Hello everyone. Good afternoon. For those who that don’t know me, my name is Ina Liko and I’m the Director of clinical Pharmacogenomics operations at RxGenomix. Welcome to our weekly webinar, I’m excited to continue talking about mental health this week as well. And particularly today, we’ll focus on stimulants. If you have any questions, please feel free to put them in the Q and A portion or the chat portion of the webinar, and then I’ll address them at the end.
So for today’s agenda, for those of you that have attended our webinars in the past, you kind of know the drill will go through a patient case. And then I’ll introduce the gene that’s related to the medication we’re discussing today, and then see if there is any literature, any guidelines, any FDA language, and then go through the patient case again, to see how we can solve that patient case. Without further review, I would like to introduce our patient. This is James. He is 19 year old, Caucasian male, and James has been diagnosed with ADHD. So attention deficit, hyperactivity disorder, he has just started college in the fall. So, once he got to college, he noticed that he had a little bit of problems concentrating. So his doctor actually started him on Adderall, very common medication, five milligrams by mouth twice a day.
Now, James, actually, once he started taking Adderall, he reported the following side effects like fast pounding heartbeat, as well as lower back pain. He was kind of surprised because some of his friends has been taking this medication in the past and it has been helping them. But with James, it really was not helping him and was causing him to fall even more behind on his studies because he just had this back pain, as well as the pounding heartbeat. Fortunately, he did have a Pharmacogenomic testing done, and these are his results. So before trying a new medication, James was actually interested to see how his genetics would affect how he would respond to another, another stimulant. So let’s see how we can help James.
And then here, before we jump into that, I just wanted for us to be reminded of what are the FDA approved stimulants. So we have a few different categories here, so amphetamine salts and that’s where Adderall falls under. So that’s approved for ADHD and narcolepsy, Dal met… Sorry, I’m having issues pronouncing that one, but Dexmethylphenidate. I swear, I’ve pronounced that before, for ADHD. And then dextroamphetamine and quinidine, this is used for pseudobulbar affect as well as multiple sclerosis and then the next three on there, so Lisdexamphetamine, methamphetamine and methylphenidate. They’re also used mainly for ADHD. So we have a couple of different options here that can be used for ADHD that are FDA approved.
Now, I also wanted to go through how does actually CPIC assign these levels for considerations, for genes and drugs. So you’ll notice that we don’t actually have any CPIC guidelines for this medication just yet, but I wanted for us to be reminded of how do they actually assign the level of evidence because some of these medications, CPIC has assigned good level of evidence, but they don’t have any guidelines yet. So hopefully guidelines will come up in the future here. So just to reorient you to this chart, we see on the top here, the particular gene and drug, and then whether the gene is already subject to a CPIC guideline, they would evaluate the alternatives and the evidence. And then will assign a level of either CPIC level A or B. So this is the highest level that a drug gene pair can be assigned to.
This is prescribing action is recommended. Alternative therapies are dosing are highly likely to be effective and safe. Or they can also get a level C which CPIC, even though they have reviewed this medications, particular drug gene pair, they have come to a conclusion that no prescribing changes should be made based on genetics. And also that alternatives are unclear or evidence is weak, but testing is common for these genes. So that’s how that level is decided. And then for genes and drugs that do not have a CPIC guideline yet. So that’s where these medications will fall under. Then they would review all of these other sources. So whether there’s actionable information in other professional society guidelines, are they nominated by CPIC members or recommended by an external group for these medications to be looked at and to potentially write a guideline in the future or not?
What is the PharmGKB annotation level? So is it 1A, 1B, 2A, or 2B? So if it’s in this level, then this is a pretty high level and CPIC will most likely if they don’t have a guideline, they most likely look into writing a guideline. And then also to look to see whether this is mentioned in professional society guidelines, but not actionable. And then based on how these are evaluated, CPIC does evaluate the alternatives, the evidence, the degree of testing, and then assign the drug gene pair one of these levels. So again, CPIC level A or B it’s prescribing action is recommended. Level C, there is no prescribing change based on genetics and then level D there’s only PharmGKB annotation available, no prescription action recommended and then alternatives or the evidence is weak or unclear. Also for these category, the test testing is rare. So pretty much just to recap here, if CPIC has assigned the level a or B that has pretty high, good evidence level C or D are a little bit on the lower evidence.
So I bring this up because then we will see that some of these medications that I talked about on the earlier slide, they have different levels of evidence from CPIC. So here the amphetamine salt, they actually have some vitamin salts, as well as the dextroamphetamine and quinidine. So they have level B/C from, from CPIC. So, not completely unactionable, but some of these information can be actionable. And then the methylphenidate is level C. So not as actionable as the amphetamine salts and methamphetamine. So it is affected by all of these genes. However, it just has that from PharmGKB level three, which again is not a very high evidence here. But these, so these two have a little bit on the higher evidence level. And you notice here that the main gene is CYP2D6. So that’s why we’re focusing again on CYP2D6 today. And I’ll just do a brief overview of CYP2D6 because we have talked about this gene in the past. But for those that haven’t attended our webinars in the past. This will be helpful.
So CYP2D6 has over 130 known allelic variants, and they’re different than how they’re expressed. So you have single nucleotide polymorphisms or what we call SNPs. You have indels, which are insertions or deletions, also duplications and multiplication. CYP2D6 is a very complex gene. So in some cases they’re hybrid genes that are composed of CYP2D6 and CYP2D7. Now depending on what these genetic variations are, they can actually, so they can alter the pharmacokinetics of the enzyme. So this altering in the pharmacokinetics of the enzyme can lead to increased function in those caring, additional functional gene copies, decreased, or no function if you have a variant that where a gene is deleted, *5 is one of those variants where we have a complete gene deletion or some of these we’re still kind of studying them. So they currently do not have any known functional consequences, but they could have functional consequences later on as they’re being discovered more.
Now, when we talk about CYP2D6, and this is a recent change on from CPIC guidelines as well, but we usually calculate on activity score. So what does that mean? If a patient is… This is a diplotype of the genetic information that we get once we genotype the patient. So if I’m saying, if a patient has, let’s say this genotype, so *1, and then *2 times N. This times, N it means that this patient has multiple copies. So that’s why they are put in this ultra rapid metabolizer status. So depending on how many copies they have, additional copies, we will multiply the number in front here. So let’s say that this patient only has one additional copy. So it’s going to be one times two, that’s a score of two. And then the one is just a score of one.
So for this particular genotype, this patient has a score of at least three, and it puts them in this ultra rapid metabolizer status where we would actually expect in most of medications, we would expect poor drug response because this patients are metabolizing medications very, very fast. So the medication is not in the system for the right amount of time that it should be there in order for them to, in order for the medication to work. So in this case, patients may need a completely different medication or an increased dose. Now on the flip side of that, we have intermediate and poor metabolizers where we would expect for the patient to have more side effects. And this is because again, the patient is not metabolizing the medication fast enough. So the medication is kind of staying behind at a higher concentrations for a longer time is supposed to be there.
So that’s why they may actually experience more side effects. So this is the case for the majority of medications. Now it can get a little bit more complicated if we’re talking about prodrugs, because for prodrugs, it’s just think the opposite of this, what I just said. So, because proneed to be activated into actually the actual active medication. So if you have an intermediate or poor metabolizer, they’re not going to be activated, activating that medication fast enough. So the concentration in the blood of the active form will be low. So in that case, the patient may actually have poor drug response. And then on the flip side of that, if we have an ultra-rapid metabolizer on a prodrug, then you are just activating that medication very, very fast. So you have higher drug concentrations in the blood. So that might actually cause more side effects for that patient. So the easier way to remember that is, again, if you’re talking about prodrugs, these definitions are reversed.
And I may also wonder, okay, great, but what is the frequency of CYP2D6 in the population? So you can see here that for an ultra-rapid metabolizer, about 5% of Americans will have a variation. And then for intermediate and poor metabolizers is about 25% of the population. So overall in the American population, about 30% of people will have a variation in CYP2D5. Now, something that I didn’t mention before about CYP2D6 is that CYP2D6 is also an important gene because it actually metabolizes about 25% of medications. So you can imagine, 30% of the population having a variation in this and because it also metabolizes this many medications, it can end up affecting a lot of people.
Now, another important concept for CYP2D6 here is the concept of phenoconversion. And for those who that have attended my webinars in the past, you’ve heard this, but it doesn’t hurt to hear it again. However, this is important for those of you that are new to these webinars and have not heard this concept before phenoconversion is what we call genotypic normal metabolizers. They are converted into phenotypic intermediate or poor metabolizers. And why is this? So this can occur in patients who take medications that are strong CYP2D6 inhibitors. So it’s important to pay attention to also the other medications that the patient is taking. Those drug-drug interactions are still important, even when we’re looking at drug gene information. So let’s say if a patient is a normal metabolizer per genotype, if they’re taking any of these strong CYP2D6 inhibitors like bupropion fluoxetine, paroxetine, quinidine, terbinafine, these are just some examples.
Then they may actually act as an intermediate or poor metabolizer due to this phenoconversion. So, because these medications are actually inhibiting CYP2D6. Now, if a patient is intermediate or a poor metabolizer, then they’re genotypically poor metabolizers so that a functionality is not there to begin with. So even though they’re taking some of these medications, they may not be affected as much. So the concept of phenoconversion for CYP2D6, it becomes important for a patient that is ultra-rapid, rapid, or normal metabolizer. So that’s why it’s important to always look at drug-drug interactions.
Now let’s look and see what is the phenotype for our patient. So just as a reminder here, the genotype there’s *5, *4 *5 for CYP2D6, the activity value of*4 is zero. So now we’re calculating activity score for this patient. The activity value of *5 is also zero and a total activity score of zero puts this patient in a poor metabolizer status. And so for CYP2D6 is a poor metabolizer. Now we’re going to keep this in mind as we move through some of these other slides where I’ll have a little bit more language on what does this mean when it comes to Adderall and CYP2D6 poor metabolizers?
So here, I just wanted to point your attention to some of the studies and the literature search that I did when it came to amphetamines and methamphetamines, as well as methylphenidate. And you can see here that the main gene that’s affecting these medications particularly is CYP2D6 so the first one is just a review article. They looked at in vitro studies of CYP2D6, mediated metabolites, and found that MDMA it’s substantially more cytotoxic compared with unchanged MDMA. So this is just confirms the need for MDMA intoxication in humans as well. And, CYP2D6 is one of the responsible enzymes here. When it comes to methylphenidate, this was a meta-analysis. So looking at 36 studies and around close to 4,000 patients. So that’s, that’s quite a few patients. They found a statistically significant association between the effectiveness of methylphenidate, as well as the following genes here.
And a lot of these genes, they are receptor genes. So not necessarily any metabolizing ones, but these were kind of the main ones. So ADRA2A, COMT, SLC6A2, SLC6A3 as well as DRD4. Now for methamphetamine and MDMA, this also review article that they found increased risk of side effects in patients carrying the CYP2D6 variant with reduced function. So either a CYP2D6 intermediate metabolizer, or poor metabolizer. Also, interestingly, the study found that there was an increased abuse potential in CYP2D6 ultra rapid metabolizers. And then again, it’s because these patients, they are actually metabolizing medication faster. So they may need a higher dose to kind of get that same effect. For methamphetamine, this is a prospective case control study. So a little bit on the smaller side, about 56 participants here, but for CYP2D6 genotype demonstrated that so poor metabolizers, they had less heart failure than normal metabolizers. So meaning that CYP2D6 normal metabolizers had kind of the highest odds of developing dilated cardiomyopathy. And this could be the case because maybe the dosing of methamphetamine was a little bit different, a little bit on the higher side for norm metabolizers.
Now the FDA also has some language when it comes to amphetamine, particularly and CYP2D6 poor metabolizers. So they say that this may affect systemic concentrations as well as adverse reaction risk. So they recommend to consider lower starting dose or to use an alternative agent. If the patient is taking amphetamine and is CYP2D6 poor metabolizer.
So atomoxetine is another medication that’s also used for ADHD. And there are actually CPIC guidelines when it comes to Atomoxetine. So here we have all of the different and the activity scores that is associated with it. So CYP2D6 ultra rapid metabolizer, it’s an activity score of more than two. And CPIC does recommend, does say that this is unlikely CYP2D6 ultra rapid metabolizers will achieve that adequate serum concentration for the intended effect at the starting dose. So the recommendation really from CPIC is they have two different recommendations depending on your phenotype, as well as your activity score. So if you are an ultra-rapid metabolizer or a normal metabolizer with an activity score of 1.5-2.0, or if you’re a normal metabolizer or intermediate metabolizer with an activity score of one, but a *10 allele is not present, then they recommend to initiate with the dose of 0.5 milligrams per kilogram per day, and then increase to this 1.2 milligrams per kilogram, per day, after three days.
And then if you don’t see a clinical response in this category and in the absence of adverse events after two weeks, they would consider to actually get what the plasma concentration of atomoxetine is. And then if it’s less than 200, then to consider, to increase the dose approach to actually until you reach this concentration of 400 nanogram per milliliter.
Now the second recommendation it’s really about, so if you’re a poor metabolizer, an intermediate metabolizer, or if you are a normal metabolizer or intermediate metabolizer with an activity score of one and *10 allele is present. So in this case, they would expect decreased metabolism of atomoxetine and higher atomoxetine concentrations as compared to normal metabolizers. So they still recommend to initiate with a dose of 0.5 milligrams per kilogram per day. And if you don’t see any clinical response, also, if the patient does not have any side effects, especially after two weeks then to consider, to obtain a plasma concentration two to four hours after dosing. So similar recommendation here, if that response is inadequate and the concentration is less than 200, then to consider increasing the dose proportionally until you reach this 400 nanogram per milliliter concentration. And if unacceptable side effects are present at any time to consider, to reduce the dose.
All right, so let’s now review our patient case. So this patient started on Adderall. He had a lot of side effects from it. So that fast heartbeat we found out that he CYP2D6 poor metabolizer. In terms of the literature search that we did. So amphetamine and methamphetamine, they do increase the risk of side effects in CYP2D6 intermediate and poor metabolizers. Also for amphetamines, the FDA table does recommend to actually consider a lower dose because it may affect systemic concentrations. Specific guidelines, there is an alternative, so atomoxetine can also be used for ADHD. And for this metabolizer status, they recommend to initiate 0.5 milligrams per kilogram per day.
So the plan for this patient, and there are other options out there as well, but just based on what we talked about, my plan for this patient would be to actually start him on atomoxetine and then see how he does from there. These are my references. Thank you so much for attending. And for listening to this presentation, please let me know if you have any questions, feel free to type them in the chat or the Q and A portion.
Interested in registering for PGx Clinical Pearls?
Every Thursday at 3:30pm Central Time
https://us02web.zoom.us/webinar/register/WN_Xmg9jxiASRmA2wAeUo3YeQ
For any questions, you can email us at [email protected]
