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Healthier World with Quest Diagnostics
31 - Pharmacogenetics: How genes can influence prescribing (20 min)
00:20:26
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- [00:04]
A
Welcome to Healthier World with Quest Diagnostics. Our goal is to prompt action from Insight as we keep you up to date on current clinical and diagnostic topics in cardiovascular, metabolic, endocrine and wellness medicine. Today, we're taking a bit of a detour from our usual conversations surrounding cardiometabolic disease to discuss a topic that is critically important in all therapeutic areas of medicine, pharmacogenetics. Pharmacogenetics, also known as pharmacogenomics and PGX testing, is an emerging field that is transforming how clinicians select and dose medications by accounting for individual genetic variability in drug metabolism, transport and response. I'm Dr. Mason Lasko, and today I'm joined by Kathleen O', Brien, board certified genetic counselor, to discuss the utility of PGX testing and how providers can integrate it into routine care. Welcome, Kathy. Thank you so much for joining me today.
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B
Thank you so much for having me.
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A
So, Kathy, before we hop into PGX testing specifically today, I would love for you to share a little bit about who you are and your experience with PGX testing.
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B
Yeah. Thank you. So I'm a genetic counselor, and so my goal is to help patients and providers integrate genetic information into patient care to ultimately improve health outcomes. And I've been with quest for over 20 years, and my interest in pharmacogenetics started when I came on board and I began learning about the various pharmacogenetic tests that we offer and seeing how that information could really help patients and providers make more informed decisions. So fast forward 20 years and we know a lot more. And the value that pharmacogenetics brings to patient care is becoming increasingly recognized by health systems, by providers and patients. And so I now work here at Quest with a team to provide input on the development of clinically useful and scientifically sound pharmacogenetic testing. And most recently, we launched a multi gene pharmacogenomic panel. And then also here in my role, I educate patients and providers about pharmacogenomic testing and how that information might be helpful in providing a more complete clinical picture action.
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A
Absolutely. And I definitely want to discuss the multi gene pharmacogenetics panel that we offer here at Quest Diagnostics. I know it looks at gene drug interactions in virtually all clinical areas like psychiatry and cardiology, oncology and neurology. But let's first pull way back on that topic for clinicians and patients listening in today who might be newer to the concept of PGX testing. How would you describe pharmacogenetics in simple, practical terms?
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B
Yeah, sure. So we are basically looking at how genetic variations can impact response to medication. And so, for example, pharmacogenetics can tell you why two patients might take the same dose of the same drug and have drastically different responses from someone who maybe doesn't respond to someone with severe side effects. And so pharmacogenomics as a field is really identifying genetic variations between individuals that might exclude why there are differences between two seemingly similar patients. And there are other things that influence medication response. But genetics can be an important piece of that puzzle.
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A
Yeah, and that's so fascinating. And of course we knew individual variation existed. That's the foundation of what genetics is. But what is so fascinating to me is how we can now bring this variation into identifying patients response to medications. Because for a long time it was largely trial and error prescribing. And from my understanding, that refers to a doctor trying different medic or changing a dose or the medication type if it's not working. And that can be really hard on a patient and a provider. So could you talk a little bit about what trial and error prescribing is and how PGX testing really helps to reduce that trial and error prescribing?
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B
Yeah, sure. So medications, if you think about it, are developed and marketed for the average person. Right. But we know that not everyone is the same. And so one size doesn't always fit all. And certainly not all medications work as intended for patients. There are many things that can contribute to that variability, but genetic variants can be an important factor. So pharmacogenetic testing is identifying certain genetic variants that may make some medications less effective or in some cases more toxic. So knowing this beforehand can allow the provider to choose maybe a more appropriate medication or to alter the dose. And therefore they can personalize treatment to that individual patient. Patient. And that in turn really can help reduce that trial and error prescribing. And I do think that hospitals and healthcare systems are realizing just how critical this information is in terms of patient care. Statistics show that really about 18% of commercially available medications have an actionable pharmacogenetic association.
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A
Wow. So pharmacogenetics is impacting about 18% of commercially available medications. That's really impressive. So it would be my guess that PGX testing is starting to pop up in all therapeutic areas. Is that a fair assessment or is there one clinical area that's more impacted than another?
- [05:18]
B
So I think that pharmacogenetic testing has utility in nearly all areas of medicine, and there really are important pharmacogenetic associations for many medications that are used to treat very common conditions. So things like high blood pressure or high cholesterol or cancer or pain management, and those are just to name a few. There are many studies that show the benefit of pharmacogenetic testing and optimizing medication selection and dosing, and that therefore leads to improved outcomes. Right. So, for instance, in psychiatry, the use of pharmacogenomic testing can help patients get relief or reach remission faster. Or another example is the anticoagulant warfarin, which has a very narrow therapeutic index and a very large interpatient variability in terms of the dose requirement. So genetic plays a part in a portion of that variability. Pharmacogenetic testing does have the potential to shorten the time to a stable inr. That's the measurement of how long it takes blood to clot and reduce either underdosing or overdosing during the initial treatment period. And if you have genetic test results before you start the medication, it can help target a more optimal dose. And that in turn can result in reduced risk of bleeding and clotting events. For statins, which are drugs that reduce cholesterol, they can sometimes cause something known as statin associated musculoskeletal symptoms, or SAMs, and the symptoms of that include muscle pain or weakness, cramping and fatigue. And this happens in about 5 to 20% of users. And there are several genes that can affect systemic exposure to statins and that can increase the likelihood of SAMs. And some statins are more impacted by these variants than others. So if you test for genes like SLCO1B1 or ABCG2 and CYP2C9, this can help providers select the most appropriate medication and dose to treat the patient. Patient. And there are also a number of studies showing that for many medications, using information that you get from pharmacogenetic testing can substantially reduce the overall incidence of adverse drug reactions. So, in fact, there was actually a study that was conducted in Europe that showed a 30% reduction in the risk of adverse drug events when pharmacogenetic testing was used. And so it can certainly help the provider provide more personalized treatment to the individual patient and to avoid medications that are more likely to be ineffective or toxic or maybe to find more optimal dosing. And so you're really moving away from trial and error to more personalized prescribing.
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A
Yeah, thank you for that insight. I think that was a great overview of the impact of pharmacogenetic testing in many clinical areas. Now, you mentioned several drugs that have important gene drug interactions? How do genetic counselors decide which gene drug interactions are clinically meaningful, and where do they go to evaluate the strength of that evidence?
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B
Here in the United States, we tend to rely heavily on information and guidelines that come from the Clinical Pharmacogenetics Implementation Consortium, or cpic. So CPIC has guidelines that really help bring pharmacogenetic data from bench to bedside and to really help clinicians understand how to take that genetic result and make it clinically meaningful. And so they provide detailed gene drug clinical practice guidelines. And those are really very useful for providers. There are also clinical decision support tools that exist. For instance, ClinPGX has a clinical decision support tool called PharmDog where you can enter the genetic results and it will provide medication guidance that comes from various pharmacogenetic organizations like CPIC as well as the fda, and it'll give you that information based on the results. PharmDog also allows you to enter, like a specific medication, and it will tell you if there's a relevant gene drug association that you may wish to evaluate. There are also other publicly available clinical decision support tools like Sequence to Script, and then there's also privately developed clinical decision support tools that are developed by private companies. So if providers order pharmacogenetic testing at Quest and they would like to get gene drug information, they can order test code 14271 and they will get a link to an outside company which is informed DNA, where they can get a report that's going to provide them with information on gene drug relationships.
- [09:54]
A
Well, that's really great to know that so many different tools exist to help support pharmacogenetics. So now that we have an understanding of how genetic counselors evaluate evidence and determine clinical relevance, can you give us a few examples of genes that may have particularly strong or well established clinical support?
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B
Yeah. So there are many genes which are important and many of them have solid clinical utility. And I think the answer to the question depends on what your concerns are. So what medications the patient may be taking or medications that are being considered? It's important to know whether or not a medication that a clinician is considering may have an important pharmacogenetic association. And you can find that information in places like Clin, pgx, PGX or cpic, or the package insert or the FDA websites. But when we talk about genes that are common, important genes, CYP2D6, for example, is a very important gene. About 25% of all medications are metabolized by CYP2D6. And so this gene is very important for a lot of medications. CYP2D6 is important in the metabolism of metoprolol, which is a beta blocker, or tamoxifen, which is used to treat and prevent certain kinds of breast cancer. CYP2D6 is also important for the metabolism of codeine, which is prescribed for pain. It's also important for a number of antidepressants and many other medications. And also CYP2C19 that also metabolizes a large number of commercially available drugs, and so does CYP2C9. But overall, there are many genes that really have actionable gene drug recommendations. So the Quest Polypharmacy panel has 17 genes and 4 HLA alleles. And all of the genes on that panel really have very strong clinical utility.
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A
Excellent. That's really helpful. So when you're talking about genes important for pharmacogenetics, many of the ones that you just mentioned have an impact on drug metabolism. When I think of PGX testing, I do tend to think of these genes, the ones that code for drug metabolizing enzymes. So first I wanted to ask, are there other types of pharmacogenes out there that the audience should be aware of?
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B
Yeah. So I mean, probably the majority of clinically useful pharmacogenetic associations do involve genes that code for drug metabolizing enzymes. And so that's probably the one that people think of first. Some pharmacogenes may also code for drug transporters, which are important in the absorption or distribution and excretion of drugs. There are also drug targets. And then we have the major histocompatibility complex genes, the HLA alleles. And the HLA alleles are important in immune mediated adverse drug reactions. And many of the gene drug associations involving HLA alleles can actually be quite severe. And so those can be super important in predicting some very serious adverse drug reactions.
- [12:55]
A
Yeah, that's so fascinating. I feel like we could definitely spend an entire episode on HLA alleles and their impact on adverse drug reactions. But when we talk about drug metabolizing enzymes, since you do highlight here that these are some of the more clinically useful genes, let's talk a little bit about results interpretation for pharmacogenes that code for drug metabolizing enzymes, a provider would get results that help them better understand whether or not their patient is a rapid metabolizer or a poor metabolizer. Can you expand a little bit on this and help us better understand what these results mean?
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B
Sure. So enzymes are important in Drug metabolism. So if you have a change in a gene that codes for drug metabolizing enzymes, it can alter enzyme levels, and therefore it can alter the rate at which drugs are metabolized. So these terms normal, intermediate, poor, rapid, and ultra rapid metabolizer, these are ways to describe how much enzyme activity there is for a given genotype or diplotype. So we call that description the phenotype. And usually most individuals are normal metabolizers, meaning that they have typical enzyme levels and are expected to metabolize a given drug as it's intended. But poor metabolizers, right, have very little to no enzymatic activity. And intermediate metabolizers have enzyme levels that are in between normal and poor metabolizers. So they have some enzyme, but they have less than normal metabolizers. So intermediate and poor metabolizers will metabolize drugs more slowly. Now, the other end of the spectrum, right, you have rapid or ultra rapid metabolizers, and they have genetic variations that cause them to produce a higher amount of a given enzyme, and therefore they're going to metabolize drugs more quickly. So these changes in enzyme levels can impact the rate at which drugs are metabolized, which in turn, right, can impact blood levels and drug efficacy or toxicity. So just as an example, right, if we take the drug clopidogrel. Clopidogrel is a commonly prescribed antiplatelet drug, and it's also a pro drug. And that means that it has to be turned on in the body by the enzyme CYP2C19 in order to work. So if someone has reduced levels of this enzyme, they're going to have less of the active metabolite in their circulation, and so they're more likely to experience drug failure. And so for those patients, physicians may use that information to either decide if an alternate antiplatelet medication might be appropriate, or if they need to change the dose or do more frequent monitoring. But conversely, if we talk about an active drug, right, something like the antidepressant citalopram, where the drug is inactivated by CYP2C19, someone who has less CYP2C19 is going to actually have higher blood levels of the active drug and is more likely to experience side effects. And so the genetic result can have different consequences depending upon the medication. And the consequence of these alterations in enzyme levels is going to vary based on the particular drug and the properties and metabolism of that medication.
- [16:05]
A
So that's a really important key takeaway, that the metabolizer genes are coding for enzymes that either activate or inhibit a certain medication. So the consequence of being an ultrarapid metabolizer or a poor metabolizer depends entirely on the drug's properties. So what I hear is Quest Diagnostics is very grateful to have you on our team to help walk us through these results. And I appreciate you helping explain this in such simple terms. Which brings me to my next point. You helped Quest Diagnostics develop a panel of clinically useful pharmacogenes. Can you tell me more about that panel and what a provider could expect if they get that pharmacogenetics panel through Quest?
- [16:47]
B
Absolutely. So Quest has several single gene pharmacogenetic tests, but we also have a multi gene polypharmacy panel. The polypharmacy panel has 17 genes and four HLA alleles. And these genes all have clinically actionable pharmacogenetic associations. In the testing, we do include all AMP tier one variants when those recommendations are available. So AMP is the association for molecular pathology, and basically they weigh the information and they look at the frequency of certain variants in different populations, as well as how much we know about the impact a particular genetic variant has on a gene or gene function. And so they have recommendations in terms of which variants are important to test for. And again, we do include all AMP Tier 1 variants when those recommendations are available. There are two test codes for our polypharmacy panel for Both test codes 14271 and 14272. Quest will provide information on the genetic result, which is often called the diplotype in pharmacogenetics, as well as the phenotype. But if the clinician orders test code 14271, they will also get a link that will take them to a different company, which is informed DNA, where they can get a report that has gene drug information on it.
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A
Excellent. So both panels give you information on the diplotype and the phenotype. But if the provider wants a little more information, they can order 14271, which will give them a link to inform DNA where they can get a little more information on that gene drug interaction. So, as we round out today, do you have any final thoughts that you would like to share with the audience?
- [18:29]
B
Thank you. So I think PGX testing has relevance for almost all of us. Right. Since most people are likely carrying a variant that impacts a medication that they're going to need at some point in their lifetime. If we think about the statistics again from earlier, over 90% of patients are going to have a clinically actionable pharmacogenetic association. And again, if we think that about 18% of medications that are currently on the market have a clinically actionable pharmacogenetic association, chances are that most of us are going to have a variant that's going to impact a medication that we're going to need at some point. So if you have a polypharmacy panel, you do it once, you pay for it once, and you have the results for the rest of your life. And that information can be utilized throughout your lifetime. And in fact, there are a number of studies that show that the utility of preemptive pharmacogenetic testing can be very impactful. And many hospitals and healthcare systems are starting to incorporate this information into their EMRs. And many even have alert systems that inform the provider when they're about to prescribe a medication that has a relevant gene drug interaction in that patient. And so I think PGX testing is going to become much more integrated into mainstream medical care in the future.
- [19:47]
A
Well, that's fantastic. What an exciting topic and a really important time for medicine. So thank you so much for joining me today, Kathy. It was a pleasure to have you on, and I look forward to our next conversation.
- [19:58]
B
Thank you.
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A
That's a wrap on this episode of Healthier World with Quest Diagnostics. Please follow us on your favorite podcast app and be sure to check out Quest Diagnostics Clinical Education center for more resources, including educational webinars and research publications. Thank you for joining us today as we work to create a healthier world one life at a time.