Hello, everyone. Welcome to PGx Clinical Pearls this week. For those of you that don’t know me, my name is Ina Liko and I’m the Director of Clinical Pharmacogenomic Operations at RxGenomix.
All right, so today we’ll be continuing to talk about mental health and particularly I’ll be focusing on a medication that is used to treat schizophrenia. The gene that we been talking about this month actually is CYP2D6, and that’s because CYP2D6 does affect a lot of medications, but also it affects particularly a lot of mental health medications. So for some of you that have attended our webinars in the past, I’m sure you’re now experts on CYP2D6 because we’ve been talking about it the last couple times. But for those of you that are new, this will be really useful information for you. So I will just go over this very briefly. And if you have any questions, I do have some additional videos on our website at RxGenomix under Clinical Pearls that go in more detail with CYP2D6. You can go to that website and listen to those videos as well to just get a little bit more detail.
I’ll keep it short on CYP2D6 today because we have been talking about it in the past couple of weeks. And then after we talk about the gene, I’ll actually introduce again the patient case and then talk about any guidance with the medications that the patient is taking, looking at any guidance from the FDA, as well as the Dutch Working Group or CPIC guidelines. And then we’ll go back to the patient case to see how we can solve it. If you have any questions, feel free to type them in the chat or the Q and A portion of this webinar and then I’ll address them at the end.
So this is Brittany. She is 15 year old, Caucasian female, and she’s been diagnosed with schizophrenia. Actually she had just been diagnosed with it a couple of months prior. Her doctor started her on Risperidone, 6 mg daily. This is the maximum dose that the patient would be started on, especially at this age. However, after being on it for about a month or so, her schizophrenia is still not controlled. It actually, this medication, did not work for her at all. So her parents are a little worried about it. She’s not doing well in school. She has the symptoms all the time. So they actually were interested, had heard about, pharmacogenetic testing and had her do a pharmacogenetic test because they have heard that it does affect how you respond to medications. So after she did the testing, these are her results. So we do see a CYP2D6 result there, and that’s the gene that we’ll be focusing on today for Risperidone.
So for those of you that are not familiar with CYP2D6, CYP2D6 is actually a gene that has a lot of allelic variants and they’re over 130 known allelic variants. Now based on this variations, they can actually affect the way that the patient, the enzymes, and how you respond to different medications. So it does alter the pharmacokinetics of the enzyme itself. Now this alterations or variation in the pharmacokinetics of the enzyme can lead to increased function in those patients that carry additional functional gene copies, so they may actually need a higher dose. Or it can also lead to decreased or no function. In some cases there’s some gene deletions with it. And some other ones, they have no functional consequences at all. CYP2D6 does have a lot of different variations as well. So a lot of genes will have what we call SNPs, or single nucleotide polymorphisms. However, with CYP2D6, you’ll actually also see insertions, deletions, duplications, as well as multiplications of the gene. So that’s what makes it a little bit harder to actually genotype as well.
And in terms of the phenotypes, I’m sure probably you have seen this before, but there are four different phenotypes that are genetically mediated for CYP2D6. So we have an ultrarapid metabolizer. In the majority of drugs we would expect poor drug response. And the way that we are calculating this for CYP2D6, and some other genes have also switched to this standard of terminologies, actually will calculate an activity score. So that activity score, we are calculating it based on this diplotype examples. So for example, star one star two times N here, star one will get an activity value of one. And then star two times N, this is going to be two times the number of duplications. Let’s say that this patient has one duplication so it’s going to be two times one. It’s going to be a value of two. And then we add these two together, so we get a score of three and then as long as the activity score is more than 2.25, you will be an ultrarapid metabolizer. And then for intermediate or poor metabolizer, we would expect more side effects because you have a higher drug concentration in your system.
You may also wonder, “Okay, that’s great, but what about how common are these variations in the general population out there?” So, all in all CYP2D6 in the Americans, there’s about 30% variation. So 5% of that is going to be ultrarapid metabolizers and then about 25% is intermediate and poor metabolizers. So, we’re expecting 30% of Americans to have a different response or variation in response when it comes to medications that are being metabolized from CYP2D6. And about 25% of all medications are metabolized by CYP2D6 so that’s just a large number of medications. And 30% of the population is also quite a bigger number than if it was just 1 or 2%.
Now, talking again here about phenoconversion. So phenoconversion is the concept of genotypic normal metabolizers that are converted to phenotypic intermediate or poor metabolizers. So this may happen if the patient is actually taking strong CYP2D6 inhibitors. So our patient is not taking any of these medications, but if she was, and we’ll find out in a little bit what her metabolizer status is, but if she was taking any of these and if she was an ultrarapid or a normal metabolizer of CYP2D6, then actually she may act as an intermediate or poor metabolizer. So that’s why it’s really important to look at drug-drug interactions.
Because as we will see next, when we determine her phenotype, actually our patient is an ultrarapid metabolizer. So that would’ve been important for her to kind of see. If she was taking any of those medications, she may actually have side effects because of Risperidone. And then if we didn’t take that into account, it wouldn’t necessarily make sense to us of why she’s having side effects since she’s an ultrarapid metabolizer. So you would think that she would actually metabolize Risperidone very, very fast. The concentration would not be high enough, but because maybe if she was taking some of those medications, they are inhibiting CYP2D6. So Risperidone doesn’t have a chance to actually be metabolized and it may build up in the system and cause her to have side effects. So that’s why, again, I bring it up again here that looking at those drug-drug interactions is also really important. Genetics are just one piece of the puzzle. We have to look at other factors, other clinical factors, with a patient as well, because it will change the outcomes and our decision.
So Risperidone here in terms of the pathway, CYP2D6 is a very important enzyme. So it goes from Risperidone to actually this active metabolite, which is this 9-hydroxyrisperidone, and this is actually another medication out there, a newer medication then Risperidone called Paliperidone. So that’s what this molecule is. And then in terms of how Risperidone is metabolized, so only 5% of it is excreted renally. And these other two they are just inactive metabolites. Now, even for its active metabolite with Risperidone, CYP2D6 and CYP3A4 do play a role in metabolizing it into inactive metabolites. And about 60% of it is excreted unchanged in the urine. So that’s where we see CYP2D6 play kind of a double role here, so it is needed to metabolize Risperidone to the active metabolite and then from there, even this active metabolite needs CYP2D6 to be metabolized to its inactive metabolites.
So that’s why, for example, if you have a poor metabolizer, then this dose would be a little bit higher because you will have a higher concentration of this Paliperidone that is not being metabolized. And then you’ll also have a higher concentration of the parent drug, Risperidone. So if you have that, in those cases, the patient may experience side effects because they just have higher concentrations of both of these compounds. And then in our case for an ultrarapid metabolizer, actually Risperidone is being converted very fast with this Paliperidone and then this is being converted by CYP2D6 to its inactive metabolites also very fast. So it’s just not enough of that concentration in the blood to do its job. So maybe that could be one of the reasons why our patient was not responding to this medication.
So there aren’t any CPIC guidelines out there, but there are Dutch Working Group guidelines for Risperidone particularly, and our patient is an ultrarapid metabolizer. So actually there’s some literature out there that says that the percentage of patients that have therapeutic failures increases from 16% to 37%. That’s almost a little bit over 20% change here. So 16% would be the failure rate of Risperidone for individuals that are normal metabolizers. And then if you’re an ultrarapid metabolizer, so 37%, it’s almost 40% of those patients are expected to fail this medication. And the recommendation is to choose an alternative or to titrate the dose according to the maximum dose. Our patient was actually taking the maximum dose because they didn’t see any improvements on her. So the option for her would be to choose an alternative.
Now, when it comes to CYP2D6 intermediate metabolizers, there isn’t as much evidence out there to support an increase in side effects that are caused by this gene variation. However, they do say that this gene variation may lead to a decrease in the required maintenance dose. However, as the effect on the dose is smaller than that of the normal biological variation, you don’t actually need to make any dose changes based on this genetic variation. If the patient is a poor metabolizer of CYP2D6, the percentage of patients with therapy failure is going to increase from 16% to 26%, so there is a 10% difference here. And then this therapy failure here, it would mean that the patient will have more side effects. So because of that, they’ll most likely not adhere to the medication, stop the medication. So that’s why we have this terminology here.
So the recommendation is to use the 67% of the standard dose, so you’re reducing the dose by 33%. And then if problematic side effects originating in the CNS occur even when you have reduced the dose by a third there, then you would reduce the dose even further to 50% of the standard dose. That’s what the recommendation would be.
Now, the FDA label actually in this table of pharmacogenomic associations, they also have some language when it comes to CYP2D6, poor metabolizers particularly, and Risperidone. They don’t have any particular dosing recommendations, but they do say that if you’re a CYP2D6 poor metabolizer and you’re taking Risperidone because this alters the systemic parent drug and metabolite concentrations. So they’re only talking about the pharmacogenomics here, not necessarily relating it with any those associations.
Now, since we actually have to switch our patient to a different medication, thankfully there are other medications out there. But we want to be conscious in terms of well, what medication should we switch her to? Because even these other medications, and I’ve just included three here, which is Aripiprazole, Brexpiprazole, and Haloperidol, they also have some genetic indications as well and interactions. So fortunately here for an ultrarapid metabolizer, there are Dutch Working guidelines as well. So for CYP2D6 ultrarapid metabolizer, Aripiprazole and Brexpiprazole, we don’t need to do any dose adjustments. So they can start at that normal dose. If we were to choose Haloperidol, we could also choose that one. However, we may need something that has a higher dose to increase the dose. So, the Dutch Working Group says the alert of possible reduced plasma concentration can increase the dose, or they say in alternatively, since there are other medications out there to choose a medication that’s not metabolized by CYP2D6.
Now for intermediate metabolizer, so similarly as it was for Risperidone, we don’t need any dose adjustments. And then for poor metabolizers, CYP2D6 poor metabolizers, we actually do need dose adjustments. So Aripiprazole was pretty similar to Risperidone. The max dose administer is 10 mg, which is actually 67 to 75% of the standard maximum dose of Aripiprazole. And then Brexpiprazole and Haloperidol, the Dutch Working Group recommends to reduce that by 50%. So I’ve just included these other phenotypes here for completeness, but our patient was an ultrarapid metabolizer.
And then in terms of the FDA, so the FDA also has some language. Again, this is mainly for CYP2D6 poor metabolizers for Aripiprazole and Brexpiprazole. It is results in higher systemic concentrations, higher adverse reaction risk. So to reduce the dose by 50%, which is in line with the Dutch Working Group guidelines.
All right, so now if we go back to our patient, just as summary here. So in terms of the assessment, she was taking 6 mg of Risperidone. Did not have an effect in resolving her schizophrenia for her. So then we found out that she is a CYP2D6 ultrarapid metabolizer, and here I’ve just included the Dutch Working Group guidelines. So the patient was taking Risperidone. The Dutch Working Group recommends to choose an alternative or to titrate the dose to the maximum dose. However, our patient was on the maximum dose there, and it still didn’t work for her. For Aripiprazole and Brexpiprazole, they don’t have any particular dose adjustments. And then for Haloperidol, they say to reduce the plasma concentration. So we’ll probably need higher dose if we were to choose Haloperidol. So the plan here, this is just what I chose just based on this guidance, so we could either start her on Aripiprazole or Brexpiprazole and then see how she does from there.
All right, these are my references. Thank you so much for attending. Please let me know if you have any questions. And if any questions come up later, feel free to email me. This is my email address.
Interested in registering for PGx Clinical Pearls?
Every Thursday at 3:30pm Central Time
For any questions, you can email us at [email protected]
