Hello everyone. Thank you for joining us today. Again for PGx Clinical Pearls. For those of you that don’t know me, my name is Ina Liko and I’m the director of Clinical Pharmacogenomics Operations at RxGenomix.
This month, we’re entering February already a couple days ago, and it’s actually heart month. So I will be focusing on cardiovascular conditions this month, starting off today with beta blockers and CYP2D6. We have talked about CYP2D6 a lot in the past as well. So it’ll just be a brief introduction. Also, for those of you that are not familiar with it, for those of you that have attended in the past, you already kind of know the flow here, but I’ll start off with a patient case and then introduce the gene, look at if there are any guidelines that would apply to the medications of the gene that we’re talking about. And then actually go back and see how we can solve that patient case.
If you have any questions at all about this presentation or how to implement pharmacogenomics in your practice, feel free to either type them in the Q&A or the chat section here, and then we’ll address them at the end. I’ll also share my email at the end of this presentation, if any questions come up later. All right. Well, it is a little bit after 3:30. So without further ado, I’ll start off with a patient case.
So before we dive into the details of really the genetics and the genes here, I would like to first introduce this patient. This is JT, he’s an 80 year old Asian male who has hypertension, high cholesterol, and unfortunately he also suffered from MI in the past. So his doctor put him on a few medications here to just prevent MI and then to also control his high blood pressure and hyperlipidemia. So he is put on Atorvastatin, Clopidogrel, Lisinopril, and Metoprolol.
Now you’ll notice here that the Metoprolol dose is a hundred milligrams twice a day. So that’s 200 milligrams daily, which should be enough to actually control his heart rate. However, if you notice is that his heart rate is still pretty high. It’s 140 and also his blood pressure, it’s really not controlled, 155 over 90. We definitely, especially since he has comorbidities, would want that number to be a lot lower.
So for him, definitely less than 140 over 80. Fortunately he does have a pharmacogenetic testing done, and these are his results. So we’re looking at a few different genes here, SLCO1B1, which mainly applies to the statins and then CYP2C19 is going to be for Clopidogrel and then CYP2D6 here, which this is what we’re going to focus on with the beta blockers for this session. But I brought up these other genes for you to see that this, we’re looking at the patient as a whole here. And even though in these sessions, I try to keep them focused on one drug gene pair, we have to consider the whole patient and the multiple drugs and genes that affect them.
So just as a review here, CYP2D6, a very, very popular gene. So very briefly here, it is very highly polymorphic. It has over 130 known alleles, and these alleles are variants. They’re actually different. They differ from each other and differ also from other genes that we’ve seen. So the majority of the other genes that we talk about, they have the single nucleotide polymorphisms or variations. With CYP2D6, you also have gene deletions. So, with the gene, that particular variation is not there at all, so that star five is, it’s a deletion. You also have insertions. So then that will cause those frame shift mutations. Some of these are duplicated. And you’ll see if you notice, our patient has a times N after his genotype. So that means that it’s duplicated, as well as multiplication. However, there are also some of these variants that actually, we don’t really know the functionality for, so the majority of these variants, they will alter the pharmacokinetics of the enzyme.
What does this mean? So this means that it’ll lead to increased function in those that are carrying additional functional gene copies. So this would mean for individuals that have inserts and duplications and multiplication, and then to decrease function or no function for variations that are gene deletions. And that star five is one of them. And then, like I said, some of these also don’t have any functional consequences that we know of yet, maybe in the future, we’ll discover more about them and assign them some functions as well.
And then just based on these variants, we have four different genetically mediated phenotypes here. So there’s an ultra metabolizer again, for these with CYP2D6, we also have to take into account the activities score. So how we calculate that is we look at the diplo type of the patient and we’ll actually calculate this patient’s activity score. And then the phenotype in a few spines here, but just to familiarize you again, let’s take for example, this patient right here, or this diplotype right here, where it’s star one, star two, times N. So this times N, it means that one of these two alleles here is actually duplicated. And the lab, usually depending on which one it is, you’ll have a different result. So for this particular case, if it’s star one that’s duplicated, that would be a normal response.
However, if it’s star two, it would be an ultra-rapid metabolizer. So in this case, this means that star two is duplicated. So that’s why when we calculate an activity score, so star one is going to have an activity value of one, and then star two is going to have an activity value of two. So right away, we would know then that we would add these two values together. And we would get at least the value of three, which is more than this activity score of 2.25. So this patient would be ultra-rapid metabolizer, and then for intermediate and four metabolizers for these patients, so they’re not necessarily, I have there that would expect more side effects for medications that are not for drugs. So that’s the caveat that I want to talk about there, because for these medications, we’re just not having enough enzyme to actually clear the medication out of the system.
So maybe that’s why these patients are having more side effects because that drug is being in the system for longer than it’s supposed to be there for. And in the case of a trial drug, we would need to activate that medication. So it would have the opposite effect.
Now you may also wonder, okay, great, but how frequent is this in the population? So I would focus here. If you look at Americans, the ultra-rapid metabolizer, about 5.4% and then the intermediate and poor metabolizers, and we see so together in about 25%. So that’s about a quarter of the population. So that’s quite a few people that we have to consider. Now with CYP2D6, and I’ve talked about this in the past as well, but this is a very important concept, is this concept of pheno-conversion. Now pheno-conversion, it just means there is a mismatch between the individual’s genotype based prediction of drug metabolism, and they’re true capacity to metabolize drugs due to non-genetic factors. For example, changes due to drugs, inhibiting or inducing metabolizing enzymes, they can severely impact an individual’s ability to respond to a medication.
So if a patient is a normal metabolizer per genotype, and they take one of these medications here that are, I have here, like Bupropion, Fluoxetine, Paroxetine, Quinidine, or Terbinafine, these are medications that are very strong CYP2D6 inhibitors. They may actually act as an intermediate or poor metabolizer due to this phenoconversion, because what these medications are doing is they’re actually inhibiting CYP2D6. So even though they are a rapid metabolizer, you would expect them to really clear the drug fast and maybe increase the dose. If they’re taking one of these medications, it’s interacting and they may actually need a lower dose. So I bring this up again to remind you that looking at, so we’re looking at the drug gene interaction is important, but also looking at the patient as a whole and what other drugs they’re taking, because also taking into account those drug interactions is also really important.
It can actually change the clinical picture here, just in terms of where does actually CYP2D6, why is it important for Metoprolol in particular? And it’s important here because you see that this is the major enzyme that would metabolize Metoprolol to all of those three different inactive metabolize. And what I wanted to point out here again, is that while CYP2D6 is the main enzyme, there are other enzymes here. So we have CYP2D4, CYP2B6, and CYP2C9, that may also need to be taken into account when deciding about how this medication is really affecting that patient, depending on the variations that patient has.
All right. Now, the exciting part will determine what this patient’s phenotype is. So CYP2D6, as a reminder, here, there are star one, star one times two. So star one activity value of one, and then star one times two. So this is a duplication. And so that would be an activity value of two. So the activity score is activity score of three, and that their phenotype is an ultra rapid metabolizer. So I do want to pause here to also explain the pheno-conversion again for this patient, because they are an ultra rapid metabolizer. If they’re taking any of those interacting medications, they may actually act as an intermediate or poor metabolizer. So we may not necessarily look at what the exact guidelines say when it comes to just the drug gene interaction, and this patient wasn’t taking any interactive medications, but if he was then we would maybe consider a different recommendation for him.
So CPIC doesn’t have any guidelines or recommendations when it comes to this drug gene pair. However, the Dutch working group does. So for an auto rapid metabolizer, they say to use the maximum dose. And then if the effectiveness is insufficient, which was actually the case with our patient, because it wasn’t controlling his heart rate or his blood pressure, then they say to increase the dose to 2.5 times the standard dose, or to select an alternative. Fortunately, there are many alternatives out there for beta blockers as well, so we have a choice here.
And just for completeness, I did want to talk about the intermediate and poor metabolizers. So for intermediate metabolizer, they say, again, increase the dose in smaller steps. So see how the patient is responding and then prescribe no more than 50% of that standard dose for a poor metabolizer. So similar guidance to increase the dose in smaller steps, and then we’re prescribing no more than 25% of that standard dose. And again, it’s because Metoprolol is not a pro drug. So if we’re prescribing the standard dose, the patient may have more side effects as more of it hangs out in the system longer.
Now the FDA actually also has some language when it comes to Carvedilol and Metoprolol. This is only for CYP2D6 metabolizers. So for Carvedilol, they say this may result in higher systemic concentration, as well as a higher adverse reaction risk or dizziness. And then Metoprolol is a little bit of a softer language where they just say it results in higher systemic concentrations. However, they’re not necessarily correlating it with any adverse events and they don’t also necessarily have any dosing recommendations for us, but they’re talking about that PK or pharmacokinetic correlation.
So what could be some other alternatives here? So Atenolol and Bisoprolol, they’re good alternatives because they do not depend on CYP2D6 for elimination, and they’re mainly eliminated through the kidneys. So we have to actually look at the patient’s kidney function as well, so that’s another thing to consider when we’re choosing an alternative. Again, it may make sense to choose it based on the drug gene interactions, but we have to make sure to check on other drugs that they’re taking. Is there any drug interaction? Check their liver function, kidney function, and whether it is the right drug to treat that condition that they have.
Carvedilol, on the other hand, doesn’t mainly depend on the kidneys for elimination, but it is metabolized by CYP2D6 and CYP2C9, so, you kind of have to pick your battles in terms of choosing an alternative. If this patient’s kidneys were compromised, then it’s probably, either lower the increased, I’m sorry, increase the dose of Metoprolol since he’s an ultra-rapid metabolizer or choose Carvedilol, again, knowing that also Carvedilol’s metabolized by CYP2D^ and CYP2C9, and maybe look at his metabolism or his genetic makeup for CYP2C9 as well to make that decision. And then this is just the visual representation here of Carvedilol again. So CYP2D6 is the major enzyme as well as CYP2C9.
All right. Now, let’s go and take a look at our patient. I gave you a few hints here already for therapies, but as a reminder, relevant medications here, we have listed Lisinopril five milligrams and then Metoprolol as well, a hundred milligrams twice daily for CYP2D6. He is an ultra-rapid metabolizer, we know that he has, his heart rate is not controlled as well as his blood pressure is not controlled. His heart rate is 57, which, for an 80 year old, it is actually pretty good. And the Dutch working group guidelines say for Metoprolol that they can increase the dose to two and a half times that standard dose, or we can select an alternative therapy. And in terms of the plan here, so this is just what I chose, of course, there’re other routes of treatments there, but in terms of alternatives, based on what I think would be good for this patient, based on what we know about him so far is Atenolol is a good option because there is no drug gene interaction.
And then it doesn’t necessarily affect the kidneys, as well as Bisoprolol, it could be another option because again, no drug gene interactions there. It is indicated for the condition that he has. And then again, there is no effect on the kidneys.
All right, these are my references. And what questions do you have for me? Feel free to type them in the chat or the Q&A portion. And if any questions come up later, feel free to email us. My email is on the top there.
Great question, Melissa. We talk a lot about CYP2D6 phenoconversion, yes, because it is an important foreign one to keep in mind. All enzymes be pheno-onverted? Well for CYP2D6, potentially they could, but for CYP2D6, it’s because these medications, they’re just really strong inhibitors of it. So it’s mainly where it’s meaningful right now in terms of genetics, CYP2D6 is one of the more meaningful ones. But for other enzymes, it’s not as meaningful, but great question.
Anela has a question. Why would Carvedilol not be appropriate for this patient? That’s also a great question. So like I said, I chose those medications because they didn’t have any CYP2D6 interaction. And then also because of the kidney function, Carvedilol could also be an option for him. However, it is affected by CYP2D6. So we have to take into account that interaction. I just chose medications that don’t pass through CYP2D6, but you could choose Carvedilol and see how it goes.
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