Hello everyone. My name is Ina Liko and I’m the director of Clinical Pharmacogenomics Operations at RxGenomix. For those of you that haven’t attended our webinars in the past, welcome and for those attended in the past, welcome back. We’re excited to start off June with continuing talking about mental health as well for this month. I started off last month because May was Mental Health Month and I’ll continue it throughout this month, because I realized there are a lot of different topics and medications that we can cover, when it comes to pharmacogenetics and mental health.
So, for those of you that haven’t attended our webinars in the past, I’ll just lay all the agenda here. Have a similar format of talking about a patient case first and then introducing the genes that are related to some of the medications that the patient is taking. Look to see whether there are any guidelines or any FDA table of pharmacogenetic associations, any FDA language there, and then continue on with the patient case to see how we can solve it.
For the rest of this presentation, I would like for you to keep in mind, James. He’s a 40 year old Caucasian male that has past medical history of depression and neuropathic pain.
In terms of his medical history, he was taking Amitriptyline 150 milligrams at that time, Citalopram 20 milligrams daily, Doxepin 150 milligrams daily, as well as Nortriptyline. He was then switched to Nortriptyline because you couldn’t take Amitriptyline and Nortriptyline together. For Amitriptyline, Doxepin as well as Nortriptyline he actually failed therapy. Those two did not work for him. Citalopram, he experienced some side effects and fortunately he did have pharmacogenic testing done. So these are the genes that he mainly tested on. We’re going to be focusing today on CYP2D6 and CYP2C19. These are the two genes that really affect a lot of mental health medications.
For those who that have attended our webinars in the past, you’ve already heard me talk about these two genes, but I’ll have an overview as well. Also, something else to note about James here is that we see that he has neuropathic pain and Amitriptyline and Nortriptyline are also used for neuropathic pain here. So, we just want to make sure that those two, can we find a different dose for him? Can kind of help with neuropathic pain as well, in addition to helping became with his depression diagnosis.
So just briefly here, I’ve talked about statistics in the past, but as a review here, CYP2D6 is a gene that has a lot of different variations. There are over 130 variations and based on these variations, they alter the pharmacokinetics of the enzyme and this can lead to an increased function in those carrying additional function gene copies or lead to decreased or no function, or actually gene deletion, if an individual is carrying those different variations. And some of these variations, they don’t have any functional consequences as of yet, but more research is being done about them and will know more in the future.
Now, they’re generally four different phenotypes. So we have an ultrarapid metabolizer. So generally, this would mean that we would expect a poor drug response because the patient is just metabolizing the medication really, really fast. And it’s not there for a certain amount of time that it needs to be there to do its job. On the flip side of that, we have an intermediate or poor metabolizer, where would where we would expect more side effects for the majority of the medications because the medication is just hanging around in the system for a lot longer than it’s supposed to be there and may cause some of those side effects.
Now, this is not the case with prodrugs. So for pro drug, it really needs some of these enzymes to activate it into its active form. So if you have a normal, if you… Excuse me, if you have an intermediate metabolizer and it’s a prodrug, then what this really means is that this enzyme is not really activating the medication and for this patient that medication might not really work for them because the enzyme is not converting the medication to its active form.
On the flip side of that, if you have an ultrarapid metabolizer or even a rapid metabolizer for a prodrug, the activated form, it is just the medication is being activated really, really fast. So you have a lot higher concentration that what you would expect because this enzyme is working a lot faster to activating that medication. So you end up with a higher concentration in the blood and this may actually also lead to side effects. So, when we think about prodrugs, I would actually think the opposite of what I’ve laid out here on this slide.
Also, I forgot to mention the beginning, but if you have any questions about this presentation, feel free to type them in the chat or the Q&A portion, and then I’ll address them at the end.
Now you may also wonder, “Okay, great. So we have these different phenotypes and they can lead to different functional consequences. But what is actually, what is the frequency?” So for CYP2D6, I just laid out some of the phenotype frequencies here. So, you see that for intermediate and poor metabolizers, it’s about 25% of Americans will have that variation. And about 5% will ha will be ultrarapid metabolizers. So, overall here is about 30% of the population in America will have a variation in CYP2D6. Now, CYP2D6 is also an important gene and that’s why it has actually come up for a lot of these medications because it does metabolize about 25% of medications.
It’s important to understand how that particular gene affects all of the different medications. Now, another important concept that some of you have heard in the past, but it really bears repeating because it is an important concept to keep in mind, is this phenoconversion. Phenoconversion, what it really is, it’s a mismatch between the individual’s genotype based prediction of drug metabolism and their true capacity to metabolize drugs due to non-genetic factors. For example, changes due to drugs, inhibiting or inducing metabolizing enzymes can severely impact an individual’s ability to respond to a medication. So for example, if a patient is a normal metabolizer per genotype, they may actually act as an intermediate or a poor metabolizer due to this phenoconversion. So for CYP2D6, this occurs in patients who take medications that are strong CYP2D6 inhibitors, and some of these have just listed some examples here, like Bupropion, Fluoxetine, Paroxetine, Quinidine and Terbinafine.
If the patient is taking any of these, and if they are already a normal metabolizer or even a rapid or an ultrarapid metabolizer, because these medications are actually inhibiting CYP2D6, the patient may act like they’re an intermediate or poor metabolizer when it comes to responding to these medications. Now, if a patient is already an intermediate or a poor metabolizer, then these drug-drug interactions don’t really matter because they’re already a poor metabolizer, for example. So in that case, they’re not going to respond or maybe they’ll have some side effects to that medication because it’s already due to their genotype, not necessarily these interacting medications. But I do bring this up because just to remind you as well that here, we’re talking about drug genes, but keeping in mind, the full clinical picture that actually the patients take other medications as well. So keeping in mind drug-drug interactions and not forgetting about those, when we’re looking at these genetic reports as well.
Now, switching gears a little bit, CYP2C19. CYP2C19 also metabolizes about 10% of common medications. Not as much as CYP2D6, but still quite a lot of medications. And it also has a lot of different variations. It’s about at least 30 known allelic variants, and they’re mainly single nucleotide polymorphisms or SNPs. Now the most commonly reported alleles, they’re categorized as increased function, normal function or no function. And this again, can lead to increased, decreased or no function, enzyme activity. And some of these also, they don’t have any functional consequences of yet. Some of them are still being studied.
So generally here, similarly to CYP2D6, there are four different phenotypes. We have an ultrarapid metabolizer. So this is two increased function alleles or one normal function and one increased function. An intermediate metabolizer is to be one normal function allele or one increased, and one no function allele. A poor metabolizer would be someone that has two, no function alleles. Now the biggest difference here between CYP2C19 and CYP2D6, is that CYP2C19 this is the definition of how a genotype can be translated into a phenotype, where as with CYP2D6, we’re actually are calculating activity scores. And based on that score, that’s how it’s translated into a phenotype. And I’ll have an example, we’re going to actually calculate our patient’s activity score as well to see what metabolizer status they fall into. CYP2C19, it’s a little bit more common especially in African Americans here. However, in Americans, in general, so about 22% are intermediate and poor metabolizers and about 0.7% are ultrarapid metabolizers. The majority of the population will fall into this intermediate metabolizer category for CYP2C19.
Now here, I just have an example of where do these genes actually work and how they’re related to the medication we’re talking about. Something to note here, we see Amitriptyline and we see CYP2D6 is important in order for it to be activated or converted to one of these active metabolites here. And then you see that also CYP2C9 and CYP2C19 as well as CYP2C8 and CYP2CA4 are important for converting Amitriptyline to Nortriptyline. Then, with Nortriptyline here, which our patients took Amitriptyline and then they also took Nortriptyline, you see that also Nortriptyline is also affected by CYP2C19 and CYP2D6, as well as CYP1A2. I did want to point out that even though we see all of these different enzymes here, the ones that have the most clinical studies are CYP2C19 and CYP2D6, where we’ve seen a lot of those associations.
However, research is always evolving, always doing a lot more research, even as we speak. So, in the future, there could be some involvement or more research come out with stronger data for some of these other enzymes as well, because as you can see, they also can affect the metabolism of Amitriptyline, Nortriptyline and all of these other metabolites.
All right. Now, that we are a little bit familiar with CYP2C19 and CYP2D6, and for some of you, this may be a little bit of a review, now let’s find out what the patient’s phenotype is for these two genes. We’re going to look at CYP2D6 first and calculate the activity score. As a reminder, the patient case, this is CYP2D6*1/*2XN. For activity value of *1 is going to be 1. And then, the activity value of the *2XN. So the XN, it means that this gene is actually at least duplicated or triplicated. So there are more than one copy of this genotype here. So in this case, I’m going to assume that it is just, the N is 1. That’s why we got the 2, so it’s 2X1, but it can be two, three, it can be multiplied multiple times.
This multiplication is mainly with CYP2D6 as some other genes, but it’s not with all of the genes or other genetic variations, it’s not as common. And then, we’re going to actually add this two activity values. So, 1 plus 2, and we get an activity score of three, which actually this corresponds to a phenotype of an ultrarapid metabolizer. So, our patient is ultrarapid metabolizer for CYP2D6. Now what about CYP2C19? This is their phenotype, they’re *2/*3. *2 is a no function allele and so is *3. And if you remember from a few slides ago, for patients that have two no function alleles, they will fall into a poor metabolizer status. So to recap here, our patient has kind of the two extremes, CYP2D6 they’re an ultrarapid metabolizer and CYP2C19, they’re a poor metabolizer.
So let’s see how we can explain some of these variations or that the patient also had with some of the medications. So there are CPIC guidelines for TCAs here and the strongest one, it’s going to be so. These recommendations you have laid out for Amitriptyline and Nortriptyline, and then these are where the recommendations are the strongest and then classification of recommendations for other TCAs. It’s not recommendation, is more optional, the data is not as strong, but with Amitriptyline and Nortriptyline, you have stronger data. For CYP2D6 ultrarapid metabolizer, CPIC recommends to avoid use of Amitriptyline and Nortriptyline. And then again, it’s because with this ultrarapid metabolizer, the medication is just not in the system for long enough to actually have an effect on the patients.
Our patient, they failed this therapy. They can either use a much higher dose or actually avoid the medication and use a completely different medication because there are other alternatives, fortunately, out there, if you’re an intermediate metabolizer, CPIC recommends to consider a 25% dose reduction and if you’re a poor metabolizer, CPIC recommends to… So again, this is for CYP2D6, CPIC recommends to either avoid use. And if use is warranted, to reduce the dose by 50%.
Now, I’ve included other tertiary amines here for completeness, even though our patient wasn’t really taking them, but mainly taking Amitriptyline, Nortriptyline. And then we’ll see on the next slide, Doxepin actually falls into this category. So, they’re mainly affected by both CYP2C19 and CYP2D6. So we have different combinations here, but generally, so if a patient is a CYP2D6 ultrarapid metabolizer, regardless of their CYP2C19 status, CPIC recommends to avoid use.
And then, you can read all of these different combinations here as well. But also, if the patient is CYP2C19 poor metabolizer, regardless again of the CYP2D6 status, it’s across the board to avoid use, unless there is CYPD2D6 normal metabolizer, CYP2C19 poor metabolizer and use is really warranted, then they would recommend to reduce the dose by 50%.
I also wanted to point out that the dosing recommendations, they’re mainly based on studies focusing on Amitriptyline, but because tricyclic antidepressants have comparable pharmacogenetic properties, it may be reasonable to apply these guidelines to other tertiary amines that do include Clomipramine, Doxepin, Imipramine as well as Trimipramine. But I just wanted you to keep that in mind, most studies are Amitriptyline and Nortriptyline.
The FDA also has some language. This is coming from the FDA Table of Pharmacogenetic Associations. So for CYP2D6, ultrarapid, intermediate or poor metabolizer. So if the patient has any of these and the main recommendation is for Amitriptyline, Clomipramine and Nortriptyline. They say that it may alter systemic concentrations. So, not necessarily giving a particular dose recommendation, but just saying that PK may be affected.
Now, if the patient is CYP2C19 intermediate or poor metabolizer, or if they are CYP2D6, again ultrarapid, intermediate, or poor metabolizer for Doxepin, again, they’re saying for CYP2C19, it may result in higher systemic concentration. And then, for CYP2D6, these phenotypes may alter systemic concentrations. And then the same thing for Imipramine and Trimipramine. So you can note here that FDA doesn’t necessarily have any particular dosing recommendations, but mainly making you aware that there could be some pharmacogenetic guidance there.
Right. So, now let’s go back to our patient and see what we can recommend for him. So there’s a recap here for Amitriptyline, Doxepin and Nortriptyline. He failed therapy. And again, it’s mainly could be because he’s a CYP2D6 ultrarapid metabolizer. For Citalopram, he experienced some side effects, Citalopram is an SSRI but we didn’t really talk about it too much today, but I’ve talked about it in the past. Actually, I talked about it two weeks ago. So poor metabolizer, it of CYP2C19, this could explain why the patient was experiencing some side effects with Citalopram. Now, CPIC guidelines, they do say for Amitriptyline, Doxepin and Nortriptyline to avoid use. And I’ve just brought in Citalopram here again. This is from a couple of weeks ago, but just for completeness of this case, CPIC does recommend for CYP2C19 poor metabolizer to reduce the dose by 50% for Citalopram.
Our patient has a few options here, and these are just some of the options that I picked, there are other options out there as well, but Bupropion could be a good option. It’s metabolized by CYP2C19 to some extent, however, there aren’t any strong recommendations not to use Bupropion. Duloxetine is also another option. Again, potentially metabolized by CYP2D6. However, not enough evidence to suggest that CYP2D6 variations would affect response. Duloxetine can also potentially help with neuropathy because that’s also a goal that we’re treating here. Mirtazapine can also be another option again, metabolize a little bit by CYP2D6 to some extent, but not enough evidence suggest that CYP2D6 variations would affect response.
Here are my references, and thanks so much for attending again. Please let me know if you have any questions. You don’t have any questions at the moment, but they come up later, please free to email me. Here’s my email address as well. Again, as a reminder, you can put your questions in the chat or the Q&A.
Marni has a question. Do you test all patients or only after failure? Marni, that’s a great question. This is something that the provider or the pharmacist can really what they prefer to do with it, but we test all patients. And actually, so in my opinion, if a patient hasn’t had any medications in the past, or they haven’t tried anything, they could be a really good patient test because they can then know preemptively, what medications are not going to work for them. So, currently we test all patients and we’ve had some patients that haven’t had any medications after doing the test. They’ve really found it valuable because they can see what medications will be working and what medications will not be working for them. So in case they need anything in the future, they can be more informed about it. Great question. You’re welcome.
I have a question from Eniola. So how is the patient’s neuropathic pain then managed? That would really depend on what the goals are for that patient. I mean, Duloxepine can manage neuropathic pain as well. So that’s an option that I had, and there are some other options out there as well for the patient. I hope that answers your question. So Duloxepine can answer that.
Have another question from Marni. How long is turnaround time? Ours can be weeks for results. So turnaround time will also depend on when, once we receive the sample, but I would say about one to two weeks, after the patient has sent the sample to us.
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