[MUSIC] This module continues theme of high risk pharmacogenetics and focuses on a case of an unexpected adverse event after tonsillectomy. A 12-year-old undergoes uneventful tonsillectomy and is given codeine for pain control. They're found unresponsive at home and brought to the emergency room where they're given naloxone, the opioid antagonist and the sensorium clears. So what are the possible explanations? Well again, this is not a problem of non-compliance. This could be a problem of too much drug, clearly. It could also be a problem of a drug interaction and it may be a problem that has a genetic story. So let me tell you a little bit about coding and why it is that the FDA no longer recommends that we use coding in patients who are getting tonsillectomy and other kinds of simple kind of pain control situations. Codeine is a pro drug, just like clopidogrel. It undergoes bioactivation and its bioactivation is accomplished by CYP2D6. And the active metabolize is a compound that many of us are familiar with, morphine. So when you give codeine, you expect the patients will generate morphine and receive pain relief. Poor metabolizers predictably have less morphine generation and, in fact, less pain relief. And we know that. But that's not the problem here, is it? The problem seems to be too much of a drug effect rather than too little of a drug effect. So let's come back to this graph for a second and notice that the distribution among extensive metabolizers Is pretty broad. There's some extensive metabolizers who have some activity. And there are other extensive metabolizers who have a ton of activity, that little tail over on the left. So, what is the explanation? Well some of it is just variability across individual patients for reasons that we don't understand, but there are patients who are known to have more than one copy of the CYP2D6 gene, and in fact when you have more than one copy, your liver processes the gene in the way its used to but generates twice as much or three times as much or 13 times as much protein depending on how many copies of the gene you have. So our ultra rapid metabolizers are individuals who are at that tail of the distribution, often they're ultra-rapid metabolizers, because they have more than one copy, more than one functional copy, of the CYP2D6 gene. And that's a genetic variant that's particularly common in certain parts of East Africa and The Arabian Peninsula but occurs world wide. So the problem in this child was that they got coding, they're an ultra-rapid metabolizer that generate huge amounts of morphine from the coding and required rescue with the opioid antagonist. This story goes back a long long long way. This is a study long before anybody had heard of CYP2D6, or even deprizine for hydroxylase, done by an investigator in Sweden, and he looked at plasma concentrations of what was then one of the most widely used antidepressants in the world, nortriptyline. And what he noticed was that there was tremendous variability in plasma concentrations of nortriptyline. There were some individuals on the right who had very very high concentrations, that one bar on the right. Each bar is a patient, that one bar on the right is probably a poor metabolizer. Their concentration is very very high nortriptyline is a CYP2D6 substrate. There is also a couple of patients on the left who have no side effects. The side effects are patients who have asterisks over their little bars, who have no side effects but also have very, very, low drug concentrations. So time passes, 25 years later we start to understand the mechanism underlying variability in CYP2D6 substrate plasma conentrations. And here's what happens with you give nortriptyline to patients as a function of how many copies of the CYP2D6 gene they have. Notice that if you have 13 copies, that must be some kind of world record of the CYP2D6 gene. Your concentrations of drug are very, very, very low compared to the concentrations in somebody who has one copy or no copies, the poor metabolizer. And the concentrations of the metabolite that's generated by CYP2D6 are shown on the right, and those, of course, mirror those. They're upside down. The highest concentrations are patients who have 13 copies, and the lowest concentrations are patients who have 0 copies, the poor metabolizers. So, that's an explanation for variability in drug response. It's been around for a long time. But now we understand the mechanisms. And just like we could with CYP2C19 in one of the previous modules, we can now make a little cascade of what the dose adjustments should be for a patient who is a poor metabolizer, an intermediate metabolizer, an extensive metabolizer, for CYP2D6 we often don't make the distinction between intermediate and extensive because there's a lot of overlap, and an ultra-rapid metabolizer with respect to drug doses of CYP2D6 substrates that are antidepressants and many of these the same drugs that are also CYP2C19 substrates so when a drug is a substrate for both the dose adjustment becomes a little bit riskier to make, or a little bit more uncertain, because you don't know exactly what the contribution of each individual pathway is. But, you're reassured, because there are two pathways. Another example that is taken on some currency, and some controversy is the the breast cancer drug tamoxifen. So tamoxifen turns out to be like codeine and clopidogrel a prodrug. Requires bioactivation, one of the major active metabolites is the compound called endoxifen. There are other active metabolites in. One of the major pathways probably the major pathway for tamoxifen bioactivation is CYP2D6. This is a study from Germany that looked at over a thousand patients with breast cancer treated with tomaxifen and followed the risk of recurrence over time. Now, what these investigators were able to do was take the entire population that was studied and genotype them and predict whether they would be extensive or poor metabolizers, and it turned out that the extensive metabolizers had a much better outcome then the poor metabolizers. That makes sense because the poor metabolizers fail to generate the active metabolite. The extensive metabolizers do. We don't expect absolutely everybody who is a poor metabolizer to have a breast cancer recurrence. Nor do we expect absolutely everyone who receives tamoxifen to be protected against breast cancer recurrence but there are these differences. These have become quite controversial. People have tried to replicate these data and sometimes they use breast cancer tissue as a source of genotyping material. And as we'll talk about in subsequent modules, cancers tend to have their own genomes. And so whether you can predict if somebody is going to be the extensive report metabolizer from a tumor block is somewhat controversial. And the difference here, it's not huge, it's not black and white answer. It's a bit of a shade of gray answer and so you have to ask yourself, is it worth the trouble of genotyping everybody just to see this relatively small difference. And again, it comes back to how complicated it is to get the information, how hard it is to interpret, what the cost of getting the information is, storing information, delivering the information and acting on the information. We'll cover all those topics in later modules. So as with CYP2C19, there is CYP2D6 inhibitors. The main ones in clinical use are some of the SSRIs, as I talked about in the previous module. And these are data, again, from a pharmaceutical benefits provider, Medco, in this case. And they asked the question, after somebody started tamoxifen, what is the risk of breast cancer recurrence in their data set, and clearly patients who are getting a CYP2D6 inhibitor along with the tamoxifen had a worse outcome than patients who were getting no CYP2D6 inhibitor and tamoxifen. You can, this is not a randomized trial, so you can ask all kinds of questions about whether this is a a real difference or a difference somehow because some patients maybe depressed patients or maybe patients who are taking SSRIs take them for different reasons. There's also a mythology that some of the SSRIs may actually help get rid of some of the side effects of tamoxifen, notably the hot flashes that women often complain about. Of course, getting rid of the hot flashes by using an SSRI may mean you're getting rid of the therapeutic efficacy as well. Those are all relatively controversial points. The hazard ration here is almost two, so that's a pretty large hazard ratio as you've seen in previous slides or previous examples, but again, retrospective data, quite controversy in the oncology world, but there it is. And it looks like tamoxifen metabolism is clearly CYP2D6 dependent and that must have functional consequences. In at least some patients. So we have again the situation of high-risk pharmacokinetics with a pro drug that requires a single pathway to activation and we now have three examples of pro drugs, clopidogrel, codeine, and tamoxifen where either the genetics or the presence of an inhibitor drug can result in failure of bioactivation and less therapeutic efficacy. You also have this situation of the ultra-rapid metabolizer with clopidogrel possibly, I said that was controversial. With codeine, there's absolutely no question. In fact, there's such a large effect of the ultra-rapid metabolizer that the FDA as I said before, has now recommended that codeine not be used for routine pain control in situations like tonsillectomy, where there is a risk of respiratory arrest. So again, the take home messages are there are multiple sources for variability in drug action, pro drugs and other situations of high risk pharmacokinetics are a special problem that. That were conditions me to look out for both in terms of the genetics as well as in terms of the potential for drug interactions. [MUSIC] [SOUND] >> [APPLAUSE]
