Hello, everyone. Good afternoon. For those that don’t know me, my name is Ina Liko, and I’m the Director of Clinical Pharmacogenomics Operations at RxGenomix. Thank you again for joining us again today.
So, today, we’re going to be continuing on pain medications, and switching gears a little bit when it comes to the genetic information, we’re going to be talking about CYP2C9. But we’re actually will be continuing to talk about the same patient because we haven’t resolved his case yet. So, I’ll start with the patient introduction again, and then talk about CYP2C9, scissoring guidelines with these medications, and the FDA language within them, and then also go back to the patient’s case to solve it.
Well, again here, this is Jake, our patient that we started talking about him for the past couple of weeks to try to see why his pain medication did not work for him and what medication can you start him on. So again, he’s a 60-year-old Caucasian male. He’s undergoing knee surgery. Don’t really have much of a medical history except for depression. However, he was started on Paroxetine for his depression. He had to go to the hospital because he actually fell and broke his hip, so they started him on codeine, 60 mg in the hospital after his surgery.
Then he reported his pain of nine out of 10 pain score in the hospital. Whenever he went home, they switched him to Tramadol 100 mg every four to six hours for pain. He returned back to the pain clinic again because he was still having a lot of pain. So, still nine out of 10. We did call, a consultation with a pharmacist last time, and we recommended for him to actually discontinue tramadol because of his genetic makeup, so he was CYP2D6 poor metabolizer.
And because of that, tramadol is not really working for him, because it’s not getting activated to morphine. So he’s not really getting any pain relief from tramadol. So we would recommend for him to start on an NSAID, however NSAIDs are also effected by genetics so throughout today we’ll just go over what medication should we recommend for him because we don’t want him to come back again and say, “Well, this is giving me side effects. This is not really working for me.” In this approach today we’ll be a little bit more proactive in terms of looking at his genetics before prescribing or giving a recommendation for a particular NSAID.
The main gene that we’ll focus on today is CYP2C9. Before we go into the specifics of NSAIDs and CYP2C9, it’s important to kind of understand a little bit of the basics about CYP2C9 and then what are the particular genomes.
So CYP2C9, it metabolizes 15-20% of all medications that are undergoing phase I metabolism, metabolized in the liver. There are over 61 known allelic variations of CYP2C9. The majority of them are single nucleotide polymorphisms. However there are also some insertions or deletions. Also CYP2C9 has multiple sub alleles and you’ll usually see them annotated as CYP2C9*2.002 for example. That, in terms of functionality, it will be similar functionality as CYP2C9*2 so a lot of the labs will not record these sub alleles, but just record the main allele there because functionality is usually the same. And that’s what we really care about. We care about the function of this particular genetic variation and the phenotype and then how can that relate to response to medications.
In terms of the most commonly recorded alleles, they’re categorized as normal function, decreased function, and no function. Genetic variants, they can alter the pharmacokinetics of the enzyme and can lead to decreased or no function. And some of these do not have any functional consequences just yet. They’re still being researched and studied.
In terms of genetically medicated CYP2C9 phenotypes, we have three phenotypes and we have a normal metabolizer, so individual carrying two normal function alleles, intermediate metabolizer would be an individual carrying one normal function allele plus one decreased function or two decreased function alleles. And then poor metabolizer would be someone that has one no function allele plus one decreased function allele or an individual carrying two no function alleles.
But if you can also notice here there is an activity score right next to this and what that means is really we’re calculating, based on the activity values of each of these alleles. We’ll actually calculate our patient’s CYP2C9 activity score to see what area he falls under. But generally the way you calculate this, for example, for *1 *2 here, *1 will have an activity score of 1 and then *2 will have an activity score, activity value of 0.5, so then you just add these two. In this case it would be 1.5 and that’s why it’s in this section here.
Now let’s calculate our patient’s activity score. A reminder here, the CYP2C9*2/*3, like I said earlier, the activity value of *2 will be 0.5 and an activity value of *3 is actually 0, so the total activity score will be 0.5, which puts him on a phenotype of poor metabolizer. So we found out that our patient is a CYP2C9 poor metabolizer.
Now here I’d like to point out the pathway of how one of the NSAIDs, in this case Celecoxib, is metabolized. So CYP2C9, as you can see is the primary metabolizing enzyme for Celecoxib and in the case of our patient, they are a poor metabolizer, so Celecoxib may accumulate and they may experience side effects. So either a lower dose or maybe a completely different medication may work better for them.
And also wondering if this is just a rare variant for our patient, so this chart kind of shows the CYP2C9 phenotype frequencies. I want to point out that he… So poor metabolizers is not very common but intermediate metabolizers are a lot more common, about 0.4% of Americans will have poor metabolizers CYP2C9 phenotype but a little bit over 16% will have intermediate metabolizers.
Moving on and switching gears a little bit, so we’re using our knowledge of the gene and knowing that our patient is a poor metabolizer of CYP2C9 to the medications. There are CPIC guidelines and recommendations here. In terms of these four medications, so Celecoxib, Flurbiprofen, Lornoxicam, and Ibuprofen, they have similar guidelines because their half-life is also similar. So for normal metabolizer, we would initiate the recommended starting dose. For intermediate metabolizer, it really depends on the activity score. The activity score of 1.5, we would initiate with recommended starting dose of… Just the recommended starting dose. However if they have an activity score of 1, we would initiate a therapy with the lowest recommended starting dose just to preemptively avoid those side effects.
And then when it comes to poor metabolizers, so this is going to be an activity score of 0.5 which is our patient, or 0. You would initiate therapy with 25-50% of the lowest recommended starting dose and titrate the dose upward to clinical effect. And that is because we would like to, again, avoid those side effects. You’d expect more side effects if you were to start these medications at the standard dose. Upward dose titration should not occur until after steady-state is reached.
So Meloxicam has a little bit different recommendations here because it has a longer half-life than the medications we’ve just spoke about so it sticks around the body a bit longer than Celecoxib and ibuprofen, for example. So for normal metabolizers, you would initiate therapy with recommended starting dose and then you do the same if the patient was intermediate metabolizer and an activity score of 1.5. But recommendations change if the patient has an activity score of 1. We would initiate therapy with 50% of the lowest recommended starting dose and titrate the dose upward to clinical effect. For poor metabolizers, recommended to choose a completely different medication, which is an alternative therapy.
Piroxicam and Tenoxicam, they had even a longer half-life than Meloxicam. They have the longest half-life out of all of the NSAIDs that we’re talking about here. The recommendation is also different here in that CPIC recommends actually alternative therapy if the patient is an intermediate metabolizer with an activity score of 1 or they’re poor metabolizer. And then to kind of put this into perspective with the other medications we have been talking about, if you just look at the intermediate metabolizer activity score of 1, if the patient was taking ibuprofen or Celecoxib then the recommendations say to just start with the lowest recommended dose. If they’re taking Meloxicam, we would cut the dose in half and then if they’re taking Piroxicam or Tenoxicam, then we’d recommend an alternative therapy.
An alternative therapy could be Celecoxib, ibuprofen, or Meloxicam at the 50% dose reduction. And again, this is mainly because of the half-life. So the longer the medication stays in the system or the longer the half-life is, then the more it would stick around in the system for a lot longer, higher concentrations, so we want to make sure that we’re getting the right recommendation so the patient does not have side effects.
The FDA also has some language when it comes to these medications and it’s mainly focused on CYP2C9 poor metabolizers. So for Celecoxib, it specifies to reduce the starting dose by 50%. and then for Flurbiprofen, Meloxicam, and Piroxicam, a reduced dosage is recommended. We don’t really have many of those in guidance there. And then for ibuprofen, it recognizes that higher systemic concentrations may occur, but no dose recommendations made. The main… Those recommendations here is for Celecoxib.
All right, so on that, we go back to our patient just to remind ourselves. A reminder here, codeine and Tramadol have failed to control his pain because of the CYP2D6 poor metabolizer status. And today we also found out that he’s also CYP2C9 poor metabolizer so he can use NSAIDs but we have to be careful of which ones we recommend. For CPIC guidelines, Flurbiprofen, Celecoxib, and Ibuprofen can be used at a reduced dose of 25-50% of the lowest recommended starting dose. And then Meloxicam, Piroxicam, and Tenoxicam we would actually avoid it for him because he’s a poor metabolizer.
So we have a couple of options for him. We could start him with Celecoxib or Ibuprofen at 25-50% of the lowest recommended dose there. Or we can actually start naproxen at recommended doses because if you notice naproxen was not mentioned here at all so it’s not affected by CYP2C9, it’s an alternative medication for this patient as well.
Here are my references. Thank you so much for attending the presentation today. What questions do you have for me? Feel free to put them in the chat or the Q&A portion.
Annie has a question, would aspirin be okay to use. To consider aspirin as well, I’m not sure how much it would affect his pain but in terms of genetics, you can also consider aspirin. If you don’t have any questions for me right now, feel free to email me as well.
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