's CYP2D6 phenotype showed he was a poor metabolizer. This means that for prodrugs like venlafaxine, metabolized by CYP2D6, he can't fully activate the prodrug into its active form, which is why he did not get the desired therapeutic effect.
On the other hand, a patient who is an ultra-rapid metabolizer activates the prodrug too quickly, resulting in too high of a concentration of the active form. This may result in adverse drug reactions. Patients with the form of the enzyme that works too slowly or too quickly may require dose adjustment or even alternative medications.
Let's contrast the previous example of a prodrug with the effect of CYPs in active drugs that don't need to be metabolized to have their desired effect. For example, the drug fluoxetine is an active drug that is metabolized to its inactive form by CYP2D6. Because Dan is a CYP2D6 poor metabolizer, he may end up with too high of drug levels and be at a greater risk for adverse drug reactions. In contrast, someone who was a CYP2D6 ultra-rapid metabolizer would inactivate the drug too quickly and may not reach therapeutic levels. It is important to note that most recommendations for drug dosing assume that patients metabolize, or react to, drugs normally.
So, let's review. Dan is a CYP2D6 poor metabolizer. For prodrugs, he will have lower than expected active drug levels and may not get the desired effect. For active drugs, he will have higher than normal levels, and is at a risk of adverse drug reactions. The opposite is true for ultra-rapid metabolizers. "Ultra-rapid metabolizer" isn't just a description of enzyme activity, it's also the technical term used for describing one of the phenotypic results. "Poor metabolizer" is a term used to describe those variants that metabolize the slowest.
The term used for the normal form of the enzyme is less intuitive. A person with normal enzyme function is known as an "extensive metabolizer." There's also an "intermediate metabolizer" phenotype. Even more confusing, Mayo Medical Laboratories reports additional phenotype categories. An important takeaway from the list of phenotypes is to remember that a normal metabolizer may also be referred to as an extensive metabolizer.
Dan's case illustrates that using pharmacogenomics information in clinical practice can help prescribe the right drug, at the right dose, and at the right time for patients. At Mayo Clinic, pharmacogenomics may become part of your clinical practice in several ways, including: pharmacogenomic test results in the electronic health record (whether ordered by you or another provider); clinical decision alerts when prescribing a medication; and patient inquiry regarding pharmacogenomic testing.
Finding pharmacogenomic results in electronic health record can vary. If you are the provider that ordered the testing, you'll receive an inbox message with the results. If a provider orders a pharmacogenomic test at Mayo Clinic, pharmacogenomic test results are availed in the electronic health record (EHR). In Rochester, pharmacogenomics test results are listed in Synthesis under Labs, Genotype.
For some pharmacogenomic tests, there's a scanned copy of the report in the Pharmacogenomics Drug Report section. Or sometimes, the scanned report may also be found in the Documents/Images tab as a Sent-Out Lab Test Report. Here are some sample pharmacogenomic testing reports that you may see in the electronic health record. Patients may find a copy of this report on the patient portal. In the Cerner platform, pharmacogenomics test results are listed in Results Review, Hereditary/Metabolic or Genetics tab, or in the Results Review, Pharmacy, Pharmacogenomic Test Results.
Some pharmacogenomic results may also be found in the EHR by looking at the problem list and the allergy list. In Epic, pharmacogenomic results are found in the patient chart under the Genomic Indicator tab. Results may also be found under Chart Review, Lab, Lab Report.
You also be impacted by pharmacogenomics when ordering a prescription for a patient. If you order a prescription for a patient who has a pharmacogenomic test result that impacts the prescription, you may receive a pop-up alert via clinical decision support. The alert may recommend changing either the drug or the dose.
As a provider, you are in the best position to determine how this information may be used to provide the best care for your patients. For example, when a provider orders tramadol for patient with a pre-existing actionable pharmacogenomic test result, an alert will be triggered. This alert indicates that the patient is a poor metabolizer for CYP2D6 and therefore an alternative medication may be considered.
In some instances, an alert may recommend testing prior to initiation of therapy in the absence of pharmacogenomic results. Certain genotypes are associated with severe hypersensitivity reactions to the drugs. For example, when prescribing Allopurinol an alert may recommend testing to determine if this drug is safe to use. To learn more about pharmacogenomics for this medication, click the link to Ask Mayo Expert (AME). Ask Mayo Expert includes information on interpretation of test results and may provide alternative medication and testing options.
For list of all existing pharmacogenomic alerts in the Mayo Clinic EHR, type pharmacogenomics in the AME search box. Remember, the current alerts are for a limited number of drugs. These alerts are based on established guidelines and are approved by the Mayo Clinic pharmacogenomics task force. AME also includes a list of experts who have agreed to help with questions you may have. You can view availability of the expert, click on the name and page them. If you have additional questions about pharmacogenomics, including tests, interpretation, dosing recommendations, or alternative drugs and testing options, you may consult any friendly Mayo Clinic pharmacist.
Due to increased awareness of individualized medicine and pharmacogenomics, some patients are asking their providers about testing. Pharmacogenomic testing may be ordered by any Mayo Clinic provider when indicated. Additional information on pharmacogenomics, associate drugs, and how to order tests maybe founded by typing PGx into the Internet Explorer address bar.
At this point, you should have a better understanding of key pharmacogenomics vocabulary and concepts, how pharmacogenomics can impact your practice, and how to identify resources for additional information. Thanks for watching, and if you have feedback or suggestions regarding additional pharmacogenomic education please email IndividualizedMedicine@mayo.edu.